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Selective induction of CYP3A4‐dependent vitamin D catabolism via pregnane X receptor in human hepatocytes and healthy volunteers

Long‐term therapy with certain drugs, especially hPXR ligands, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency. Human CYP24A1 and CYP3A4 can inactivate vitamin D, although their relative contributions appear to be tissue‐specific and not well characterized. In this study, formation of specific metabolites, 4β,25(OH)2D3 (CYP3A4) and 24R,25(OH)2D3 (CYP24A1) from 25OHD3 was measured, along with mRNA levels for these VDR/PXR target genes. In human hepatocytes, treatment with rifampin significantly increased the levels of CYP3A4 but not CYP24A1 mRNA. Cells treated with 25OHD3, after rifampin pretreatment, showed an 8‐fold increased formation of the major metabolite, 4β,25(OH)2D3; this effect was diminished by addition of DHB, a specific CYP3A4 inhibitor. 24R,25(OH)2D3 was a minor metabolite, and its formation occurred predominantly from induction of CYP24A1 via VDR activation. In healthy volunteers, the plasma level of 4β,25(OH)2D3 were increased 60% (p < 0.01) after rifampin administration. In contrast, a small reduction in plasma 1α,25(OH)2D3 (−10%; p = 0.03) and no change in 24R,25(OH)2D3 (−8%; p = 0.09) levels were observed. Analysis of the plasma metabolite/25OHD3 ratios indicated selective induction of the CYP3A4 pathway of 25OHD3 elimination. These results suggest that induction of hepatic CYP3A4 may be important in the etiology of drug‐induced osteomalacia.