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1.
Xenobiotica ; 40(9): 650-62, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20608842

RESUMEN

The metabolism and excretion of taranabant (MK-0364, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2{[5-(trifluoromethyl)pyridine-2-yl]oxy}propanamide), a potent cannabinoid-1 receptor inverse agonist, were evaluated in rats and rhesus monkeys. Following administration of [¹4C]taranabant, the majority of the radioactivity was excreted within 72 h. In both rats and rhesus monkeys, taranabant was eliminated primarily via oxidative metabolism, followed by excretion of metabolites into bile. Major pathways of metabolism that were common to rats and rhesus monkeys included hydroxylation at the benzylic carbon adjacent to the cyanophenyl ring to form a biologically active circulating metabolite M1, and oxidation of one of the two geminal methyl groups of taranabant or M1 to the corresponding diastereomeric carboxylic acids. Oxidation of the cyanophenyl ring, followed by conjugation with glutathione or glucuronic acid, was a major pathway of metabolism only in the rat and was not detected in the rhesus monkey. Metabolism profiles of taranabant in liver microsomes in vitro were qualitatively similar in rats, rhesus monkeys and humans and included formation of M1 and oxidation of taranabant or M1 to the corresponding carboxylic acids via oxidation of a geminal methyl group. In human liver microsomes, metabolism of taranabant was mediated primarily by CYP3A4.


Asunto(s)
Amidas/metabolismo , Agonismo Inverso de Drogas , Piridinas/metabolismo , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Amidas/sangre , Amidas/química , Amidas/farmacocinética , Animales , Anticuerpos Monoclonales/farmacología , Líquidos Corporales/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Femenino , Haplorrinos , Humanos , Cetoconazol/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Piridinas/sangre , Piridinas/química , Piridinas/farmacocinética , Radiactividad , Ratas
2.
Xenobiotica ; 37(5): 487-502, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17523052

RESUMEN

BIO1211 is a small peptidyl potent antagonist of the activated form of alpha4beta1 integrin. The effect of enalapril on the in vitro and in vivo cleavage of BIO1211 was investigated. In heparinized blood, plasma and rat liver, lung and intestinal homogenates, BIO1211 was converted rapidly to BIO1588 by hydrolytic cleavage of the terminal dipeptide moiety. This cleavage could be inhibited by EDTA and the ACE inhibitor, enalaprilat, the de-esterified acid derivative of enalapril. Enalaprilat inhibited the hydrolysis of BIO1211 in a concentration-dependent manner with IC(50) values of 2 nM in human and sheep plasma and 10 nM in rat plasma. In rat lung homogenate supernatant, the maximum inhibition of the conversion of BIO1211 to BIO1588 was approximately 80% at 1 microM with no further effect up to 100 microM of enalaprilat. Following a concomitant IV administration of enalapril and BIO1211 at 3 mg/kg each, the AUC and the half-life values of BIO1211 increased 18- and 10-fold, respectively. The AUC of BIO1588 decreased approximately 2-fold with no change in its plasma half-life. When rats were dosed intravenously with enalapril followed by an intratracheal dose of BIO1211, there was approximately 2.5-fold decrease in the AUC of BIO1588 and a 2.4-fold increase in its plasma half-life.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Enalapril/farmacología , Integrina alfa4beta1/antagonistas & inhibidores , Oligopéptidos/metabolismo , Oligopéptidos/farmacología , Animales , Biotransformación/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Estabilidad de Medicamentos , Enalaprilato/farmacología , Humanos , Hidrólisis/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Oligopéptidos/sangre , Oligopéptidos/farmacocinética , Especificidad de Órganos/efectos de los fármacos , Peptidil-Dipeptidasa A/aislamiento & purificación , Peptidil-Dipeptidasa A/metabolismo , Unión Proteica/efectos de los fármacos , Factores de Tiempo
3.
Xenobiotica ; 37(5): 514-33, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17523054

