• Journal of Pharmaceutical Investigation
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• v.28 no.2
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• pp.73-80
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• 1998

In order to elucidate the effect of N-demethylation on the in vivo metabolite kinetics, especially hepatic first-pass effect of trimebutine(TMB), the N-demethylation of TMB to N-monodesmethyl trimebutine(N-TMB) was studied in rats. TMB(10 mg/kg) and N-TMB(10 mg/kg) were injected into the femoral and the portal vein, respectively. And the pharmacokinetic parameters were obtained from the plasma concentration-time profiles of TMB and N-TMB determined by the simultaneous analysis using high-performance liquid chromatography. It was supposed that these drugs were almost metabolized in vivo because the urinary and biliary excreated amounts of TMB and N-TMB were lower than 0.1% of the administered dose. According to the hepatic biotransformation model and metabolic pathways of TMB proposed, it was found that the fraction of systemic clearance of TMB which formed N-TMB in liver$(G_{mi})$ was 0.826, that of TMB which furnishes the available N-TMB to the systemic circulation$(F_{mi})$ was 0.083, and the absolute hepatic bioavailability of N-TMB formed trom TMB$(F_{mi.p})$ was 0.1. These results showed that TMB was suspected of the sequential hepatic first-pass metabolism and N-demethylated by 82.6%. Therefore, the residue would be hydrolyzed by the esterase in the liver. That is, the ability of N-demethylation of TMB was 4.75-fold larger than that of hydrolysis by the esterase in rats.

• Journal of Pharmaceutical Investigation
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• v.22 no.4
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• pp.301-306
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• 1992

The influence of phenobarbital (PB) pretreatment (75 mg/kg/day, i.p. for 4 days) on the metabolite kinetics of diltiazem (DTZ) was studied in rats in order to elucidate the effect of esterase induced by PB on the formation of DTZ to desacetyldiltiazem (DAD), DAD was injected via portal vein (3 mg/kg) to the control and PB-pretreated rats, The intrinsic hepatic clearance of DAD was significantly increased by PB pretreatment and the absolute bioavailability of DAD was significantly decreased in the PB-pretreated rats. According to the hepatic biotransformation model of DTZ, the fraction of systemic clearance of DTZ which forms DAD $(G_{mi})$ was different from that of DTZ which furnishes the available DAD to the systemic circulation $(F_{mi})$ in control rats. This result shows that DTZ was suspected of the sequential hepatic first-pass metabolism. On the other hand, PB pretreatment enhanced the $G_{mi}$ value of DTZ by 44%. It may be concluded that the deacetylation of DTZ to DAD in rats is increased by the esterase induced by PB but the transfer rate of DAD immediately formed from DTZ into systemic circulation is not affected by PB due to the 27% decreased absolute bioavailability of DAD resulting from PB pretreatment.