Acetazolamide is fairly rapidly absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 2 hours after administration by mouth. It has been estimated to have a plasma half-life of about 4 hours. It is tightly bound to carbonic anhydrase and accumulates in tissues containing this enzyme, particularly red blood cells and the renal cortex. It is also bound to plasma proteins. It is excreted unchanged in the urine; renal clearance being enhanced in alkaline urine.
Diamox® (Acetazolamide) Tablets 250mg UK Summary of Product Characteristics, Mercury Pharma Group, updated November 2011

Acetazolamide is excreted unchanged by the kidneys via tubular secretion and passive reabsorption. After administration of the oral tablets or after IV injection, 70–100% (average 90%) of the dose is excreted in urine within 24 hours; 47% of the dose is excreted within 24 hours following administration of the extended-release capsules.
AHFS Drug Information, published by the American Society of Health-System Pharmacists Inc, January 2009

(See Summary)

At doses of adefovir dipivoxil 6- to 12-fold higher than the 10 mg dose recommended for the treatment of chronic hepatitis B, there was no interaction with nelfinavir.
Hepsera Summary of Product Characteristic, Gilead Sciences Ltd, October 2007.

A study was conducted with 38 participants split into six different groups A-F. Groups A and B received saquinavir and ritonavir plus delavirdine A) or adefovir dipivoxil (B), group C received all four drugs. Groups D, E and F were as A, B and C but received nelfinavir instead of ritonavir. There was a decrease of ~50% in delavirdine levels when given with adefovir dipivoxil compared with delavirdine alone. This was a significant decrease and this interaction was not expected and additional studies are required.
Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV-infected subjects ACTG884. Fletcher CV, Acosta EP, Cheng H, et al. AIDS, 2000, 14:2495–501.

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The specific enzymes involved in the sulphoxidation of albendazole were determined in vitro. Comparison of Vmax values obtained following heat inactivation (3min at 45 degrees C) of flavin monoxygenases (FMO), chemical inhibition of FMO with methimazole and addition of an antiserum directed against cytochrome P450 reductase indicate that FMO and CYP contribute approximately 30% and 70%, respectively, to albendazole sulfoxide production in vitro. Comparison of CLint values suggests CYP is a major contributor in vivo. A significant reduction in albendazole sulphoxidation (n = 3) was seen with ketoconazole (CYP3 A4; 32-37%), ritonavir (CYP3 A4: 34-42%), methimazole (FMO: 28-49%) and thioacetamide (FMO; 32-35%). Additive inhibition with ketoconazole and methimazole was 69 +/- 8% (n = 3). Recombinant human CYP3 A4, CYP1A2 and FMO3 produced albendazole sulfoxide in greater quantities than control microsomes, with those expressing CYP3A4 producing threefold more albendazole sulfoxide than those expressing CYP1A2. Production of albendazole sulfoxide in human liver is mediated via both FMO and CYP, principally CYP3A4, with the CYP component being the major contributor.
Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes. Rawden HC, Kokwaro GO, Ward SA, Edwards G. Br J Clin Pharmacol. 2000 Apr;49(4):313-22.

In vitro and in vivo studies have shown that delavirdine reduces CYP3A activity and inhibits its own metabolism. In vitro studies have also shown that delavirdine reduces CYP2C9, CYP2D6, and CYP2C19 activity.
Rescriptor® US Prescribing Information Pfizer Inc, Revised May 2008

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Coadministration of this drug and delavirdine is contraindicated. It is predicted that delavirdine may increase plasma concentrations of this drug which may result in potentially serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

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Delavirdine has the potential to increase plasma concentrations of this drug. Caution is warranted and therapuetic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with delavirdine.
Rescriptor Product Information, ViiV Healthcare, April 2012.

It is predicted that delavirdine may increase plasma concentrations of this drug. Caution is warranted and clinical monitoring of the patient is recommended.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Ampicillin is excreted mainly in the bile and urine with a plasma half life of 1-2 hours.
Penbritin® (ampicillin) UK Summary of Product Characteristics, Chemidex Pharma Ltd. Updated February 2009

Ampicillin is metabolised to some extent to penicilloic acid which is excreted in the urine. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion; it is reduced by probenecid. About 20 to 40% of an oral dose may be excreted unchanged in the urine in 6 hours; urinary concentrations have ranged from 0.25 to 1 mg/mL after a dose of 500 mg. After parenteral use about 60 to 80% is excreted in the urine within 6 hours.
Martindale Complete Drug Reference. Pharmaceutical Press (via Medicines Complete), latest modification: 20-August-2010

Doses of an antacid and delavirdine should be separated by at least one hour, because the absorption of delavirdine is reduced when coadministered with antacids. Coadministration of an antacid (Maalox, 20 ml) and delavirdine (300 mg single dose) to 12 subjects resulted in a 52% decrease in delavirdine Cmax and a 44% decrease in AUC.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

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LHPG Comment: Apomorphine is not metabolised by CYP450 isoforms. However, since it is metabolised by glucuronidation there is the potential for some NNRTIs to induce. In the absence of data we would suggest caution.

LHPG Comment: Artemisinin, and its derivatives such as artesunate and artemether, are rapidly metabolized via CYP3A4 to a biologically active metabolite, dihydroartemisinin (the metabolism of artesunate is so rapid that it may be considered a pro-drug for dihydroartemisinin). Although the parent drugs and dihydroartemisinin all have antimalarial activity, dihydroartemisinin has greater potency than the parent drugs. Inhibition of CYP3A4 would reduce dihydroartemisinin, but increase concentrations of the parent drug and potentially increase the half life of the parent drug. The effects of protease inhibitors and non-nucleoside reverse transcriptase inhibitors are unclear.

