title: In vitro metabolism of zatosetron. Interspecies comparison and role of CYP 3A.
abstract: The major in vivo human metabolite of zatosetron is 8-alpha-methyl,8-beta-oxo zatosetron [N-O (1) zatosetron]. N-Desmethyl zatosetron (NdM zatosetron) and 3-hydroxy-zatosetron (3-OH-zatosetron) are minor human metabolites. In the rat, the primary in vivo metabolite is 3-OH-zatosetron. The enzyme kinetics of zatosetron metabolism were determined using human, rat, and monkey hepatic microsomal incubations. In the rat, the intrinsic clearance (IC; IC = Vmax/KM = microliter/min/mg of protein) of 3-OH-zatosetron (IC = 5.2) was favored over N-O (1) zatosetron (IC = 3.0) and NdM zatosetron (IC = 1.4). In the monkey, N-O (1) zatosetron exhibited the highest IC (IC = 7.0) relative to that for 3-OH-zatosetron (IC = 4.4) and NdM zatosetron (IC = 2.9). Monkey microsomes also formed 8-beta-methyl,8-alpha-oxo zatosetron (IC = 2.2). In two human samples (identified as HL-E and HL-J), the metabolic clearance of zatosetron favored the formation of N-O (1) zatosetron (HL-E, IC = 6.9; HL-J, IC = 2.9) over NdM zatosetron (HL-E, IC = 0.6; HL-J, IC = 0.3) and 3-OH-zatosetron (HL-E and HL-J, IC = 0.1). These results indicate that the monkey is better than the rat as a model for the exposure of humans to zatosetron and its metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Drug Metabolism and Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
authors.forename: B J
authors.initials: BJ
authors.lastname: Ring
authors.forename: C J
authors.initials: CJ
authors.lastname: Parli
authors.forename: M C
authors.initials: MC
authors.lastname: George
authors.forename: S A
authors.initials: SA
authors.lastname: Wrighton
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001572:Benzofurans / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D012702:Serotonin Antagonists / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D001572:Benzofurans; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D012702:Serotonin Antagonists; C064877:zatosetron; D003577:Cytochrome P-450 Enzyme System; D011794:Quercetin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating