Prediction of species differences (rats, dogs, humans) in the in vivo metabolic clearance of YM796 by the liver from in vitro data.
The bioavailability after oral administration of (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro [4,5] decane-L-tartarate monohydrate (YM796), which is being developed as an antidementia drug, at a dose of 1 mg/kg was very low (3.4%) in rats, but considerably higher (16.1%) in dogs. The oral clearances (CLoral, Dose/AUCoral) in rats and dogs were, respectively, 300 and 18 times more than that already reported in humans. We have previously reported successful attempts to predict the in vivo hepatic metabolic clearance of YM796 from in vitro data in humans. In our study, the in vitro metabolism of YM796 was determined using liver microsomes prepared from both rats and dogs and we also investigated if the species difference observed in vivo could be quantitatively reproduced in vitro. In rats, total metabolite formation could be described by single component kinetics with a Km of 13.4 microM and a Vmax of 520 nmol/min/g liver. However, in dogs, total metabolite formation could be described by three components, as also reported for humans. The Km and Vmax values for the high-affinity, low-capacity component (Km1 and Vmax1) in dogs and humans were, respectively, 8.1 and 1.7 microM, and 10.9 and 1.2 nmol/min/g liver. The overall intrinsic metabolic clearances estimated from the in vitro studies (CLint,in vitro) for rats and dogs were 38.8 and 2.6 ml/min/g liver, respectively, being approximately 40 and 3 times more than that previously reported for humans (0.94 ml/min/g liver). The overall intrinsic hepatic clearances (CLint,in vivo) calculated from in vivo CLoral were 30.4, 3.4 and 0.73 ml/min/g liver for rats, dogs and humans, respectively, indicating that the in vivo hepatic clearance of YM796 can be predicted from in vitro metabolism data in each species. Thus, the pronounced species difference in the metabolic clearance observed in vivo can be quantitatively predicted from in vitro metabolic data using liver microsomes, and was predominantly due to the large difference in the Vmax values.
Iwatsubo
T
T
Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co., Ltd., 1-1-8, Azusawa, Itabashi-ku, Tokyo, 174, Japan.
Suzuki
H
H
Sugiyama
Y
Y
D000818:Animals; D003704:Dementia / Q000188:drug therapy; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010277:Parasympathomimetics / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D013141:Spiro Compounds / Q000493:pharmacokinetics*
C067766:2,8-dimethyl-3-methylene-1-oxa-8-azaspiro(4,5)decane; D010277:Parasympathomimetics; D013141:Spiro Compounds