Coadministration of delavirdine and this drug is contraindicated as delavirdine may increase plasma concentrations and result in potentially serious and/or life threatening events such as cardiac arrhythmias.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Systemic use: Atropine is metabolised in the liver by oxidation and conjugation to give inactive metabolites. About 50% of the dose is excreted within 4 hours and 90% in 24 hours in the urine, about 30 to 50% as unchanged drug.
Atropine Injection BP Minijet UK Summary of Product Characteristics, International Medication Systems (UK) Ltd, updated October 2005

Ocular use: Atropine is also absorbed by mucous membranes but less readily from the eye and skin, although significant toxicity can sometimes occur through absorption of excessive eye drops. Atropine is metabolised by hepatic oxidation and conjugation to inactive metabolites, with about 2% undergoing hydrolysis to tropine and tropic acid. About 30% of the dose is excreted unchanged in the urine. Only trace amounts of the dose are eliminated in the faeces.
Minims Atropine Sulphate 1%, Eye drops solution UK Summary of Product Characteristics, Bausch & Lomb U.K Limited, updated July 2012

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Delavirdine has the potential to increase the concentration of bepridil. Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Bupivacaine is extensively metabolised in the liver, predominately by aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to PPX, both mediated by cytochrome P4503A4. About 1% of bupivacaine is excreted in the urine as unchanged drug in 24 h and approximately 5% as PPX. The plasma concentrations of PPX and 4-hydroxy-bupivacaine during and after continuous administration of bupivacaine are low as compared to the parent drug.
Marcain® Polyamp Steripack 0.25% and 0.5% UK Summary of Product Characteristics, AstraZeneca UK Limited, updated May 2012

Coadministration of delavirdine (600 mg twice daily for 7 days) and buprenorphine was studied in 10 HIV-, opioid-dependent individuals who had been stable for at least 2 weeks on sublingual buprenorphine/naloxone (16/4 to 20/5 mg daily). Fifteen healthy control participants were used to determine the effect of buprenorphine on delavirdine. Buprenorphine AUC was increased by >4-fold, whilst the AUC of norbuprenorphine was significantly decreased. No participants had symptoms associated with opiate withdrawal. There was no effect on the disposition of delavirdine, except for a modest delay in absorption, as reflected in a longer Tmax. Adjustments of doses of either buprenorphine or delavirdine are not likely to be necessary when these drugs are administered for the treatment of opiate dependence and HIV disease.
Interactions between buprenorphine and antiretrovirals. I. The non-nucleoside reverse-transcriptase inhibitors efavirenz and delavirdine. McCance-Katz EF, Moody DE, Morse GD, et al. Clin Infect Dis, 2006, 43 (Suppl 4): S224-234.

When administered with a potent inhibitor of CYP3A4, a low dose of buspirone, used cautiously, is recommended. When used in combination with a potent inducer of CYP3A4, e.g. phenobarbital, phenytoin, carbamazepine, St. John's wort, an adjustment of the dosage of buspirone may be necessary to maintain buspirone’s anxiolytic effect.
Buspirone Summary of Product Characteristics, Actavis UK Ltd, August 2012.

Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect.
Buspar Prescribing Information, Bristol Myers Squibb, November 2010.

Population pharmacokinetic data from eight individuals receiving carbamazepine and delavirdine (300-400 mg three times daily) suggest that trough delavirdine concentrations are substantially reduced (~90% decrease). This drug should not be coadministered with delavirdine as it decreases delavirdine plasma concentrations and may reduce its therapeutic effect. This may lead to loss of virological response and possible resistance to delavirdine or NNRTIs.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Carboplatin is excreted primarily by glomerular filtration in urine, with recovery of 65% of a dose within 24 hours. Most of the drug is excreted within the first 6 hours. Approximately 32% of a given dose of carboplatin is excreted unchanged.
Carboplatin 10 mg/ml Intravenous Infusion, UK Summary of Product Characteristics, Hospira UK Ltd, updated June 2009
Carboplatin Injection, US Prescribing Information, Hospira Inc, updated August 2007

Interaction of nine human hepatic cytochromes P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) with six platinum complexes was studied using pooled human microsomes. The compounds used were cisplatin, oxaliplatin, carboplatin, transplatin, and trans-[PtCl2(NH3) (Am)], where Am=2-methylbutylamine or sec-butylamine. No significant inhibition of all CYP activities by carboplatin was observed.
Interaction of antitumor platinum complexes with human liver microsomal cytochromes P450. Masek V, Anzenbacherová E, Machová M et al.  Anticancer Drugs. 2009 Jun;20(5):305-11

An in vitro study determined CYP3A4 activities in human liver microsomes from 2 donors using the oxidation of the dihydropyridine denitronifedipine, a specific CYP3A4 substrate, at a concentration of 50 microM (= KM). Formation of the pyridine metabolite was measured using HPLC.  No inhibitory effect on CYP3A4 was observed with carboplatin.
Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes. Baumhäkel M, Kasel D, Rao-Schymanski RA et al. Int J Clin Pharmacol Ther. 2001 Dec;39(12):517-28

(See Summary)

Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine.
Suprax® tablets (Cefixime) Summary of Product Characteristics, Sanofi-Aventis, updated November 2010

Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. There is no evidence of metabolism of cefixime in vivo.
Suprax® (cefixime) US Prescribing Information, Lupin Pharmaceuticals INC, updated November 2011

In vitro studies using human liver microsomes have suggested that cefixime neither inhibited nor induced the metabolism of probe substrates via activity of cytochrome P450 metabolic enzymes CYP1A1/2, CYP2A6, CYP2B6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. Cefixime would not be expected to cause clinically significant interactions with other drugs, which are metabolized by CYP450 enzymes.
Effect of cefixime and cefdinir, oral cephalosporins, on cytochrome P450 activities in human hepatic microsomes. Niwa T, Shiraga T, Hashimoto T, Kagayama A. Biol Pharm Bull. 2004; 27: 97-9.

