The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans.
Drug Metab Dispos
; 42(4): 759-73, 2014 Apr.
Article
en En
| MEDLINE
| ID: mdl-24464803
ABSTRACT
Tofacitinib is a novel, oral Janus kinase inhibitor. The objectives of this study were to summarize the pharmacokinetics and metabolism of tofacitinib in humans, including clearance mechanisms. Following administration of a single 50-mg (14)C-labeled tofacitinib dose to healthy male subjects, the mean (standard deviation) total percentage of administered radioactive dose recovered was 93.9% (±3.6), with 80.1% (±3.6) in the urine (28.8% parent), and 13.8% (±1.9) in feces (0.9% parent). Tofacitinib was rapidly absorbed, with plasma concentrations and total radioactivity peaking at around 1 hour after oral administration. The mean terminal phase half-life was approximately 3.2 hours for both parent drug and total radioactivity. Most (69.4%) circulating radioactivity in plasma was parent drug, with all metabolites representing less than 10% each of total circulating radioactivity. Hepatic clearance made up around 70% of total clearance, while renal clearance made up the remaining 30%. The predominant metabolic pathways of tofacitinib included oxidation of the pyrrolopyrimidine and piperidine rings, oxidation of the piperidine ring side-chain, N-demethylation and glucuronidation. Cytochrome P450 (P450) profiling indicated that tofacitinib was mainly metabolized by CYP3A4, with a smaller contribution from CYP2C19. This pharmacokinetic characterization of tofacitinib has been consistent with its clinical experience in drug-drug interaction studies.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piperidinas
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Pirimidinas
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Pirroles
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Hidrocarburo de Aril Hidroxilasas
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Inhibidores de Proteínas Quinasas
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Citocromo P-450 CYP3A
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Quinasas Janus
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Hígado
Límite:
Female
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Humans
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Male
Idioma:
En
Revista:
Drug Metab Dispos
Asunto de la revista:
FARMACOLOGIA
Año:
2014
Tipo del documento:
Article