STEREOSELECTIVE N-DEMETHYLATION OF CHLORP HENIRAMINE IN RAT-LIVER MICROSOMES - STUDIES ON AGE AND SEX-DIFFERENCES

We have established a simple method for the chiral stationary-phase li quid chromatographic resolution of racemic chlorpheniramine (Chp) and its two N-demethylated metabolites, monodesmethylchlorpheniramine (DMC hp) and didesmethylchlorpheniramine (DDMChp), using an ovomucoid-conju gated column with respective quantitation limits of 5 ng/ml. The assay was used to study the age and sex difference in stereoselective N-dem ethylation of Chp by rat liver microsomes. The formation rate of each DMChp from racemic Chp was about 2.2 times faster with the S-(+)-enant iomer than the R-(-)-enantiomer in male rats at the age of only 8 week s, whereas the rate of N-demethylation in male rats was not different between S-(+)- and R-(-)-enantiomers at the age of 3 and 24 weeks. The V-max/K-m value for the formation of S-(+)-DMChp increased with age i n male rats, but the value in 8-week-old rats was lower than that in 3 -week-old rats in the formation of R-(-)-DMChp. In female rats, on the other hand, the formation rate of DMChp from racemic Chp did not diff er between S-(+)- and R-(-)-enantiomers at each age, suggesting a lack of stereoselectivity in the microsomal N-demethylation. Moreover, the K-m and V-max values for N-demethylation of Chp enantiomers were near ly identical between two consecutive ages in female rats. Further meta bolism of DMChp to DDMChp was not observed between both enantiomers in male and female liver microsomes at the age of 3, 8 and 24 weeks.