Approximately 20-36% of an intravenously administered dose of 14C-cefotaxime is excreted by the kidney as unchanged cefotaxime and 15-25% as the desacetyl derivative, the major metabolite. The desacetyl metabolite has been shown to contribute to the bactericidal activity. Two other urinary metabolites (M2 and M3) account for about 20-25%. They lack bactericidal activity.
Cefotaxime for injection US Prescribing Information, Pfizer Labs, updated December 2009

Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390ml/minute and renal clearance 145 to 217 ml/minute.
Probenecid interferes with renal tubular transfer of cefotaxime delaying its excretion and increasing the plasma concentration.
Cefotaxime for injection Summary of Product Characteristics, Wockhardt UK Ltd, updated August 2008

Ceftazidime is not metabolised in the body and is excreted unchanged in the active form into the urine by glomerular filtration. Approximately 80 to 90% of the dose is recovered in the urine within 24 hours. Less than 1% is excreted via the bile, significantly limiting the amount entering the bowel.
Fortum® 500 injection (ceftazidime) Summary of Product Characteristics, GlaxoSmithKline UK, updated August 2009

Approximately 80% to 90% of an IM or IV dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. After the IV administration of single 500-mg or 1-g doses, approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 4 and 8 hours later. The calculated plasma clearance of approximately 115 mL/min indicated nearly complete elimination of ceftazidime by the renal route. Administration of probenecid before dosing had no effect on the elimination kinetics of ceftazidime, suggesting that ceftazidime is eliminated by glomerular filtration and is not actively secreted by renal tubular mechanisms.
Fortaz® (ceftazidime for injection) US Prescribing Information, GlaxoSmithKline, updated August 2010

Ceftriaxone is eliminated mainly as unchanged drug; approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The elimination of ceftriaxone is not altered by probenecid
Rocephin® (ceftriaxone) 250mg, 1g and 2g vials Summary of Product Characteristics, Roche Products Limited, updated May 2011

Thirty-three percent to 67% of a ceftriaxone dose was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. The elimination of ceftriaxone is not altered by co-administration with probenecid.
Rocephin® (ceftriaxone sodium) for injection, US Prescribing Information, Genentech USA, Inc, updated November 2010

The inhibitory effect of chloramphenicol on human cytochrome P450 (CYP) isoforms was evaluated with human liver microsomes and cDNA-expressed CYPs. Chloramphenicol had a potent inhibitory effect on CYP2C19-catalyzed S-mephytoin 4'-hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation, with apparent 50% inhibitory concentrations of 32.0 (7.7) and 48.1 (10.6) microM, respectively. Chloramphenicol also weakly inhibited CYP2D6, with an apparent 50% inhibitory concentration of 375.9 (75.8) microM. In conclusion, inhibition of CYP2C19 and CYP3A4 is the probable mechanism by which chloramphenicol decreases the clearance of coadministered drugs, which manifests as a drug interaction with chloramphenicol.
Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes. Park JY, Kim KA, Kim SL. Antimicrob Agents Chemother. 2003 Nov;47(11):3464-9.

Eight healthy volunteers received a single 8mg oral dose of rac-chlorphenamine either given alone or following administration of quinidine 50mg every 6 h for 2 days prior to the study day and every 6 h thereafter until the end of the study. For (S)-(+)-chlorphenamine, administration of quinidine, an inhibitor of CYP2D6, resulted in an increase in Cmax to 13.94 (P<0.01), a reduction in CLoral to 0.22 l h-1 kg-1 (P<0.01), and a prolongation of elimination half-life from 18.0 h to 29.3 h (P<0.001). Administration of quinidine decreased CLoral for (R)-(-)-chlorphenamine to 0.60+/-0.10 l h-1 kg-1 (P<0.005). In CYP2D6 poor metabolizers, systemic exposure was greater after chlorphenamine alone than in extensive metabolizers, and administration of quinidine resulted in a slight increase in CLoral. Stereoselective elimination of chlorphenamine occurs in humans, with the most pharmacologically active (S)-(+)-enantiomer cleared more slowly than the (R)-(-)-enantiomer. CYP2D6 plays a role in the metabolism of chlorphenamine in humans.
The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorphenamine. Yasuda SU, Zannikos P, Young AE et al. Br J Clin Pharmacol. 2002 May;53(5):519-25

In vitro and in vivo studies have shown that delavirdine reduces CYP3A activity and inhibits its own metabolism. In vitro studies have also shown that delavirdine reduces CYP2C9, CYP2D6, and CYP2C19 activity.
Rescriptor® (Delavirdine mesylate) tablets US Prescribing Information, Pfizer Inc, revised May 2008

Delavirdine has the potential to increase concentrations of this drug. Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with delavirdine.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

This drug increases gastric pH and may reduce the absorption of delavirdine. Although the effects of this drug have not been evaluated, chronic use of this drug with delavirdine is not recommended.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Coadministration of delavirdine and this drug is contraindicated. It is predicted that delavirdine may increase plasma concentrations of this drug which may result in potentially serious and/or life-threatening reactions such as cardiac arrhythmias.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

LHPG Comment: Citalopram is a weak inhibitor of CYP1A2 and CYP2D6, and has minimal or no inhibitory effect on CYP2C9, CYP2C19, CYP2E1 and CYP3A4. Therefore the potential for citalopram affecting the concentrations of other drugs is low. However, citalopram is extensively metabolised by CYP450; since there are no interaction data, caution is required as citalopram concentrations may be altered by other drugs.

