In vitro metabolism of zatosetron. Interspecies comparison and role of CYP 3A.

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)