Metabolism, Excretion and Pharmacokinetics of MLN3897, a CCR1 Antagonist, in Humans.
Drug Metab Lett
; 10(1): 22-37, 2016.
Article
em En
| MEDLINE
| ID: mdl-26031460
ABSTRACT
UNLABELLED MLN3897 is a small molecule antagonist of the C-C chemokine receptor-1. Since preclinical studies showed that the molecule was metabolized into two halves, the metabolism, excretion, and pharmacokinetics of MLN3897 were investigated in humans using MLN3897 14C-radiolabeled either on the chlorophenyl (CP) or the tricyclic (TC) half of MLN3897 after an oral dose. OBJECTIVE:
To evaluate the mass balance, metabolism and pharmacokinetics of MLN3897 in two cohorts of six randomized healthy subjects.METHOD:
After receiving informed consent, subjects were dosed after an overnight fast of 10-hours followed by at least 4- hours after dosing on day-1. Each cohort received a single 29 mg oral dose of either the CP or the TC as an oral solution in water. Serial blood samples, urine and feces were collected over a 10-day period post-dose.RESULTS:
For both radiolabeled moieties, 55-59% of the dose was recovered in feces and 32% recovered in urine. MLN3897 was metabolized extensively in humans, with minor amounts of intact MLN3897 detected in the urine and feces. N-oxidation of the tricyclic moiety (M28) and N-dealkylation of the piperidinyl moiety were the primary metabolic pathways leading to further formation of the carboxylic acid metabolite (M19) and the (4-(4-chlorophenyl)-3,3- dimethylpiperidin-4-ol) metabolite (M40). Oxidative metabolites M11, M19, M28, M44 were present at >10% of the total circulating radioactivity and also at >25% of MLN3897 exposure. Metabolites resulting from the chlorophenyl-labeled moiety (M40) had significantly more systemic exposure compared to the tricyclic-labeled moiety (M19).
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores CCR1
/
Anti-Inflamatórios
Tipo de estudo:
Clinical_trials
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Drug Metab Lett
Assunto da revista:
FARMACOLOGIA
/
METABOLISMO
Ano de publicação:
2016
Tipo de documento:
Article