In a study in 6 individuals of delavirdine (300 mg three times daily for 30 days) and clarithromycin (500 mg twice daily for 15 days), it was found that delavirdine increased plasma concentrations of this drug (~100% increase in clarithromycin AUC). There was no significant effect of clarithromycin on the Cmax, AUC or Cmin of delavirdine. When coadministered with delavirdine, clarithromycin should be adjusted in patients with impaired renal function. For creatinine clearances of 30-60 ml/min, the clarithromycin dose should be reduced by 50%; for creatinine clearances <30 ml/min, the clarithromycin dose should be reduced by 75%.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

(See Summary)

A study aimed to define the role of CYP2D6 and CYP3A4 in the in vitro metabolism of enclomiphene, the more active isomer of clomiphene. Enclomiphene (25 microM) was incubated with human liver microsomes (from 4 extensive (EM) and 1 poor metaboliser with respect to CYP2D6) and with microsomes from lymphoblastoid cells expressing CYP2D6. Microsomes from all the EM livers and recombinant CYP2D6 metabolised enclomiphene (the disappearance of drug ranged from 40-60%). No metabolism was detected in microsomes from the PM liver. Quinidine (1 microM) completely inhibited the metabolism of enclomiphene by all the EM livers and by recombinant CYP2D6 (p<0.001, one way ANOVA). Ketoconazole (2 microM) had no significant effect on enclomiphene metabolism in 3 out of the 4 EM livers. The extent of enclomiphene metabolism was correlated with the amount of CYP2D6 present (p<0.001, Pearson correlation test). The findings indicate that CYP2D6 is primarily responsible for the metabolism of enclomiphene.
CYP2D6 is primarily responsible for the metabolism of clomiphene. Ghobadi C, Gregory A, Crewe HK, Rostami-Hodjegan A, Lennard MS. Drug Metab Pharmacokinet. 2008;23(2):101-5.

A study investigated clomiphene metabolism and action in vitro and in vivo by pharmacogenetic, -kinetic and -dynamic investigations. Human liver microsomes were incubated with clomiphene citrate and nine metabolites were identified by mass spectrometry and tested at the oestrogen receptor for their antagonistic capacity. (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed strongest inhibition of the oestrogen receptor activity with 50% inhibitory concentrations of 2.5 and 1.4 nm, respectively. CYP2D6 has been identified as the major enzyme involved in their formation using recombinant CYP450 isozymes as confirmed by inhibition experiments with CYP monoclonal antibodies. The CYP2D6 genotype of 30 human liver donors was correlated with the microsomal formation rate of active metabolites and observed a strong gene-dose effect. A healthy female volunteer study confirmed the in vitro data that the CYP2D6 polymorphism substantially determines the formation of the active clomiphene metabolites. Comparison of the C(max) of (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed 8 and 12 times lower concentrations in subjects with non-functional CYP2D6 alleles. The results highlight (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene as the active clomiphene metabolites, the formation of which strongly depends on the polymorphic CYP2D6 enzyme. The data provide evidence of a biological rationale for the variability in the response to clomiphene treatment.
Genetic polymorphism of cytochrome P450 2D6 determines oestrogen receptor activity of the major infertility drug clomiphene via its active metabolites. Mürdter TE, Kerb R, Turpeinen M et al. Hum Mol Genet. 2012 Mar 1;21(5):1145-54

In vitro studies have also shown that delavirdine reduces CYP2C9, CYP2D6, and CYP2C19 activity.
Rescriptor® (delavirdine mesylate) tablets US Prescribing Information, Pfizer Inc. updated May 2008

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(See Summary)

(See Summary)

Protease Inhibitors and Non Nucleoside Reverse Transcriptase Inhibitors are known inhibitors of Cytochrome P450 IIIA (CYP-3A) and may also have a role in the inhibition of the drug transporting protein, P-glycoprotein (P-gp). Daunorubicin and other anthracyclines may undergo some metabolism by CYP-3A and are known substrates of P-gp. There is therefore a theoretical possibility of interaction between DaunoXome and these two groups of antiviral therapy. To date however, a single study has indicated that there is no effect of PI’s or NNRTI’s on DaunoXome’s pharmacokinetic properties. Limited data from one small study where patients were treated with and without protease inhibitors indicate that there were no major changes in DaunoXome associated toxicity.
DaunoXome® Injection (liposomal daunorubicin) UK Summary of Product Characteristics, Galen Ltd, updated October 2011

The plasma pharmacokinetics of DaunoXome(daunorubicin citrate liposome injection) differ significantly from the results reported for conventional daunorubicin hydrochloride. DaunoXome has a small steady-state volume of distribution of 6.4 L, (probably because it is confined to vascular fluid volume), and clearance of 17 mL/min. These differences in the volume of distribution and clearance result in a higher daunorubicin exposure (in terms of plasma AUC) from DaunoXome than with conventional daunorubicin hydrochloride. The apparent elimination half-life of DaunoXome is 4.4 hours, far shorter than that of daunorubicin, and probably represents a distribution half-life. Daunorubicinol, the major active metabolite of daunorubicin, was detected at low levels in the plasma following intravenous administration of DaunoXome.
DaunoXome® (daunorubicin citrate liposome injection) US Prescribing Information, Galen Limited, updated December 2011

An in vitro study determined CYP3A4 activities in human liver microsomes from 2 donors using the oxidation of the dihydropyridine denitronifedipine, a specific CYP3A4 substrate, at a concentration of 50 microM (= KM). Formation of the pyridine metabolite was measured using HPLC. Daunorubicin hydrochloride showed an inhibitory effect on CYP3A4, IC50 value for the 2 microsome sample was 206/200 micromol/l. Comparing IC50 values with plasma concentrations present during antineoplastic therapy, potential for daunorubicin to cause clinical drug interactions by inhibition of CYP3A4 was thought to be relatively low.
Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes. Baumhäkel M, Kasel D, Rao-Schymanski RA, Böcker R, Beckurts KT, Zaigler M, Barthold D, Fuhr U. Int J Clin Pharmacol Ther. 2001 Dec;39(12):517-28

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(See Summary)

Coadministration of delavirdine and this drug is contraindicated as delavirdine may increase plasma concentrations and result in potentially serious and/or life threatening events such as acute ergot toxicity characterised by peripheral vasospasm and ischaemia of the extremities and other tissues.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

