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...
Aim To evaluate whether berberine hydrochloride (BBR) could modify the pharmacokinetic profiles of midazolam (MDZ), a substrate of CYP3A, and rhodamine 123 (Rh123), a substrate of P-glycolprotein (P-gp), in male rats.MethodsThe rats were given with varied does of BBR or 75 mg/kg ketoconazole as a positive control for 10 days by intragastric administration. Single-pass duodenum perfusion of 20 mg/kg MDZ and inguinal artery canulated rats were used in the study. Plasma concentrations of MDZ and 1′-hydroxymidazolam (1′-OH-MDZ) were analyzed by high performance liquid chromatography (HPLC). The rats were given with varied does of BBR or 4 mg/kg verapamil as a positive control for 10 days by intragastric administration. Blood was obtained from the caudal vein of rats after single-pass intragastric administration of 5 mg/kg Rh123. HPLC was used to analyze the plasma concentrations of Rh123.ResultsBBR produced similar results as the ketoconazole (positive control group) with a dose-dependent increase in the AUC(0−t) and AUMC (0−t) of midazolam except at the dose of 50 mg/kg (p < 0.01). And BBR could significantly increase the peak plasma concentrations (Cmax) of MDZ (p < 0.01), but reduce the clearance rate (CLz) and the apparent volume of the distribution (Vz) of MDZ (p < 0.05). The results also indicated that BBR had no significant impact on the half-life period (t1/2) and the time to reach peak concentration (tmax). Meanwhile, BBR could dose-dependently decrease AUC(0−t) and AUMC(0−t) of 1′-OH-MDZ significantly (p < 0.05), and expedite the clearance rate of 1′-OH-MDZ while gaining its apparent volume of distribution (p < 0.05), but had no significant impact on t1/2 and Tmax. The result also showed that BBR, except at the dose of 50 mg/kg, and the positive verapamil group could significantly increase the AUC(0−t) and AUC(0−∞) of Rh123 (p < 0.001), meanwhile raise Cmax of Rh123 and shorten its Vz inversely (p < 0.05). Additionally, pre-treatment with BBR had no significant influence with the half-life period of Rh123, while significantly reduced its clearance rate (p < 0.05).ConclusionThe metabolism of MDZ and Rh123 was controlled by BBR. The results were most likely due to the inhibition by BBR on CYP3A enzymes and P-gp transporter.
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