Our aim was to investigate the inhibitory effects of schisandrin A and schisandrin B on cytochrome P450 (CYP3A) activity in rat liver microsomes and the mechanism of this interaction. 1'-Hydroxy midazolam and midazolam 1-hydroxylation catalyzed by CYP3A were analyzed by high performance liquid chromatography (HPLC). Results showed that schisandrin A and schisandrin B inhibited CYP3A activity with IC(50) values of 6.60 and 5.51 microM and K(i) values of 5.83 and 4.24 microM, respectively. A dilution assay plot of each inhibitor gave a slope value of up to 91% that of the control samples. The inactivation of CYP3A activity by schisandrin A and schisandrin B was found to be both time-and concentration-dependent (schisandrin A: K(I) = 4.51 microM, K(inact) = 0.134/min; schisandrin B: K(I) = 3.01 microM, K(inact) = 0.112/min). We conclude that the inhibition of CYP3A activity in rat liver microsomes by schisandrin A and schisandrin B is mostly attributed to a mixed noncompetitive and complete inhibition.

The objective of this study was to evaluate the ability of schisandrin A (SchA) to inhibit the P450 enzyme CYP3A in vivo. Male Sprague-Dawley rats were intragastrically administered with varied doses of SchA (8 mg ⁄ kg or 16 mg ⁄ kg or 32 mg ⁄ kg) or 75 mg ⁄ kg ketoconazole for three consecutive days. Ketoconazole, a chemical inhibitor of CYP3A, was used as positive control. Subsequently, changes in hepatic microsome CYP3A activity and the pharmacokinetic profiles of midazolam (MDZ), a specific CYP3A substrate, were studied as indicators of rat hepatic microsomal activity of CYP3A. Differences in the plasma concentrations of MDZ and its related metabolites and the hepatic microsome concentrations of 1¢-hydroxymidazolam were analysed by high-performance liquid chromatography. The current results provide direct and explicit evidence that SchA produced concentration-dependent inhibition of MDZ metabolite formation in rat liver microsomes (p < 0.01 or p < 0.001). Regular SchA consumption also caused concentration-dependent increase in C max and area under the concentration-time curve (AUC 0-t and AUC 0-¥ ) of peroral MDZ (p < 0.05 or p < 0.01) compared to vehicle-treated rats, whereas those of its metabolites (1¢-hydroxymidazolam) were reduced (p < 0.05 or p < 0.01). Analysis of the data suggests that changes in the pharmacokinetic profiles of peroral MDZ in the rat model were contributed mainly to SchA inhibition of CYP3A activity. These results suggest that SchA, as an inhibitor of CYP3A, possesses a clinically beneficial property of altering the disposition of drugs metabolized by CYP3A.Fructus schisandra (the Chinese wu-wei-zi), of the Chinese Pharmacopoeia, consists of two members: Schisandra chinensis (Turcz.) Baill and Schisandra phenanthera Rehd.et Wils, and in western botany, the Chinese wu-wei-zi has been known as S. chinensis (Turcz.) Baill. It is a plant native to China with a long history of folk medicine use in the treatment of viral and drug-induced hepatitis [1], and it is first reported in Divine Husbandman's Classic of the Materia Medica as a superior drug. Now, it is widely used in various solid-organ transplantations in China when drug-induced hepatitis occurs. Case files of transplant recipients showed that drug interaction of F. schisandra often occurred when combined with immunosuppressive drugs such as tacrolimus and sirolimus. Notably, it is necessary for all organ transport recipients to take immunosuppressive drugs for the rest of their lives to prevent organ transplant rejection. As the drug interaction has the desirable effect of raising blood concentrations of co-administering immunosuppressive drug and decreasing the total drug expense, F. schisandra supplements or extracts are used carefully under the guidance of highly experienced doctors in China. Yet the underlying mechanism of such beneficial drug interaction remains unclear.Herb-drug interactions may stem from the ability of various phytochemicals to modulate the activity of cytochrome P450 enzymes and ⁄ or drug transpo...