It is predicted that delavirdine may increase plasma concentrations of this drug. Caution is warranted and clinical monitoring of the patient is recommended.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

(See Summary)

Doxycycline is almost completely absorbed and is not subject to presystemic metabolism, the mean bioavailability being approximately 93%. No significant metabolism occurs and Doxycycline is cleared intact by renal and biliary mechanisms. Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment.
Doxycycline Capsules BP 100mg, UK Summary of Product Characteristics, Actavis UK Ltd, updated June 2011

Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40% and 60% of an administered dose can be accounted for in the urine by 92 hours, and approximately 30% in the faeces.
Efracea® 40mg Modified Release Hard Capsules, Summary of Product Characteristics, Galderma (U.K) Ltd, updated November 2011
Oracea® US Prescribing Information, Galderma Laboratories, US Prescribing Information, updated May 2010

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No studies have been performed with efavirenz in combination with other NNRTIs. Since use of two NNRTIs proved not beneficial in terms of efficacy and safety, coadministration of efavirenz and another NNRTI is not recommended.
Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2015.

After intravenous doses about 80% is excreted unchanged in the urine in 24 hours. The terminal elimination half-life is about 3 hours. It is distributed to the CSF.
Less than 1% of a dose is absorbed after topical application.
Martindale Complete Drug Reference. Pharmaceutical Press (via Medicines Complete), latest modification: 23-Sep-2011

Eflornithine was administered to six healthy men in single intravenous doses of 5 and 10 mg/kg and oral doses of 10 and 20 mg/kg. Peak plasma concentrations were reached within 6 hr after oral doses. The decay of the plasma concentrations followed first-order kinetics with a mean half-life (t 1/2) for all four doses studied of 199 +/- 6 min (+/- SD). Mean renal clearance was determined as 0.99 +/- 0.03 ml . min-1 . kg-1, accounting for 83% of drug elimination. Mean apparent volume of distribution (aVD) was 0.337 +/- 0.031 l/kg-1, corresponding to 24 l for 70 kg of body weight. The amount of unchanged drug in 24-hr urine samples was 47 +/- 7% and 40 +/- 11% after 10 and 20 mg/kg orally, and 78% and 81 +/- 8% after 5 and 10 mg/kg intravenously. Twenty-four-hour urinary recovery of unchanged drug was 46.9% of the 10mg/kg and 40.3% of the 20 mg/kg oral doses. >86% of the oral doses were cleared from the body by renal filtration. In the case of intravenous dosing, 81% of the drug was eliminated by the kidneys.
Kinetics of alpha-difluoromethylornithine: an irreversible inhibitor of ornithine decarboxylase. Haegele KD, Alken RG, Grove J et al. Clin Pharmacol Ther. 1981 Aug;30(2):210-7.

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In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation. Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.
Emtriva Summary of Product Characteristics, Gilead Sciences International Ltd, November 2016.

At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP 2C9, CYP2C19, CYP2D6 and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5’-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.
Emtriva Prescribing Information, Gilead Sciences Inc, November 2012.

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(See Summary)

Coadministration of delavirdine and this drug is contraindicated as delavirdine may increase plasma concentrations and result in potentially serious and/or life threatening events such as acute ergot toxicity characterised by peripheral vasospasm and ischaemia of the extremities and other tissues.
Rescriptor Prescribing Information,ViiV Healthcare, April 2012.

Coadministration of delavirdine and this drug is contraindicated as delavirdine may increase plasma concentrations and result in potentially serious and/or life threatening events such as acute ergot toxicity characterised by peripheral vasospasm and ischaemia of the extremities and other tissues.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

This drug increases gastric pH and may reduce the absorption of delavirdine. Although the effects of this drug have not been evaluated, chronic use of this drug with delavirdine is not recommended.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

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Delavirdine has the potential to increase concentrations of ethinylestradiol, however, the clinical significance of this is unknown.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl-dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis. Less than 1% of the oral dose is excreted as ethionamide in urine.
Trecator® US Prescribing Information, Wyeth Pharmaceuticals Inc. (now Pfizer) revised November 2007

An in vitro study examined the inhibitory effects of pyrazinamide and ethionamide, both of which are chemically related to isoniazid, on the CYP-mediated activities in human liver microsomes and compared them to that of isoniazid. No remarkable effects on any CYP activities were observed by pyrazinamide and ethionamide.
Inhibitory effect of antituberculosis drugs on human cytochrome P450-mediated activities. Nishimura Y, Kurata N, Sakurai E, Yasuhara H. J Pharmacol Sci. 2004 Nov;96(3):293-300.

Flavin-containing monooxygenases (FMOs) are a superfamily of flavoprotein monooxygenases active towards a wide range of xenobiotics. ethionamide (ETA) is a pro-drug requiring bioactivation to exert toxicity. M. tuberculosis possesses a flavin monooxygenase (EtaA) that oxygenates ETA first to the sulfoxide and then to 2-ethyl-4-amidopyridine, presumably through a second oxygenation involving sulfinic acid. ETA is also a substrate for mammalian flavincontaining monooxygenases (FMOs). A study examined activity of expressed human and mouse FMOs toward ETA, as well as liver and lung microsomes. All FMOs converted ETA to the S-oxide (ETASO), the first step in bioactivation. Co-incubations with the general CYP and FMO inhibitors SKF-525A and thiourea, suggest that ETA S-oxygenation in mouse liver and lung microsomes is predominantly, FMO-mediated.
Metabolism of the anti-tuberculosis drug ethionamide by mouse and human FMO1, FMO2 and FMO3 and mouse and human lung microsomes. Henderson MC, Siddens LK, Morré JT, et al. Toxicol Appl Pharmacol. 2008 Dec 15;233(3):420-7

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Combining two NNRTIs has not been shown to be beneficial. Etravirine and other NNRTIs should not be co-administered. Concomitant use of etravirine with delavirdine may increase plasma concentrations of etravirine.
Intelence Prescribing Information, Tibotec Pharmaceuticals Ltd, March 2012.

