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Effect of Huang‐Lian‐Jie‐Du‐Decoction on pharmacokinetics of verapamil in rats
Authors:Shan‐Shan Xie  Nan Hu  Xin‐Yue Jing  Xiao‐Dong Liu  Lin Xie  Guang‐Ji Wang  Chang‐Hui Liu
Affiliation:1. Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China;2. Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
Abstract:Objectives The aim was to investigate the effect of Huang‐Lian‐Jie‐Du‐Decoction (HLJDD) on the pharmacokinetic behaviour of verapamil in rats. Methods Rats orally received 3.33 g/kg of HLJDD extract for 14 days, and pharmacokinetics of verapamil was investigated after oral and intravenous verapamil. Norverapamil formation for assessing cytochrome P450 3A activity in hepatic and intestinal microsomes of the HLJDD‐treated rats was investigated. The inhibitory effect of berberine on the formation of norverapamil in intestinal and hepatic microsomes was also evaluated. Key findings HLJDD treatment increased the plasma concentration of verapamil and decreased the plasma concentration of norverapamil, resulting in a 24% increase in the AUC0–480 of verapamil and a 25% reduction in the AUC0–480 of norverapamil after oral administration. However, HLJDD did not alter the pharmacokinetic behaviour of verapamil after intravenous administration. Norverapamil formation showed biphasic kinetics in both intestinal and hepatic microsomes. HLJDD treatment significantly decreased the intrinsic clearance of verapamil in intestinal microsomes, but had no effect on the hepatic metabolism of verapamil. Berberine also inhibited norverapamil formation in both intestinal and hepatic microsomes; the extent of inhibition was larger in intestinal microsomes. Conclusions HLJDD displayed a route‐dependent effect on the pharmacokinetics of verapamil in rats. HLJDD treatment increased the bioavailability of verapamil partly via inhibiting first‐pass verapamil metabolism in the intestine.
Keywords:first‐pass metabolism  herb–  drug interaction  Huang‐Lian‐Jie‐Du‐Decoction  norverapamil  pharmacokinetics  verapamil
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