Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice

Vitamin D(3) (VD(3)) induces intestinal CYP3A that metabolizes orally administered anti-leukemic chemotherapeutic substrates dexamethasone (DEX) and dasatinib potentially causing a vitamin-drug interaction. To determine the impact of VD(3) status on systemic exposure and efficacy of these chemotherapeutic agents, we used VD(3) sufficient and deficient mice and performed pharmacokinetic and anti-leukemic efficacy studies. Female C57BL/6J and hCYP3A4 transgenic VD(3) deficient mice had significantly lower duodenal (but not hepatic) mouse Cyp3a11 and hCYP3A4 expression compared to VD(3) sufficient mice, while duodenal expression of Mdr1a, Bcrp and Mrp4 were significantly higher in deficient mice. When the effect of VD(3) status on DEX systemic exposure was compared following a discontinuous oral DEX regimen, similar to that used to treat pediatric acute lymphoblastic leukemia patients, male VD(3) deficient mice had significantly higher mean plasma DEX levels (31.7 nM) compared to sufficient mice (12.43 nM) at days 3.5 but not at any later timepoints. Following a single oral gavage of DEX, there was a statistically, but not practically, significant decrease in DEX systemic exposure in VD(3) deficient vs. sufficient mice. While VD(3) status had no effect on oral dasatinib’s area under the plasma drug concentration-time curve, VD(3) deficient male mice had significantly higher dasatinib plasma levels at t = 0.25 hr. Dexamethasone was unable to reverse the poorer survival of VD(3) sufficient vs. deficient mice to BCR-ABL leukemia. In conclusion, although VD(3) levels significantly altered intestinal mouse Cyp3a in female mice, DEX plasma exposure was only transiently different for orally administered DEX and dasatinib in male mice. Likewise, the small effect size of VD(3) deficiency on single oral dose DEX clearance suggests that the clinical significance of VD(3) levels on DEX systemic exposure are likely to be limited.