ENANTIOSELECTIVE PHARMACOKINETICS OF HOMOCHLORCYCLIZINE - DISPOSITIONOF (-HOMOCHLORCYCLIZINE AND(-)-HOMOCHLORCYCLIZINE AFTER INTRAVENOUS AND ORAL-ADMINISTRATION OF RACEMIC HOMOCHLORCYCLIZINE TO RATS())

Concentrations of homochlorcyclizine enantiomers in blood, urine, and tissues of the liver, lung, kidney, brain, heart, spleen, intestine an d stomach of rats after drug administration were determined by high-pe rformance liquid chromatography on a chiral-stationary phase. After in travenous administration (10 mg kg(-1)), homochlorcyclizine was rapidl y distributed in many tissues, with the highest concentration in lung. No differences were found between enantiomers in blood concentrations . After oral administration (50 mg kg(-1)), the concentrations of the (+)-isomer in nearly all tissues were higher than those of the (-)isom er. The AUC(0-infinity) values of the (+)- and (-)-isomers differed si gnificantly. The absorption of racemic homochlorcyclizine from rat sma ll intestine was not enantioselective. These results suggested that th e different concentrations between enantiomers after oral administrati on were not caused by enantioselective absorption or distribution but rather by preferential first-pass metabolism of the (-)-isomer in the liver. The enantioselectivity of metabolism was also demonstrated by i n-vitro experiments.