Effect of First-Pass Metabolism on Enantioselective Pharmacokinetics after Oral Administration of (+)-, (-)- and Racemic Homochlorcyclizine to Rats

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The enantioselective relationship between the pharmacokinetics and hepatic metabolism of homochlorcyclizine hydrochloride (HCZ) was investigated using rats. There were no significant differences in blood concentrations between the three forms after intravenous administration (5 mg/kg) of (+)-, (-)-and racemic HCZ. On the other hand, there were significant differences in the pharmacokinetics between (-)-and (+)-HCZ and between (-)-and racemic HCZ after oral administration (50 mg/kg) of these three forms. The C_<max> and AUC_<0-∝> of (-)-HCZ were lower than those of (+)-isomer and racemate, and its CL_0 was clearly higher than the others. The (+)-isomer and racemate showed no significant differences in their pharmacokinetic parameters. At a lower dose (10 mg/kg), however, no enantiomeric differences were found in the pharmacokinetic parameters of (+)- and (-)-HCZ. Also examined was the cytochrome p-450-dependent-oxidative metabolism of (+)-, (-)-and racemic HCZ in vitro using rat liver 9000×g supernatant fraction. The in vitro metabolism of (-)-HCZ was extremely fast, compared with those of the (+)-isomer and the racemate. The V_<max> in vitro showed a good correlation with the CL_0 in vivo after oral administration (50 mg/kg) of all three forms of HCZ. In vitro study of enantiomeric inhibition of the metabolism showed that (+)-HCZ was a competitive inhibitor of (-)-HCZ metabolism, with a K_i of 6.96 μM. (-)-HCZ was also a competitive inhibitor of (+)-HCZ metabolism, with a K_i of 20.4 μM. This is consistent with the observation that the (+)/(-) ratio of AUC_<0-∝> after dosing with a racemic mixture was clearly lower than after dosing with the individual enantiomers. Moreover, the blood concentrations of racemic HCZ were similar to those of (+)-HCZ rather than intermediate between those of (+)-and (-)-HCZ, probably because of the stronger inhibitory effect of (+)-HCZ on (-)-HCZ than vice versa. These results suggest that the enantiomeric differences in the pharmacokinetics of HCZ after oral administration were caused by enantioselective first-pass metabolism in the liver, and that the pharmacokinetics of HCZ after the administration of its racemate was affected by the enantiomeric inhibitory interactions in the hepatic metabolism.
公益社団法人日本薬学会の論文
1994-09-15

Effect of First-Pass Metabolism on Enantioselective Pharmacokinetics after Oral Administration of (+)-, (-)- and Racemic Homochlorcyclizine to Rats

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