Aki Nakai

Enantioselective pharmacokinetics of homochlorcyclizine II: disposition and metabolism of (+)-, (−)- and racemic homochlorcyclizine after oral administration to man

SummaryThe pharmacokinetics of a single oral dose of 20 mg (+)-, (-)- and racemic homochlorcyclizine (HCZ) have been studied in humans. The formation of the quarternary ammonium-linked glucuronide was an important metabolic pathway, and the metabolic process was enantioselective as a result of differing urinary excretion rates of (+)-, (-)- and racemic glucuronide.There were significant differences between (+)-, (-) and racemic HCZ in AUC (0-14 h) and plasma protein binding, but all HCZ enantiomers were slowly absorbed and eliminated (elimination half-lives about 11 h).The results shows help to establish a more efficient dosage regimen for HCZ therapy.

Enantioselective pharmacokinetics of homochlorcyclizine. III. Simultaneous determination of (+)- and (-)- homochlorcyclizine in human urine by high-performance liquid chromatography.

A method is described for the simultaneous determination of (+)- and (-)-homochlorcyclizine (HCZ) in human urine by high-performance liquid chromatography on a chiral stationary phase of ovomucoid-bonded silica. The pH of the buffer and organic modifier in the mobile phase markedly affected the chromatographic separation. A mobile phase of methanol-0.02 M acetate buffer (pH 4.7) (25:75,v/v) at a flow-rate of 1.0 ml/min was used for the urine assays. The ultraviolet absorption was monitored at 240 nm, and diphenhydramine was employed as the internal standard for the quantitation. (+)-HCZ, (-)-HCZ and the internal standard were eluted at retention times of 15, 25 and 8 min, respectively. The limit of determination for HCZ enantiomers was ca. 50 ng/ml of urine. One of the metabolites in human urine, which was a quaternary ammonium-linked glucuronide, could also be determined in a manner similar to unchanged HCZ after beta-glucuronidase hydrolysis. A pharmacokinetic study was conducted with three healthy volunteers, who each received a single oral dose of racemic HCZ (20 mg). Distinct differences were found between the two enantiomers, particularly in the metabolic process, that is, the urinary excretion as (-)-HCZ-glucuronide within 48 h was ca. four times higher than that of the (+)-isomer. This method should be very useful for enantioselective pharmacokinetic studies of HCZ.

Enantioselective Pharmacokinetics of Homochlorcyclizine: Disposition of (+)- and (–)-Homochlorcyclizine after Intravenous and Oral Administration of Racemic Homochlorcyclizine to Rats

Abstract— Concentrations of homochlorcyclizine enantiomers in blood, urine, and tissues of the liver, lung, kidney, brain, heart, spleen, intestine and stomach of rats after drug administration were determined by high‐performance liquid chromatography on a chiral stationary phase. After intravenous administration (10 mg kg−1), homochlorcyclizine was rapidly 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 (–)‐isomer. The AUC0‐x values of the (+)‐ and (–)‐isomers differed significantly. The absorption of racemic homochlorcyclizine from rat small intestine was not enantioselective. These results suggested that the different concentrations between enantiomers after oral administration 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 in‐vitro experiments.