title: Sex difference in pharmacokinetics of the novel sulfonylurea antidiabetic glimepiride in rats.
abstract: Glimepiride (Hoe 490, CAS 93479-97-1), a novel sulfonylurea antidiabetic agent, was studied for the cause of sex-related difference in the elimination clearance of the unchanged drug in rats. After intravenous and oral administration, the serum level of the unchanged drug was higher in female rats and AUC and t1/2 (beta) values were about 1.7- and 1.4-fold those for males, while Vss and oral bioavailability were nearly equal. The excretion clearance of the unchanged drug was quite small in both male and female animals, and most of the administered drug was excreted into the bile as a hydroxymethyl derivative, M1. In the in vitro metabolism study, M1 was found to be formed mainly in the liver microsomal fraction, and its hydroxylation activity was significantly higher in males. This metabolic activity was dependent on NADPH and was inhibited by proadifen. On the other hand, formation of M2, a carboxyl derivative, from M1 was observed in the cytosol fraction and showed no sex difference. Its metabolic activity depended on NAD and was inhibited by pyrazole. These results suggest that the sex difference observed in rat pharmacokinetics is mainly due to different hydroxylation activities of the side chain methyl group based on the participation of sex dependent cytochrome P-450 in liver microsomes.
authors.affiliation: Pharma Research Laboratories, Hoechst Japan Limited, Saitama.
authors.forename: H
authors.initials: H
authors.lastname: Yamazaki
authors.forename: S
authors.initials: S
authors.lastname: Tabata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D003067:Coenzymes / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000963:Antimetabolites; D003067:Coenzymes; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride