RESUMEN
Pioglitazone is in the class of compounds known as the thiazolidinediones and is used to treat type 2 diabetes mellitus. The first in its class compound, troglitazone, was withdrawn from the U.S. market in 2000 due to a high incidence of hepatotoxicity and drug-induced liver failure. Reactive ring-opened products of troglitazone have been identified and evidence suggests that these reactive intermediates might be a potential cause of hepatotoxicity. The present work shows that pioglitazone has a reactive ring-opened product which was trapped by glutathione and positively identified by high performance liquid chromatography with tandem mass spectrometry accurate mass measurements. The novel thiazolidinedione ring-opened products of pioglitazone were identified in rat and human liver microsomes and in freshly isolated rat but not human hepatocytes.
Asunto(s)
Hepatocitos/metabolismo , Microsomas Hepáticos/metabolismo , Tiazolidinedionas/metabolismo , Animales , Hepatocitos/química , Humanos , Masculino , Microsomas Hepáticos/química , Pioglitazona , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Tiazolidinedionas/análisis , Tiazolidinedionas/químicaRESUMEN
1. The metabolism of 1-ethylphenoxathiin-10,10-dioxide (BW1370U87), an experimental compound designed as an inhibitor of monoamine oxidase-A for use as a possible anti-depression agent, has been studied in a human liver microsome preparation. 2. The identities of the metabolites have been determined using directly coupled hplc-1H nmr at 600 MHz in the stop-flow mode in this first study of in vitro xenobiotic metabolism using hplc-nmr. 3. The xenobiotic substances that were identified comprised the parent compound BW1370U87 (with -CH2CH3 at C1) together with sidechain-oxidized metabolites with C1 substituents of -CHOH.CH3, -CH2.CH2OH, -CHOH.CH2OH and -CH2.COOH, plus the unsubstituted phenoxathiin-10,10-dioxide.
Asunto(s)
Compuestos Heterocíclicos/farmacocinética , Microsomas Hepáticos/metabolismo , Inhibidores de la Monoaminooxidasa/farmacocinética , Biotransformación , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Microsomas Hepáticos/química , Espectrofotometría Ultravioleta , Xenobióticos/metabolismoRESUMEN
1. The toxicokinetics of cis- and trans-tetramethrin isomers were investigated using the isolated perfused rat liver preparation. 2. The concentration of cis- and trans-tetramethrin decreased rapidly in the plasma perfusate and was initially replaced by N-(hydroxymethyl)3,4,5,6-tetrahydrophthalimide (MTI) and then by 3,4,5,6-tetrahydrophthalimide (TPI). Plasma perfusate concentrations of the intact cis-isomer were higher than those of the trans-isomer. Concentrations of MTI and TPI were higher in livers treated with the trans-isomer. 3. Tetramethrin and its metabolites were rapidly excreted in the bile. Bile from livers perfused with trans-isomer contained higher concentrations of parent isomer and metabolites MTI and TPI, than did bile from livers treated with the cis-isomer.
Asunto(s)
Hígado/metabolismo , Piretrinas/metabolismo , Animales , Bilis/metabolismo , Captano , Técnicas In Vitro , Cinética , Hígado/efectos de los fármacos , Masculino , Perfusión , Ftalimidas/metabolismo , Piretrinas/toxicidad , Ratas , Ratas Endogámicas , EstereoisomerismoRESUMEN
1. The pharmacokinetics and metabolism of (1R, cis)- and (1R, trans)-isomers of tetramethrin (i.v. 0.25 mg/kg) were studied in rats. 2. The experimental data for the time course of the concentration of tetramethrin isomers in plasma fit a pharmacokinetic two-compartmental open model. Plasma levels of both isomers were similar. The terminal half-life of the trans-isomer in plasma was greater (125 min) than the cis-isomer (72 min). 3. The concentrations of the two metabolites, 3,4,5,6-tetrahydrophthalimide (TPI) and N-(hydroxymethyl)-3,4,5,6-tetrahydrophthalimide (MTI), were consistently higher in the plasma of rats treated with the trans-isomer than in those treated with the cis-isomer. 4. In rats treated with the trans-isomer, the majority of radioactivity excreted after 96 h was found in urine. The faeces was the major excretory route for rats treated with the cis-isomer (26% urine, 69% faeces with cis-isomer; 64% urine, 29% faeces with trans-isomer). 5. Metabolism of each isomer was rapid and complete. Parent chemical was not detected in urine and only small quantities of the intact cis-isomer were found in the faeces. MTI, TPI, and cyclohexane-1,2-dicarboximide (HPI) were detected in both urine and faeces. 6. The amount of radioactivity excreted into the bile was similar for both isomers. However, levels of the intact parent compound and TPI were higher in the bile isolated from rats treated with the trans-isomer. The trans-isomer was found to undergo enterohepatic circulation.