High-dose supplementation with natural ¦Á-tocopherol does neither alter the pharmacodynamics of atorvastatin nor its phase I metabolism in guinea pigs

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• 作者：Maren C. Podszun^a ; Nadine Grebenstein^a ; Ute Hofmann^b ; Jan Frank^a ; ^c ; ^{jan.frank@nutrition-research.de} ;
• 关键词：ATV ; atorvastatin ; CEHC ; carboxyethyl hydroxychromanol ; CYP ; cytochrome P450 ; HFC ; high-fat control ; OATP C ; organic anion-transporting peptide C ; T ; tocopherol
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2013
• 出版时间：1 February, 2013
• 年：2013
• 卷：266
• 期：3
• 页码：452-458
• 全文大小：572 K

文摘

It has been hypothesized in the literature that intake of high-dosage vitamin E supplements might alter the expression of cytochrome P₄₅₀ 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 ¦Á-tocopherol (¦ÁT) 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 ¦ÁT (250 mg/kg diet), ATV (300 mg/kg diet) or both ATV + ¦ÁT for 6 weeks. Relative to control, HFC animals had increased serum cholesterol concentrations, which were significantly reduced by ATV. High-dose ¦ÁT feeding in combination with ATV (ATV + ¦ÁT), albeit not ¦ÁT feeding alone (¦ÁT), 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 + ¦ÁT groups. In conclusion, feeding guinea pigs high-doses of ¦ÁT for 6 weeks did neither alter the hepatic expression of CYP, nor the pharmacodynamics and metabolism of ATV. High-dose ¦ÁT intake is thus unlikely to change the efficacy of drugs metabolized by CYP enzymes, particularly by CYP3A4.