Coadministration has not been studied. No interaction is expected with vitamin D when given with calcium or in a multivitamin preparation. Metabolism of vitamin D to active metabolites occurs in the liver and kidneys, and is thought to involve CYP3A4 and CYP24A1. In vitro studies have shown rifampicin (an enzyme inducer) increased metabolism of vitamin D and introduction of 6',7'-dihydroxybergamottin (a CYP3A4 inhibitor in grapefruit juice) reversed the effects of rifampicin on vitamin D clearance. These studies suggest that inducers of CYP3A4 (such as efavirenz) may increase metabolism of vitamin D and therefore reduce its effect. Various observational studies have reported increased risk for vitamin D deficiency in patients taking efavirenz containing regimens. However, no effect of efavirenz on the response to vitamin D supplementation was observed in a clinical study nor found in a PK modelling study.