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This drug increases gastric pH and may reduce the absorption of delavirdine. Although the effects of this drug have not been evaluated, chronic use of this drug with delavirdine is not recommended.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

It is predicted that delavirdine may increase plasma concentrations of this drug. Caution is warranted and clinical monitoring of the patient is recommended.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

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Delavirdine has the potential to increase plasma concentrations of this drug. Caution is warranted and therapuetic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with delavirdine.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Coadministration of fluconazole (400 mg once daily) with delavirdine (300 mg three times daily) to 8 individuals resulted in no significant effect on delavirdine Cmax, AUC or Cmin.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Coadministration of delavirdine (300 mg every 8 h) and fluconazole (400 mg once daily) resulted in fluconazole PK parameters which were similar to those previously reported for healthy volunteers and HIV+ individuals. There was no significant alteration in the pharmacokinetics of delavirdine (mean DLV trough levels in the control group ranged from 15.2 to 22.7 µM; mean DLV trough levels in the fluconazole group ranged from 12.4 to 18.0 µM). Fluconazole and delavirdine may be taken concurrently without adjustment of the dose of either drug.
Effect of fluconazole on the steady-state pharmacokinetics of delavirdine in human immunodeficiency virus-positive patients. Borin MT, Cox SR, Herman BD. Antimicrob Agents Chemother, 1997, 41:1892–1897.

Population pharmacokinetic data from 36 HIV+ individuals receiving fluoxetine and delavirdine (200-400 mg three times daily) suggest that trough delavirdine concentrations are increased by ~50%.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Fluphenazine is metabolised by P450 2D6 and is itself an inhibitor of this drug metabolising enzyme. The plasma concentrations and the effects of fluphenazine may therefore be increased and prolonged by drugs that are either the substrates or inhibitors of this P450 isoform, possibly resulting in severe hypotension, cardiac arrhythmias or CNS side effects.
Modecate® (fluphenazine) Concentrate Injection 100mg/ml UK Summary of product Characteristics, sanofi-aventis, updated December 2011

Delavirdine is primarily metabolized by cytochrome P450 3A (CYP3A), but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. The major metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation. In vitro and in vivo studies have shown that delavirdine reduces CYP3A activity and inhibits its own metabolism. In vitro studies have also shown that delavirdine reduces CYP2C9, CYP2D6, and CYP2C19 activity.
Rescriptor® (Delavirdine) US Prescribing Information, Pfizer Inc, updated May 2008

Concomitant use of fluticasone and delavirdine may increase plasma concentrations of fluticasone. Use with caution. Consider alternatives to fluticasone, particularly for long-term use.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

Delavirdine has the potential to increase concentrations of this drug. Caution should be exercised if delavirdine is used concurrently with this drug as the risk of myopathy including rhabdomyolysis may be increased. If coadministered with delavirdine, use the lowest possible dose with careful monitoring or consider using pravastatin.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

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Gentamicin is not metabolized in the body but is excreted unchanged in microbiologically active form predominantly via the kidneys.
Gentamicin 40 mg/ml Injection Summary of Product Characteristics, Hospira UK Ltd, updated August 2011

Little, if any, metabolic transformation occurs; the drug is excreted principally by glomerular filtration.  After several days of treatment, the amount of gentamicin excreted in the urine approaches, but does not equal, the daily dose administered.  As with other aminoglycosides, a small amount of the gentamicin dose may be retained in the tissues, especially in the kidneys.  Minute quantities of aminoglycosides have been detected in the urine of some patients weeks after drug administration was discontinued.  Renal clearance of gentamicin is similar to that of endogenous creatinine. Probenecid does not affect renal tubular transport of gentamicin.
Gentamicin Injection USP, US Prescribing Information, APP Pharmaceuticals, revised August 2011

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A case report in a single patient describes that ciclosporin (a CYP3A4 substrate) levels decreased 2 weeks after initiation of griseofulvin, and markedly increased on discontinuation.
Cyclosporin A and griseofulvin: another drug interaction. Abu-Romeh SH, Rashed A. Nephron. 1991;58(2):237

After intravenous or subcutaneous injection heparin is extensively bound to plasma proteins. The half-life of heparin depends on its dose and route as well as the method of calculation and is subject to wide inter- and intra-individual variation; a range of 1 to 6 hours with an average of 1.5 hours has been cited. It may be slightly prolonged in renal impairment, decreased in patients with pulmonary embolism, and either increased or decreased in patients with liver disorders. Heparin is taken up by the reticuloendothelial system. It is excreted in the urine, mainly as metabolites, although after large doses up to 50% may be excreted unchanged.
Martindale Complete Drug Reference. Pharmaceutical Press (via Medicines Complete), last reviewed 2011-11-15

Heparin is not eliminated enzymatically nor by glomerular filtration or renal tubular secretion. In all likelihood, the anticoagulant is transferred to reticuloendothelial cells, which may also provide the means for its degradation.
Estes JW. Clinical pharmacokinetics of heparin. Clin Pharmacokinet 1980; 5: 204–20.

After either subcutaneous or intravenous injection heparin is distributed primarily within the intravascular space. A short distribution phase is seen which is thought to correspond to endothelial cell binding and internalisation. The disposition curve for unfractionated heparin has a unique concave-convex shape which is the result of combined saturable and nonsaturable elimination mechanisms. The nonsaturable elimination mechanism is renal and is the primary route of elimination for low molecular weight heparins.
Kandrotas RJ. Heparin pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 1992; 22: 359–74.

This study showed hop extracts to induce the expression of drug metabolism and excretion proteins. mRNA levels for CYP3A4, CYP2B6 and MDR1 were increased in a concentration dependent manner by activating PXR. The efficacy with which hops activated PXR was comparable to that of St John's wort.
Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Teotico DG, Bischof JJ, Peng L, et al. Mol Pharmacol, 2008, 74: 1512-1520.

