title: Studies on the biotransformation of lonazolac, bromerguride, lisuride and terguride in laboratory animals and their hepatocytes.
abstract: 1. Metabolic patterns and the extents of metabolism of four drugs, namely [14C]lonazolac (LON), [14C]bromerguride)BRO), [14C]lisuride (LIS) and [3H]terguride (TER) have been studied in three experimental models, namely hepatocyte suspensions of rat, guinea pig, beagle dog and cynomolgus monkey, isolated perfused liver of rat and guinea pig and intact animals (rat, guinea pig, dog and monkey). 2. Selection of compounds was based on differences in phase I metabolic pathways. LON is exclusively hydroxylated in the N-substituting aromatic ring, BRO is mainly N-deethylated in the urea moiety, and LIS and TER are both degraded into numerous metabolites. 3. The decrease in unchanged drug levels in hepatocyte suspensions was characterized by half-lives, with LON as the most stable and LIS as the least stable compound. Marked interspecies differences were found. De-ethylation and aromatic hydroxylation were much slower in rat hepatocytes than in the liver cells of other species; BRO was slowly biodegraded in dog hepatocytes while LIS was broken down extremely quickly. 4. Liver perfusion experiments and studies in vivo were evaluated for the extents of metabolism of each drug. 5. Metabolism studies in hepatocytes did not show any quantitative correlation to those of metabolism in vivo. The suitability of evaluating parameters for in vitro studies is discussed.
authors.affiliation: Research Laboratories, Schering Aktiengesellschaft, Berlin/Bergkamen, FR Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hümpel
authors.forename: D
authors.initials: D
authors.lastname: Sostarek
authors.forename: H
authors.initials: H
authors.lastname: Gieschen
authors.forename: C
authors.initials: C
authors.lastname: Labitzky
mesh_terms: D000818:Animals; D001711:Biotransformation; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008090:Lisuride / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008252:Macaca fascicularis; D008954:Models, Biological; D015394:Molecular Structure; D010477:Perfusion; D011720:Pyrazoles / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D015262:Xenobiotics / Q000493:pharmacokinetics*
chemical_list: D011720:Pyrazoles; D015262:Xenobiotics; C017472:lonazolac; C006208:dironyl; D008090:Lisuride; C039667:bromerguride