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 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 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 (250mg/kg diet), ATV (300mg/kg diet) or both ATV+αT for 6weeks. 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 6weeks 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.