| Verapamil and norverapamil plasma levels were measured by HPLC method. After iv administration, T$sb{1over 2}$, MRT$sb{rm iv}$, V$sb{rm dss}$, V$sb{rm dbeta}$, CL$sb{rm p}$ and Cl$sb{rm u}$ of verapamil were 1.59 $pm$ 0.46, 1.26 $pm$ 0.12 hr, 2.99 $pm$ 0.57, 5.08 $pm$ 0.54 1/kg, 40.42 $pm$ 9.73 and 342.56 $pm$ 90.29 ml/min/kg, respectively. Pharmacokinetic parameters based on arterial or venous data were presented. Plasma protein binding, C$sb{rm b}$/C$sb{rm p}$ and C$sb{rm p}$/C$sb{rm c}$ of verapamil were 94.6 $pm$ 2.97%, 0.86 $pm$ 0.02 and 1.46 $pm$ 0.09, respectively. The hepatic extraction ratio based on blood and plasma were 0.86 $pm$ 0.11 and 1.34 $pm$ 0.18, respectively. The comparison of pharmacokinetic parameters of verapamil between rats and humans are presented.;After oral administration, bioavailability, mean hepatic blood flow, MRT$sb{rm po}$, and the sum of MAT and MTT$sb{rm gw}$ of verapamil were 13%, 20.75 $pm$ 3.29 ml/min, 2.38 $pm$ 0.49, and 1.06 hr, respectively.;Verapamil was absorbed from the intestinal loop rapidly, but not from stomach. The fraction of drug absorbed was estimated to be 0.99.;The mean (s.d) percentage metabolized of verapamil by intestine, liver, and muscle homogenates were 8.36 (4.31), 87.59 (1.79), and 14.43 (1.41), respectively. There was no verapamil metabolism by stomach, heart, lung, and kidney homogenates. The hepatic extraction ratio based on well-stirred and parallel-tube model were 0.227 and 0.254, respectively.;After iv verapamil administration, oral capsaicin (1 mg/kg) increased (p $<$ 0.05) MRT$sb{rm iv}$, V$sb{rm dss}$ and CL$sb{rm p}$ from 1.26 $pm$ 0.12 to 1.5 $pm$ 0.19 hr, 1103 $pm$ 132 to 1685 $pm$ 230 ml, and 14.8 $pm$ 2.2 to 18.8 $pm$ 1.7 ml/min, respectively. Capsaicin enhanced bioavailability of verapamil in a dose-dependent manner. Mean ($pm$s.d) C$sb{rm max}$ increased from 279 $pm$ 77 to 663 $pm$ 128 and 746 $pm$ 224 ng/ml (p $<$ 0.01), T$sb{rm max}$ decreased from 41 $pm$ 16 to 13 $pm$ 5 and 9 $pm$ 2 min (p $<$ 0.01), AUC$sb{0-alpha}$ increased 22% and 40%, and CL$sb{rm o}$ decreased from 101.7 $pm$ 29.1 to 88.0 $pm$ 14.9 (p = 0.1) and 67.4 $pm$ 15.4 (p $<$ 0.01) ml/min, after oral verapamil (12 mg/kg) with capsaicin 0.5 and 1.0 mg/kg, respectively. There was no significant change in T$sb{1over 2}$ (p $>$ 0.05). The estimated liver blood flow increased by 56%. Capsaicin decreased plasma protein binding and increase in situ intestinal loop absorption of verapamil significantly (p $<$ 0.01). Furthermore, capsaicin is a potent inhibitor of verapamil metabolism. The effect of change in hepatic blood flow, plasma protein binding, and drug metabolism on verapamil pharmacokinetic parameters was presented. |
