Effects of short-term and long-term pretreatment of Schisandra lignans on regulating hepatic and intestinal CYP3A in rats.

Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Drug metabolism and disposition: the biological fate of chemicals (Impact Factor: 3.33). 10/2009; 37(12):2399-407. DOI: 10.1124/dmd.109.027433
Source: PubMed

ABSTRACT This study aimed to evaluate the effects of Schisandra lignan extract (SLE) with short- and long-term pretreatment on regulating rat hepatic and intestinal CYP3A for a comprehensive evaluation of metabolism-based herb-drug interactions. Inhibitory effects of SLE and its major components on rat CYP3A were confirmed in both hepatic and intestinal microsomal incubation systems. After a single dose of SLE pretreatment, higher C(max) and area under the concentration-time curves from zero to infinity (AUC(0-infinity)) values were observed for intragastric midazolam (MDZ), whereas those for the intravenous MDZ were little changed. The mechanism-based inhibition of SLE toward CYP3A was further confirmed in vivo, characterized with a recovery half-life of 38 h. In contrast, SLE long-term treatment enhanced both hepatic (2.5-fold) and intestinal (4.0-fold) CYP3A protein expression and promoted the in vivo clearance of MDZ. When MDZ was coadministered with SLE after a consecutive long-term treatment, the AUC(0-infinity) value of MDZ was still lower than that of the control group, suggesting a much stronger inducing than inhibiting effect of SLE toward CYP3A. Furthermore, the intragastric administration of SLE exhibited a more intensive regulating effect toward intestinal than hepatic CYP3A, which could be partially explained by the relatively high exposures of lignans in the intestine. In conclusion, this study provides a comprehensive map for showing the complicated effects of SLE and its components on regulating rat CYP3A. The important findings are that SLE possesses a much stronger inducing than inhibiting effect on CYP3A, as well as a more intensive regulating effect on intestinal than hepatic CYP3A.

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