RESUMEN

MK-0524 is a potent, selective and orally active Prosglandin D(2) Receptor 1 (DP(1)) antagonist currently under clinical development for the treatment of niacin-induced flushing. Experiments to study the pharmacokinetics, metabolism and excretion of MK-0524 were conducted in rats, dogs and monkeys. MK-0524 displayed linear kinetics and rapid absorption following an oral dose. Following intravenous (i.v.) administration of MK-0524 to rats and dogs (1 and 5 mg/kg), the mean Cl(p) was approximately 2 and approximately 6 ml/min/kg, the T(1/2) was approximately 7 and approximately 13 h and the Vd(ss) was approximately 1 and approximately 5 L/kg, respectively. In monkeys dosed i.v. at 3 mg/kg, the corresponding values were 8 ml/min/kg, 3 h and 1 L/kg, respectively. Following oral dosing of MK-0524 to rats (5, 25 and 100 mg/kg), dogs (5 mg/kg) and monkeys (3 mg/kg), the absorption was rapid with the mean C(max) occurring between 1 and 4 h. Absolute oral bioavailability values in rats, dogs and monkeys were 50, 70 and 8%, respectively. The major circulating metabolite was the acyl glucuronide of MK-0524 (M2), with ratios of glucuronide to the parent aglycone being highest in the monkey followed by dog and rat. In bile duct-cannulated rats and dogs, MK-0524 was eliminated primarily via acyl glucuronidation followed by biliary excretion of the acyl glucuronide, M2, the major drug-related entity in bile.


Asunto(s)
Haplorrinos/metabolismo , Indoles/farmacología , Indoles/farmacocinética , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Bilis/metabolismo , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Perros , Estabilidad de Medicamentos , Glucurónidos/sangre , Glucurónidos/farmacocinética , Semivida , Humanos , Indoles/química , Indoles/metabolismo , Masculino , Espectrometría de Masas , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
4.
Bioorg Med Chem Lett ; 11(19): 2597-602, 2001 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-11551758

RESUMEN

Stereospecific introduction of a methyl group to the indole-3-side chain enhanced activity in our tryptamine-derived series of GnRH receptor antagonists. Further improvements were achieved by variation of the bicyclic amino moiety of the tertiary amide and by adjustment of the tether length to a pyridine or pyridone terminus. These modifications culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys.


Asunto(s)
Indoles/farmacocinética , Receptores LHRH/antagonistas & inhibidores , Triptaminas/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Perros , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Hormona Luteinizante/metabolismo , Macaca mulatta , Modelos Animales , Ratas , Relación Estructura-Actividad , Triptaminas/síntesis química , Triptaminas/química , Triptaminas/farmacología
5.
Drug Metab Dispos ; 26(10): 949-57, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9763399

