Intestinal CYP3A4 and Midazolam Disposition in Vivo Associate with VDR Polymorphisms and Show Seasonal Variation

Overview

Journal Biochem Pharmacol

Specialties Biochemistry
Pharmacology

Date 2012 Apr 10

PMID 22484315

Citations 23

Authors

Ranjit K Thirumaran

Jatinder K Lamba

Richard B Kim

Brad L Urquhart

Jamie C Gregor

Nilesh Chande

Yiping Fan

An Qi

Cheng Cheng

Kenneth E Thummel

Stephen D Hall

Erin G Schuetz

Affiliations

Soon will be listed here.

Abstract

Vitamin D, whose levels vary seasonally with sunlight, is activated to 1α,25-dihydroxyvitamin D(3) that binds the vitamin D receptor (VDR) and transcriptionally regulates intestinal CYP3A4 expression. We genotyped VDR polymorphisms and determined their associations with intestinal CYP3A4 and with midazolam pharmacokinetics, and whether intestinal CYP3A4 levels/activity varied seasonally. The VDR BsmIG > A (rs1544410) polymorphism was significantly associated with CYP3A4 jejunal expression/activity, with CYP3A4 duodenal mRNA, and with midazolam area under the curve (AUC). Intestinal CYP3A4 expression/activity was significantly higher in biopsies with the VDR promoter polymorphisms Cdx2-3731G > A and GATA-1012A > G that increase VDR activation of target genes. Duodenal CYP3A4 mRNA was significantly higher between April and September than between October and March. Midazolam p.o. AUC and oral bioavailability trended higher October through March compared to April through September. These data suggest VDR polymorphisms are predictors of intestinal CYP3A4, and that CYP3A4 intestinal expression varies seasonally--likely related to annual changes in UV sunlight and vitamin D levels.

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