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

Kavya Annu,Erin G Schuetz,William V Caufield,Kazuto Yasuda,Burgess B Freeman,Jed N Lampe

doi:10.1371/journal.pone.0258579

Kavya Annu, Erin G Schuetz + Show 4 more

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https://doi.org/10.1371/journal.pone.0258579

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Abstract

Vitamin D3 (VD3) 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 VD3 status on systemic exposure and efficacy of these chemotherapeutic agents, we used VD3 sufficient and deficient mice and performed pharmacokinetic and anti-leukemic efficacy studies. Female C57BL/6J and hCYP3A4 transgenic VD3 deficient mice had significantly lower duodenal (but not hepatic) mouse Cyp3a11 and hCYP3A4 expression compared to VD3 sufficient mice, while duodenal expression of Mdr1a, Bcrp and Mrp4 were significantly higher in deficient mice. When the effect of VD3 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 VD3 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 VD3 deficient vs. sufficient mice. While VD3 status had no effect on oral dasatinib’s area under the plasma drug concentration-time curve, VD3 deficient male mice had significantly higher dasatinib plasma levels at t = 0.25 hr. Dexamethasone was unable to reverse the poorer survival of VD3 sufficient vs. deficient mice to BCR-ABL leukemia. In conclusion, although VD3 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 VD3 deficiency on single oral dose DEX clearance suggests that the clinical significance of VD3 levels on DEX systemic exposure are likely to be limited.

Highlights

The Cyp3a subfamily of enzymes is responsible for the metabolic transformation of many drugs and some endogenous molecules
We observed no significant effect of vitamin D status on transporter expression in C57BL/6 mice (Fig 1C), whereas, in hCYP3A4-tg mice, mMdr1a and mBcrp were significantly higher in the duodenums of Vitamin D3 (VD3) deficient male mice compared to sufficient mice (Fig 1D, p
Since we could not be certain that this effect was not due to variation in amount of and time before sampling of drinking DEX water, we administered a single oral gavage of DEX and performed a more sophisticated nonlinear mixed effect modeling analysis finding that VD3 deficiency resulted in an approximately 25% lower AUC value across both sexes (p

Summary

Introduction

The Cyp3a subfamily of enzymes is responsible for the metabolic transformation of many drugs and some endogenous molecules. CYP3A4, an important member of CYP3A family in humans, can metabolize at least 50% of prescription drugs, and is found to be highly expressed in drug detoxification organs such as liver and small intestine [1]. Intestinal CYP3A-mediated first-pass metabolism of orally administered substrates such as cyclosporine, midazolam, lovastatin, felodipine, saquinavir, and buspirone is a major basis for their low oral bioavailability [2, 3]. Induction of hepatic and intestinal CYP3A4 is the basis for many drug-drug interactions. We previously determined that CYP3A4 is induced by NR1I1/Vitamin D receptor (VDR) activated by 1,25 (OH)2VD3 [7], this induction occurs primarily in intestinal enterocytes where VDR is highly expressed vs hepatocytes where it is lowly expressed [8]

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