RESUMEN

L-732,531 is a semi-synthetic analog of the macrolide tacrolimus (Prograf(R)). Like tacrolimus, L-732,531 is a potent immunosuppressant. In this study, its absorption, distribution, metabolism, and excretion were studied in rats and baboons. In rats, its blood and plasma levels were similar, whereas in baboons, its blood levels were, on average, twice as high as those in plasma. This was consistent with the in vitro blood-to-plasma ratio of L-732, 531, which in these two species, as well as in humans, was much lower than that of tacrolimus and showed a minimal concentration dependence. After iv administration to rats, the blood and plasma clearance of L-732,531 decreased from approximately 60 ml/min/kg at 0.2 mg/kg to 30 ml/min/kg when dosed at 1 and 3 mg/kg. After oral administration, plasma area under the concentration vs. time curve (AUC) and maximal plasma concentration (Cmax) increased more than proportionally to the dose. At 1, 5, and 15 mg/kg, plasma AUC was 29, 466, and 2832 ng.hr/ml, respectively, and Cmax was 10, 129, and 304 ng/ml, respectively. Bioavailability, although compromised by nonlinear kinetics, was estimated to be between 8% and 18%. In baboons, the clearance of L-732,531 was lower than that in rats, especially when calculated from blood concentrations (12 ml/min/kg at 0.2 mg/kg and 8 ml/min/kg at 1 mg/kg). After oral dosing, baboon plasma AUC and Cmax were much lower than those in rats, but as in rats, they increased more than proportionally with increasing doses. The bioavailability of L-732,531 in baboons was estimated at 3%, 9%, and 24% when animals were dosed at 5, 15, and 26 mg/kg po, respectively. After oral administration of [3H]L-732,531 at 5 mg/kg, approximately 32% of the radioactivity was recovered in bile and urine of rats, compared with 9% in baboons. High-performance liquid chromatography profiles of rat and baboon plasma, bile, urine, and feces indicated that L-732,531 was metabolized extensively to a complex mixture of products. Some intact parent drug was observed in feces of orally dosed animals, indicating incomplete absorption. In vitro, L-732,531 was metabolized more extensively by baboon liver microsomes than rat or human microsomes. Its metabolism in human liver microsomes was shown to be catalyzed primarily by cytochrome P450 3A isozymes.


Asunto(s)
Inmunosupresores/farmacocinética , Tacrolimus/análogos & derivados , Animales , Área Bajo la Curva , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Inmunosupresores/sangre , Isoenzimas/metabolismo , Masculino , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Papio , Ratas , Ratas Sprague-Dawley , Tacrolimus/sangre , Tacrolimus/farmacocinética , Distribución Tisular
6.
Drug Metab Dispos ; 25(8): 932-9, 1997 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-9280401

RESUMEN

The disposition of L-694,458, a potent monocyclic beta-lactam inhibitor of human leukocyte elastase, was studied in male Sprague-Dawley rats and rhesus monkeys. After iv dosing, L-694,458 exhibited similar pharmacokinetic parameters in rats and rhesus monkeys. The mean values for its plasma clearance, terminal half-life, and volume of distribution at steady state were 27 ml/min/kg, 1.8 hr, and 4.0 liters/kg in rats and 34 ml/min/kg, 2.3 hr, and 5 liters/kg in rhesus monkeys. The bioavailability of a 10 mg/kg oral dose was higher in rats (65%) than in rhesus monkeys (39%). In both species, concentrations of L-694,458 in plasma increased more than proportionally when the oral dose was increased from 10 mg/kg to 40 mg/kg. In monkeys a protracted plasma concentration-time profile was observed at 40 mg/kg, characterized by a delayed T(max) (8-24 hr) and a long terminal half-life (6 hr). [3H]L-694,458 was well absorbed after oral dosing to rats at 10 mg/kg, as indicated by the high recovery of radioactivity in bile (83%) and urine (6%) of bile duct-cannulated rats. Only approximately 5% or less of the radioactivity in bile, urine, and feces was a result of intact L-694,458, indicating that the compound was being eliminated by metabolism, followed by excretion of the metabolites in feces, via bile. Demethylenation of the methylenedioxyphenyl group resulting in the catechol was the primary metabolic pathway in human and rhesus monkey liver microsomes. In rat liver microsomes, the major metabolite was the N-oxide of the methyl-substituted piperazine nitrogen. In rats dosed iv and orally with [3H]L-694,458, concentrations of radioactivity were highest in the lung (the primary target tissue), adrenals, and liver. L-694,458 was unstable in rat blood and plasma, degrading via a pathway believed to be catalyzed by B-esterases and to involve cleavage of the beta-lactam ring and loss of the methylpiperazine phenoxy group. In vitro studies indicated that in human liver, L-694,458 was metabolized by CYP3A and 2C isozymes, and in both monkey and human liver microsomes the compound acted as an inhibitor of testosterone 6beta-hydroxylation.


