EFFECT OF FIRST-PASS METABOLISM ON ENANTIOSELECTIVE PHARMACOKINETICS AFTER ORAL-ADMINISTRATION OF (-HOMOCHLORCYCLIZINE, (-)-HOMOCHLORCYCLIZINE AND RACEMIC HOMOCHLORCYCLIZINE TO RATS())

The enantioselective relationship between the pharmacokinetics and hep atic metabolism of homochlorcyclizine hydrochloride (HCZ) was investig ated using rats. There were no significant differences in blood concen trations between the three forms after intravenous administration (5 m g/kg) of (+)-, (-)- and racemic HCZ. On the other hand, there were sig nificant differences in the pharmacokinetics between (-)- and(+)-HCZ a nd between(-)- and racemic HCZ after oral administration (50 mg/kg) of these three forms. The C-max and AUC(0-infinity) of (-)-HCZ were lowe r than those of (+)-isomer and racemate, and its CL(0) was clearly hig her than the others. The(+)-isomer and racemate showed no significant differences in their pharmacokinetic parameters. At a lower dose (10 m g/kg), however, no enantiomeric differences were found in the pharmaco kinetic parameters of (+)- and (-)-HCZ. Also examined was the cytochro me p-450-dependent-oxidative metabolism of(+)-, (-)- and racemic HCZ i n vitro using rat liver 9000 x g supernatant fraction. The irt vitro m etabolism of (-)-HCZ was extremely fast, compared with those of the ()-isomer and the racemate. The V-max in vitro showed a good correlatio n with the CL(0) in vivo after oral administration (50 mg/kg) of all t hree forms of HCZ. In vitro study of enantiomeric inhibition of the me tabolism showed that (+)-HCZ was a competitive inhibitor of (-)-HCZ me tabolism, with a K-i of 6.96 mu M. (-)-HCZ was also a competitive inhi bitor of(+)-HCZ metabolism, with a K-i of 20.4 mu M. This is consisten t with the observation that the (+)/(-) ratio of AUC(0-infinity) after dosing with a racemic mixture was clearly lower than after dosing wit h the individual enantiomers. Moreover, the blood concentrations of ra cemic HCZ were similar to those of (+)-HCZ rather than intermediate be tween those of (+)- and (-)-HCZ, probably because of the stronger inhi bitory effect of (+)-HCZ on ( -)-HCZ than vice versa. These results su ggest 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 th e administration of its racemate was affected by the enantiomeric inhi bitory interactions in the hepatic metabolism.