RT Journal Article SR Electronic T1 Effects of Short-Term and Long-Term Pretreatment of Schisandra Lignans on Regulating Hepatic and Intestinal CYP3A in Rats JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 2399 OP 2407 DO 10.1124/dmd.109.027433 VO 37 IS 12 A1 Lai, Li A1 Hao, Haiping A1 Wang, Qiong A1 Zheng, Chaonao A1 Zhou, Fang A1 Liu, Yitong A1 Wang, Yuxin A1 Yu, Guo A1 Kang, An A1 Peng, Ying A1 Wang, Guangji A1 Chen, Xijing YR 2009 UL http://dmd.aspetjournals.org/content/37/12/2399.abstract AB 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 Cmax and area under the concentration-time curves from zero to infinity (AUC0-∞) 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 AUC0-∞ 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.Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics