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

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 alpha-tocopherol (alpha T) 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 alpha T (250 mg/kg diet), ATV (300 mg/kg diet) or both ATV+alpha T for 6 weeks. Relative to control, HFC animals had increased serum cholesterol concentrations, which were significantly reduced by ATV. High-dose alpha T feeding in combination with ATV (ATV + alpha T), albeit not alpha T feeding alone (alpha T), 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 + alpha T groups. In conclusion, feeding guinea pigs high-doses of alpha T for 6 weeks did neither alter the hepatic expression of CYP, nor the pharmacodynamics and metabolism of ATV. High-dose alpha T intake is thus unlikely to change the efficacy of drugs metabolized by CYP enzymes, particularly by CYP3A4. (C) 2012 Elsevier Inc. All rights reserved.