Stereoselective N-Demethylation of Chlorpheniramine in Rat Liver Microsomes : Studies on Age and Sex Differences

• Published in: YAKUGAKU ZASSHI Vol. 115; no. 8; pp. 633 - 640
• Main Authors: NOMURA, Akio, SAKURAI, Eiichi, HIKICHI, Noboru
• Format: Journal Article
• Language: Japanese
• Published: Japan The Pharmaceutical Society of Japan 01.08.1995
• Subjects: age difference; Aging - metabolism; Animals; chlorpheniramine; Chlorpheniramine - metabolism; Chromatography, High Pressure Liquid - methods; Dealkylation; Female; In Vitro Techniques; Male; Microsomes, Liver - metabolism; N-demethylation; rat liver microsome; Rats; Rats, Wistar; Sex Characteristics; sex difference; Stereoisomerism; stereoselectivity
• ISSN: 0031-6903; 1347-5231
• DOI: 10.1248/yakushi1947.115.8_633

We have established a simple method for the chiral stationary-phase liquid chromatographic resolution of racemic chlorpheniramine (Chp) and its two N-demethylated metabolites, monodesmethylchlorpheniramine (DMChp) and didesmethylchlorpheniramine (DDMChp), using an ovomucoid-conjugated column with respective quantitation limits of 5 ng/ml. The assay was used to study the age and sex difference in stereoselective N-demethylation of Chp by rat liver microsomes. The formation rate of each DMChp from racemic Chp was about 2.2 times faster with the S-(+)-enantiomer than the R-(-)-enantiomer in male rats at the age of only 8 weeks, 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 Vmax/Km value for the formation of S-(+)-DMChp increased with age in 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 recemic Chp did not differ between S-(+)- and R-(-)-enantiomers at each age, suggesting a lack of stereoselectivity in the microsomal N-demethylation. Moreover, the Km and Vmax values for N-demethylation of Chp enantiomers were nearly identical between two consecutive ages in female rats. Further metabolism 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.