Effects of short-term and long-term pretreatment of Schisandra lignans on regulating hepatic and intestinal CYP3A in rats.
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.
Lai
Li
L
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Hao
Haiping
H
Wang
Qiong
Q
Zheng
Chaonao
C
Zhou
Fang
F
Liu
Yitong
Y
Wang
Yuxin
Y
Yu
Guo
G
Kang
An
A
Peng
Ying
Y
Wang
Guangji
G
Chen
Xijing
X
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004334:Drug Administration Schedule; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000302:isolation & purification / Q000493:pharmacokinetics; D006207:Half-Life; D041743:Herb-Drug Interactions; D006900:Hydroxylation; D007275:Injections, Intravenous; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D017705:Lignans / Q000008:administration & dosage* / Q000302:isolation & purification / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D032141:Schisandra / Q000737:chemistry
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D017705:Lignans; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam