Pharmacokinetics of troglitazone, an antidiabetic agent: prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data.
Sulfation and glucuronidation, the major routes of metabolism of troglitazone, an antidiabetic agent, were examined in vitro using hepatic cytosol and microsomes prepared from KK mice, an animal model of non-insulin-dependent diabetes mellitus. Stereoselectivity was observed for both conjugation reactions, and the metabolic intrinsic clearance of glucuronidation was about 3- to 100-fold higher than that of sulfation for each stereoisomer. In addition, the metabolic intrinsic clearance of glucuronidation exhibited an 8-fold difference among stereoisomers. The predicted metabolic clearance for each stereoisomer, calculated from the in vitro data based on a dispersion model, was comparable to the measured metabolic clearance in vivo, ranging from 27 to 93%. We also attempted to predict the in vivo metabolic clearance from in vitro metabolism data, to investigate species differences in the stereoselectivity of the conjugation reactions in normal animals, i.e., ddY mice and rats. For ddY mice the in vivo hepatic glucuronidation clearance was 170-fold higher than the corresponding sulfation clearance, whereas for rats the sulfation clearance was 6-fold higher than the glucuronidation clearance. The hepatic sulfation clearance in mice and rats predicted from in vitro metabolism data was 5.3- and 1.1-fold higher, respectively, than that in vivo, calculated from the plasma disposition of parent drug and biliary excretion of metabolites. For glucuronidation, the predicted values in mice and rats were 1.0- and 0.33-fold higher, respectively. These results suggest that semiquantitative extrapolation of in vitro stereoselective metabolism of troglitazone, by conjugation, to the in vivo situation is possible.
Izumi
T
T
Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Hosiyama
K
K
Enomoto
S
S
Sasahara
K
K
Sugiyama
Y
Y
D000818:Animals; D001646:Bile / Q000378:metabolism; D002839:Chromans / Q000493:pharmacokinetics* / Q000652:urine; D003600:Cytosol / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000652:urine; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013237:Stereoisomerism; D013431:Sulfates / Q000378:metabolism; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000652:urine; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D005965:Glucuronates; D007004:Hypoglycemic Agents; D013431:Sulfates; D013844:Thiazoles; D045162:Thiazolidinediones; D000077288:Troglitazone