Pharmacokinetic data indicate hydralazine has an extensive and complex metabolism depending on acetylator status: slow acetylators undergo primary oxidative metabolism, while rapid acetylators are acetylated.
Mulrow JP, Crawford MH. Clinical pharmacokinetics and therapeutic use of hydralazine in congestive heart failure. Clin Pharmacokinet. 1989 Feb;16(2):86-9

Previous studies showed that several drugs inhibited quinine 3-hydroxylation, a cytochrome P450 (CYP) 3A4-mediated reaction, in vitro. In this extended study, 13 drugs were selected and tested by human liver microsomes in order to further determine their respective inhibition constant (Ki) and type of inhibition. According to the apparent Ki values, the inhibitory rank order of these tested drugs was as follows: ketoconazole > doxycycline > omeprazole > tetracycline > troleandomycin (with pre-incubation) > primaquine > troleandomycin (without pre-incubation) > nifedipine > erythromycin > verapamil > oleandomycin > diltiazem > cimetidine > hydralazine. Among these drugs, doxycycline, tetracycline, ketoconazole, nifedipine and hydralazine were judged as mixed inhibitors; whereas, the remaining other drugs tested were judged as competitive inhibitors. When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, troleandomycin and erythromycin are likely to be inhibitors of quinine metabolism in patients when these drugs are co-administrated with quinine.
Zhao XJ, Ishizaki T. A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition. Eur J Drug Metab Pharmacokinet. 1999 Jul-Sep;24(3):272-8.

An in vitro study reports a method using cryopreserved human hepatocytes and the time-dependent aldehyde oxidase (AO) inhibitor hydralazine (K(I) = 83 ± 27 μM, k(inact) = 0.063 ± 0.007 min(-1)), which estimates the contribution of AO metabolism relative to total hepatic clearance. Using zaleplon as a probe substrate and simultaneously monitoring the AO-catalyzed formation of oxozaleplon and the CYP3A-catalyzed formation of desethyzaleplon in the presence of a range of hydralazine concentrations, it was determined that >90% inhibition of the AO activity with minimal effect on the CYP3A activity could be achieved with 25 to 50 μM hydralazine. Differences in estimated f(m(AO)) between two batches of pooled human hepatocytes suggest that sensitivity to hydralazine varies slightly with hepatocyte preparations. Substrates with a CYP2D6 contribution to clearance were affected by hydralazine to a minor extent, because of weak inhibition of this enzyme.
Strelevitz TJ, Orozco CC, Obach RS. Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance. Drug Metab Dispos. 2012 Jul;40(7):1441-8.

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The pharmacokinetics of ifosfamide exhibit considerable interindividual variation. It is a prodrug that is extensively metabolised, chiefly by cytochrome P450 isoenzymes such as CYP3A4 and CYP2B6 in the liver, to both active and inactive metabolites; there is some evidence that metabolism is saturated at very high doses. Although licensed product information states that a mean terminal elimination half-life is about 15 hours after a single high-dose intravenous bolus, most studies at lower doses recorded elimination half-lives of 4 to 8 hours. After repeated doses there is a decrease in the elimination half-life, apparently due to autoinduction of metabolism. It is excreted largely in urine, as unchanged drug and metabolites.
Martindale Complete Drug Reference. Pharmaceutical Press (via Medicines Complete), latest modification: 20-Aug-2010
Wagner T. Clin Pharmacokinet 1994; 26: 439–56; Boddy AV, Yule SM. Clin Pharmacokinet 2000; 38: 291–304; Kerbusch T, et al. Clin Pharmacokinet 2001; 40: 41–62.

In patients (n=32) with advanced solid tumours, continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 g/m2 for 3 days or 6 g/m2 for 5 days, administered every 3 weeks. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed. Ifosfamide produced decreased sunitinib blood levels due to CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this is true for anti-tumour activity needs to be further explored.
Decreased exposure to sunitinib due to concomitant administration of ifosfamide: results of a phase I and pharmacokinetic study on the combination of sunitinib and ifosfamide in patients with advanced solid malignancies. Hamberg P, Steeghs N, Loos WJ et al. Br J Cancer. 2010 Jun 8;102(12):1699-706.

An in vitro study screened 18 widely used anticancer drugs for their ability to activate PXR-mediated CYP3A4 induction. A CYP3A4 reporter gene assay was employed to identify PXR agonists among the eighteen anticancer drugs. Subsequently CYP3A4 mRNA and protein expression following treatment with these PXR agonists was assessed. Finally, the effect of pre-treatment with these agents on the 1'-hydroxylation of midazolam (a specific CYP3A4 probe) was determined. Ifosfamide was able to activate PXR and may therefore have the propensity to cause clinically relevant drug-drug interactions as a result of CYP3A4 induction.
Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Harmsen S, Meijerman I, Beijnen JH, Schellens JH. Cancer Chemother Pharmacol. 2009 Jun;64(1):35-43

In vitro studies have demonstrated that conversion to the active metabolite occurs via CYP3A4. Both CYP3A4 and CYP2B6 are involved in detoxification. CYP3A4 metabolism of (S)-ifosfamide may generate a neurotoxic metabolite.
Granvil CP, Madan A, Sharkawi M, et al. Drug Metab Dispos1999; 27: 533-41; Roy P, Tretyakov O, Wright J, et al. Drug Metab Dispos 1999; 27: 1309-18

CYP3A4 activities in human liver microsomes from 2 donors were determined using the oxidation of the dihydropyridine denitronifedipine, a specific CYP3A4 substrate, at a concentration of 50 microM (= KM). Formation of the pyridine metabolite was measured using HPLC. Ifosfamide showed an inhibitory effect on CYP3A4, IC50 3.6/2.5 mmol/l for 2 microsome sample. Comparing IC50 values with plasma concentrations present during antineoplastic therapy, ifosfamide could possibly cause clinical drug interactions by inhibition of CYP3A4.
Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes. Baumhäkel M, Kasel D, Rao-Schymanski RA, Böcker R et al. Int J Clin Pharmacol Ther. 2001 Dec;39(12):517-28

Ketoconazole given orally for 4 days, starting 1 day before intravenous ifosfamide (given as a 24-hour infusion), decreased ifosfamide clearance. However, ifosfamide metabolism to active metabolites was decreased, and urinary excretion of ifosfamide was increased. Ketoconazole may decrease the therapeutic efficacy of ifosfamide.
Kerbusch T, et al. Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin. Clin Pharmacol Ther 2001; 70: 132–41.

