title: High-dose supplementation with natural α-tocopherol does neither alter the pharmacodynamics of atorvastatin nor its phase I metabolism in guinea pigs.
abstract: It has been hypothesized in the literature that intake of high-dosage vitamin E supplements might alter the expression of cytochrome P(450) enzymes (CYP), particularly CYP3A4, which may lead to adverse nutrient-drug interactions. Because previously published studies reported conflicting findings, we investigated the pharmacodynamics of the lipid-lowering drug atorvastatin (ATV), a CYP3A4 substrate, in response to high-dose α-tocopherol (αT) feeding and determined protein expression and activities of relevant CYP. Groups of ten female Dunkin-Hartley guinea pigs were fed a control (5% fat) or a high-fat control diet (HFC; 21% fat, 0.15% cholesterol) or the HFC diet fortified with αT (250 mg/kg diet), ATV (300 mg/kg diet) or both ATV+αT for 6 weeks. Relative to control, HFC animals had increased serum cholesterol concentrations, which were significantly reduced by ATV. High-dose αT feeding in combination with ATV (ATV+αT), albeit not αT feeding alone (αT), significantly lowered serum cholesterol relative to HFC, but did not alter the cholesterol-lowering activity of the drug compared to the ATV treated guinea pigs. Protein expression of CYP3A4, CYP4F2, CYP20A1 and OATP C was similar in all groups. Accordingly, no differences in plasma concentrations of phase I metabolites of ATV were observed between the ATV and ATV+αT groups. In conclusion, feeding guinea pigs high-doses of αT for 6 weeks did neither alter the hepatic expression of CYP, nor the pharmacodynamics and metabolism of ATV. High-dose αT intake is thus unlikely to change the efficacy of drugs metabolized by CYP enzymes, particularly by CYP3A4.
authors.affiliation: Institute of Biological Chemistry and Nutrition, University of Hohenheim, D-70599 Stuttgart, Germany.
authors.forename: Maren C
authors.initials: MC
authors.lastname: Podszun
authors.forename: Nadine
authors.initials: N
authors.lastname: Grebenstein
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.forename: Jan
authors.initials: J
authors.lastname: Frank
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D000069059:Atorvastatin; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011897:Random Allocation; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A; D024502:alpha-Tocopherol