title: Intestinal CYP3A4 and midazolam disposition in vivo associate with VDR polymorphisms and show seasonal variation.
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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. Ranjit.thirumaran@stjude.org
authors.forename: Ranjit K
authors.initials: RK
authors.lastname: Thirumaran
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Lamba
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.forename: Brad L
authors.initials: BL
authors.lastname: Urquhart
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Gregor
authors.forename: Nilesh
authors.initials: N
authors.lastname: Chande
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.forename: An
authors.initials: A
authors.lastname: Qi
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hall
authors.forename: Erin G
authors.initials: EG
authors.lastname: Schuetz
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004386:Duodenum / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000378:metabolism; D007583:Jejunum / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D018167:Receptors, Calcitriol / Q000235:genetics*; D012621:Seasons; D014018:Tissue Distribution; D044465:White People; D055815:Young Adult
chemical_list: D018167:Receptors, Calcitriol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam