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1.
Drug Metab Dispos ; 33(6): 733-8, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15764718

RESUMO

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 The first in its class compound, troglitazone, was withdrawn from the U.S. market in 2000 due to a high incidence of hepatotoxicity and drug-induced liver failure.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.


Assuntos
Hepatócitos/metabolismo , Microssomos Hepáticos/metabolismo , Tiazolidinedionas/metabolismo , Animais , Hepatócitos/química , Humanos , Masculino , Microssomos Hepáticos/química , Pioglitazona , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Tiazolidinedionas/análise , Tiazolidinedionas/química
2.
Drug Metab Dispos ; 26(1): 42-51, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9443851

RESUMO

Compound LY335979 is a P-glycoprotein inhibitor currently entering phase I clinical trials for potential reversal of multidrug resistance to cancer chemotherapy. In early exploratory studies, LY335979 was found to be rapidly transformed in incubations with liver microsomes from rats, dogs, monkeys, and humans. Although the parent compound was completely metabolized, no prominent metabolite peaks were observed. One peak did appear early in the time course, but it did not increase over time. In another preliminary experiment, rats were treated iv with [3H]LY335979 (prepared for pharmacology studies), and urine and bile fractions were collected. Analysis of the urine by reverse-phase HPLC with UV and radioactivity detection revealed that almost all of the material eluted with the solvent front. More than half the radioactivity in bile was accounted for by two peaks eluting earlier than the parent compound (the rest eluted at the solvent front). With both bile and the incubations with microsomes, initial attempts to isolate metabolites were not successful. There was also evidence in both systems of products derived from cleavage of LY335979 (by both further metabolism and degradation). LC/NMR was thus used to analyze materials directly in their respective matrices. An N-oxide metabolite (LY389551) formed by oxidation of the quinoline nitrogen was identified in the microsomal incubations; in bile, three glucuronide metabolites were identified, all of which were conjugates of products formed by oxidation of the quinoline ring of LY335979. There have been few reports in the literature of LC/NMR analysis of bile, which is a more complex matrix than either urine or microsomal suspensions. However, the HPLC techniques developed in this work for the HPLC/UV and LC/MS analyses of LY335979 metabolites in the microsomal matrix and in bile proved readily adaptable for LC/NMR. Using a 500-MHz instrument, basic 1H NMR spectra could be obtained in 2-3 hr with approximately 100 ng of material in the LC/NMR microprobe. With approximately 1.5 microg of material injected onto the column, 1H-1H correlation spectroscopy spectra could be acquired overnight. Along with LC/MS data, the LC/NMR technique facilitated direct identification of a number of metabolites of LY335979 at a point at which their identification by traditional methods would not have been pursued.


Assuntos
Bile/metabolismo , Dibenzocicloeptenos/química , Dibenzocicloeptenos/metabolismo , Resistência a Múltiplos Medicamentos , Microssomos Hepáticos/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Animais , Bile/química , Cateterismo , Cromatografia Líquida , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Microssomos Hepáticos/química , Ratos , Ratos Endogâmicos F344 , Fatores de Tempo
3.
Adv Enzyme Regul ; 37: 335-47, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9381979

RESUMO

The above data indicate that LY335979 displays the following characteristics of an 'ideal modulator' of Pgp-mediated multidrug resistance: high affinity binding to Pgp, high potency for in vitro reversal of drug resistance, high therapeutic index (activity was demonstrated at doses ranging from 1-30 mg/kg) observed in in vivo antitumor efficacy experiments, and a lack of pharmacokinetic interactions that alter the plasma concentration of coadministered oncolytic agents. These desirable features strongly suggest that LY335979 is an exciting new clinical agent to test the hypothesis that inhibition of P-glycoprotein activity will result in reversal of multidrug resistance in human tumors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Dibenzocicloeptenos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Quinolinas/farmacologia , Tetra-Hidroisoquinolinas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Acridinas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Dibenzocicloeptenos/farmacocinética , Dibenzocicloeptenos/uso terapêutico , Humanos , Isoquinolinas/farmacologia , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/tratamento farmacológico , Quinidina/metabolismo , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Verapamil/metabolismo , Verapamil/farmacologia
4.
Cancer Res ; 56(18): 4171-9, 1996 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-8797588

RESUMO

Overexpression of P-glycoprotein (Pgp) by tumors results in multidrug resistance (MDR) to structurally unrelated oncolytics. MDR cells may be sensitized to these oncolytics when treated with a Pgp modulator. The present study evaluates LY335979 as a modulator both in vitro and in vivo. LY335979 (0.1 microM) fully restored sensitivity to vinblastine, doxorubicin (Dox), etoposide, and Taxol in CEM/VLB100 cells. LY335979 modulated Dox cytotoxicity even when LY335979 (0.5 microM) was removed 24 h prior to the cytotoxicity assay. LY335979 blocked [3H]azidopine photoaffinity labeling of the M(r) approximately 170,000 Pgp in CEM/VLB100 plasma membranes and competitively inhibited equilibrium binding of [3H]vinblastine to Pgp (Ki of approximately 0.06 microM). Treatment of mice bearing P388/ADR murine leukemia cells with LY335979 in combination with Dox or etoposide gave a significant increase in life span with no apparent alteration of pharmacokinetics. LY335979 also enhanced the antitumor activity of Taxol in a MDR human non-small cell lung carcinoma nude mouse xenograft model. Thus, LY335979 is an extremely potent, efficacious modulator that apparently lacks pharmacokinetic interactions with coadministered anticancer drugs and is, therefore, an exciting new agent for clinical evaluation for reversal of Pgp-associated MDR.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dibenzocicloeptenos/farmacologia , Resistência a Múltiplos Medicamentos , Etoposídeo/toxicidade , Leucemia P388/tratamento farmacológico , Leucemia P388/fisiopatologia , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Quinolinas/farmacologia , Vimblastina/toxicidade , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Sítios de Ligação , Linhagem Celular , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dibenzocicloeptenos/uso terapêutico , Etoposídeo/metabolismo , Etoposídeo/uso terapêutico , Humanos , Cinética , Camundongos , Camundongos Nus , Ligação Proteica , Quinolinas/uso terapêutico , Transplante Heterólogo , Células Tumorais Cultivadas , Vimblastina/metabolismo , Vimblastina/uso terapêutico
5.
Chemosphere ; 31(2): 2661-8, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7663950

RESUMO

The urinary metabolites of n-nonane in male Fischer 344 rats, after administering the hydrocarbon by gavage, included gamma-valerolactone, delta-hexanolactone, 2,5-hexanedione, delta-heptanolactone, 1-heptanol, 2-nonanol, 3-nonanol, 4-nonanol, 4-nonanone and 5-methyl-2-(3-oxobutyl)furan. Metabolism strongly favored the formation of monoalcohols and lactones, which are the products of appropriately substituted hydroxy carboxylic acids. The metabolites were identified using gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). High pressure liquid chromatography (HPLC) permitted the detection of the dicarboxylic acids malonic acid and glutaric acid in the n-nonane dosed rat urines.


Assuntos
Alcanos/metabolismo , Álcoois/urina , Alcanos/urina , Animais , Cromatografia Líquida de Alta Pressão , Furanos/urina , Cromatografia Gasosa-Espectrometria de Massas , Hexanonas/urina , Lactonas/metabolismo , Lactonas/urina , Masculino , Ratos , Ratos Endogâmicos F344
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