Effect of Huang-Lian-Jie-Du-Decoction on pharmacokinetics of verapamil in rats.
OBJECTIVE
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.


RESULTS
HLJDD treatment increased the plasma concentration of verapamil and decreased the plasma concentration of norverapamil, resulting in a 24% increase in the AUC(0-480) of verapamil and a 25% reduction in the AUC(0-480) 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.
Xie
Shan-Shan
SS
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Hu
Nan
N
Jing
Xin-Yue
XY
Liu
Xiao-Dong
XD
Xie
Lin
L
Wang
Guang-Ji
GJ
Liu
Chang-Hui
CH
D000818:Animals; D019540:Area Under Curve; D001599:Berberine / Q000494:pharmacology*; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D008658:Inactivation, Metabolic; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D019684:Magnoliopsida; D008297:Male; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
D004365:Drugs, Chinese Herbal; C061676:oren gedoku to; D001599:Berberine; C016904:norverapamil; D014700:Verapamil; D051544:Cytochrome P-450 CYP3A