Asunto(s)
Azetidinas/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Elastasa de Leucocito/antagonistas & inhibidores , Piperazinas/farmacocinética , Administración Oral , Animales , Azetidinas/administración & dosificación , Azetidinas/sangre , Disponibilidad Biológica , Sistema Enzimático del Citocromo P-450/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/sangre , Humanos , Isoenzimas/metabolismo , Macaca mulatta , Masculino , Piperazinas/administración & dosificación , Piperazinas/sangre , Ratas , Ratas Sprague-Dawley , Testosterona/metabolismo
8.
Arch Biochem Biophys ; 294(2): 454-60, 1992 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-1373595

RESUMEN

The metabolism of the immunosuppressant FK-506 was shown to be catalyzed primarily by cytochrome P450 isozymes of the P450 3A subfamily. Antibodies against rat P450 3A inhibited FK-506 metabolism by 82% in rat liver microsomes and by 35-56% in liver microsomes from humans, dexamethasone-induced rats, and erythromycin-induced rabbits. Poor species cross-reactivity of the antibodies, metabolic switching, and/or some metabolism by P450 isozymes other than P450 3A may be responsible for the incomplete inhibition observed. Besides anti-rat P450 3A, antibodies against rat P450 1A also appeared to have some inhibitory effect implicating these particular cytochrome P450 isozymes as having a minor role in FK-506 metabolism. The formation of 13-desmethyl FK-506, identified here as a major metabolite of FK-506 in all types of microsomes examined, was inhibited completely by anti-P450 3A in liver microsomes from dexamethasone-induced rats and erythromycin-induced rabbits but only partially in human and control rat liver microsomes.


Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Microsomas Hepáticos/enzimología , Oxigenasas de Función Mixta/metabolismo , Tacrolimus/metabolismo , Adulto , Animales , Anticuerpos , Biotransformación , Radioisótopos de Carbono , Citocromo P-450 CYP2E1 , Dexametasona/farmacología , Femenino , Humanos , Cinética , Masculino , Microsomas Hepáticos/efectos de los fármacos , Proadifeno/farmacología , Conejos , Ratas , Ratas Endogámicas , Troleandomicina/farmacología
9.
Biochem Pharmacol ; 41(9): 1325-30, 1991 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-1708254

RESUMEN

The novel immunosuppressant FK-506 and its analog FK-520 were found to inhibit the hepatic microsomal mixed-function oxidase system in male Sprague-Dawley rats. At 5 and 10 mg/kg/day, s.c., for 6 days they caused 30-80% decreases in cytochrome P450 levels, NADPH-cytochrome P450 reductase, and benzphetamine N-demethylase activities. The metabolism of FK-506 itself was inhibited by 50%. FK-506 and FK-520 had a minimal effect on the renal cytochrome P450 levels unlike cyclosporin A which produced a 67% increase after six daily 25 mg/kg doses. A single dose of FK-506 (25 mg/kg, s.c.) had a minimal effect on the hepatic or renal metabolizing enzyme system. In vitro, addition of FK-506 and FK-520 to human and control rat liver microsomes resulted in a concentration-dependent inhibition of benzphetamine N-demethylation (10-20% at 50 microM, 60-75% at 250 microM). We suggest that in view of its potential to inhibit hepatic cytochrome P450-dependent mixed-function oxidase, resulting in the inhibition of its own metabolism, FK-506 should be administered with caution to transplant patients.


Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Inmunosupresores/farmacología , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Oxigenasas de Función Mixta/antagonistas & inhibidores , Piperidinas/farmacología , 7-Alcoxicumarina O-Dealquilasa/antagonistas & inhibidores , Adulto , Animales , Antibacterianos/efectos adversos , Ciclosporinas/farmacología , Sistema Enzimático del Citocromo P-450 , Femenino , Humanos , Riñón/enzimología , Hígado/enzimología , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Oxidorreductasas N-Desmetilantes/antagonistas & inhibidores , Ratas , Ratas Endogámicas , Tacrolimus
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