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Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors such as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; ketoconazole, itraconazole; erythromycin, clarithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering imatinib with inhibitors of the CYP3A4 family. Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering Imatinib with CYP3A4 substrates with a narrow therapeutic window. Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs.
Glivec Summary of Product Characteristics, Novartis Pharmaceuticals UK Ltd, October 2012.

There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40% respectively) in healthy subjects when imatinib was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering imatinib with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir). Substances that inhibit CYP3A4 activity may decrease metabolism and increase imatinib concentrations. Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib. Particular caution is recommended when administering imatinib with CYP3A4 substrates that have a narrow therapeutic window.
Gleevec Prescribing Information, Novartis, January 2013.

Imatinib pharmacokinetics alone and in combination with ritonavir (600 mg once daily for 3 days) were evaluated in 11 cancer patients receiving imatinib for at least 2 months (400-800 mg). The dose of imatinib was decreased by 50% during coadministration with ritonavir (for safety reasons) and pharmacokinetic parameters were normalised to an imatinib dose of 400 mg. Coadministration had no significant effect on imatinib AUC or Cmax (decreases of 3% and 13%, respectively). However, plasma exposure of CGP74588 (an active metabolite) was increased by approximately 40%. A population analysis with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. The authors suggest that at steady state imatinib is insensitive to acute CYP3A4 inhibition by ritonavir and relies on alternate elimination pathways.
Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. van Erp NP, Gelderblom H, Karlsson MO et al. Clin Cancer Res, 2007, 13(24): 7394-7400.

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After intravenous administration approximately 60% of the dose is metabolised, mainly by conjugation (40%), wheras after inhalation about 77% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%). After inhalation of ipratropium bromide either with HFA 134a or CFC propellant, cumulative renal excretion over 24 hours was approximately 12% and 10%, respectively.  In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.
Atrovent® (Ipratropium bromide) 20 micrograms/actuation Inhaler CFC-Free UK Summary of Product Characteristics, Boehringer Ingelheim Limited, updated August 2011

After inhalation, around 10 to 30% of a dose is deposited in the lungs where it exerts its therapeutic effect. Only a small amount of ipratropium reaches the systemic circulation. The majority of a dose is swallowed but is poorly absorbed from the gastrointestinal tract. Following oral administration, the apparent systemic availability was around 2%, and after inhalation it was 6.9%. Ipratropium and its metabolites are eliminated in the urine and faeces.
Ensing K, et al. Pharmacokinetics of ipratropium bromide after single dose inhalation and oral and intravenous administration. Eur J Clin Pharmacol 1989; 36: 189–94.

Isosorbide dinitrate is readiliy absorbed from the oral mucosa and also following oral administration. It undergoes extensive first pass metabolism, mainly in the liver.
Isosorbide Dinitrate Tablets BP 20mg UK Summary of Product Characteristics, Actavis UK Ltd, updated October 2011

Isosorbide dinitrate (ISDN) is eliminated from plasma with a short half-life (about 0.7h). The metabolic degradation of ISDN occurs via denitration and glucuronidation, like all organic nitrates. The rate of formation of the metabolites has been calculated for isosorbide-5-mononitrate (IS-5-MN) with 0.27 h -1, and isosorbide (IS) with 0.16 h-1. IS-5-MN and IS-2-MN are the primary metabolites which are also pharmacologically active. IS-5-MN is metabolised to isosorbide 5-mononitrate-2-glucuronide (IS-5-MN-2-GLU). The half-life of this metabolite (about 2.5h) is shorter than that of IS-5-MN (about 5.1h). The half-life of ISDN is the shortest of all and that of IS-2-MN (about 3.2h) lies in between.
Isoket® (Isosorbide dinitrate) 1mg/ml injection/infusion UK Summary of Product Characteristics, UCB Pharma Limited, updated July 2010

A study was designed to elucidate the role of human cytochrome P450 isoforms on nitric oxide formation from organic nitrates using lymphoblast microsomes transfected with human CYP isoforms cDNA. CYP3A4-transfected microsomes had the most effective potential of nitric oxide formation from isosorbide dinitrate. Anti-CYP3A2 antibody (which cross-reacts with CYP3A4) or ketoconazole (an inhibitor of the CYP3A superfamily) inhibited nitric oxide formation from isosorbide dinitrate in rat heart microsomes. Immunohistochemistry of human heart also showed intense bindings of CYP3A4 antibody in the endothelium of the endocardium and coronary vessels. These results suggest that the CYP3A4-NADPH-cytochrome P450 reductase system specifically participates in nitric oxide formation from isosorbide dinitrate.
Minamiyama Y, Takemura S, Akiyama T et al. Isoforms of cytochrome P450 on organic nitrate-derived nitric oxide release in human heart vessels. FEBS Lett. 1999 Jun 11;452(3):165-9.

Population pharmacokinetic data from 26 individuals receiving ketoconazole and delavirdine (200-400 mg three times daily) suggest that trough delavirdine concentrations are increased by ~50%.
Rescriptor Prescribing Information, ViiV Healthcare, April 2012.

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Coadministration of lercanidipine with inhibitors of CYP3A4 should be avoided.
Lercanidipine Summary of Product Characteristics, Winthrop Pharmaceuticals UK Limited, August 2010.

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