Identification of novel metabolites of pioglitazone in rat and dog.
1. Four new metabolites of pioglitazone were identified by liquid chromatography-mass spectrometry (LC-MS/MS) as being formed by hydroxylation (M-VII and M-VIII), opening of the thiazolidinedione ring (M-X) and by desaturation of the terminal ethyl side chain or tether ethoxy moiety (M-IX), respectively. The structure of one of the hydroxylated metabolites (M-VII) was confirmed by chemical modification using the Jones reaction. 2. Oxidative cleavage of the thiazolidinedione ring is a novel pathway not previously reported for pioglitazone. 3. The hydroxylated M-VII was detected in incubations with rat, dog and human liver and kidney microsomes, and in plasma from rats and dogs dosed orally with [(3)H]pioglitazone. 4. The carboxylic acid derivative of M-VII (M-V) and its taurine conjugate were the major radioactive components in dog bile.
Departments of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA. zhongzhou_shen@merck.com
Z
Z
Shen
J R
JR
Reed
M
M
Creighton
D Q
DQ
Liu
Y S
YS
Tang
D F
DF
Hora
W
W
Feeney
J
J
Szewczyk
R
R
Bakhtiar
R B
RB
Franklin
S H
SH
Vincent
D000818:Animals; D001646:Bile / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D004285:Dogs; D006801:Humans; D006900:Hydroxylation; D007668:Kidney / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D000077205:Pioglitazone; D051381:Rats; D045162:Thiazolidinediones / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D014316:Tritium
D045162:Thiazolidinediones; D014316:Tritium; C089946:2,4-thiazolidinedione; D000077205:Pioglitazone