title: Preclinical pharmacokinetics of MK-0974, an orally active calcitonin-gene related peptide (CGRP)-receptor antagonist, mechanism of dose dependency and species differences.
abstract: The underlying mechanism for low oral bioavailability of MK-0974, a potent calcitonin-gene related peptide (CGRP)-receptor antagonist, in monkeys and for species-dependent non-linear pharmacokinetics in monkeys and rats were investigated. In monkeys, MK-0974 displayed moderate clearance (14-20 ml min(-1) kg(-1)), while oral bioavailability was 6%. The pharmacokinetics of MK-0974 remained linear across 0.5-10 mg kg(-1) intravenous dose in monkeys, but the oral area under the plasma concentration-time curve (AUC) increase (5-30 mg kg(-1)) was 15-fold over dose-proportional. Based on a comparison of AUC following hepatic portal vein administration and cephalic vein infusion, MK-0974 exhibited a low-to-moderate hepatic extraction ratio (36%) in monkeys. Following oral dose of [14C]MK-0974 to monkeys, the hepatic portal AUC ratio of MK-0974 versus total radioactivity was 0.32, and the total radioactivity recovered in bile and urine was 45-83%. MK-0974 undergoes significant oxidative metabolism (cytochrome P450 (CYP) 3A) in monkey intestinal microsomes. In contrast, oral AUC of MK-0974 in rats was near dose-proportional (15-100 mg kg(-1)). Following oral administration of [14C]MK-0974 to rats, the hepatic portal AUC ratio of MK-0974 to total radioactivity (0.67) was higher than in monkeys. Additionally, the metabolic rate of MK-0974 was slower in rat than in monkey intestinal microsomes. Collectively, intestinal first-pass metabolism played a significant role in the low oral bioavailability in monkeys and contributed to the species-dependent non-linear oral pharmacokinetics in rats and monkeys of MK-0974.
authors.affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Roller
authors.forename: D
authors.initials: D
authors.lastname: Cui
authors.forename: C
authors.initials: C
authors.lastname: Laspina
authors.forename: C
authors.initials: C
authors.lastname: Miller-Stein
authors.forename: J
authors.initials: J
authors.lastname: Rowe
authors.forename: B
authors.initials: B
authors.lastname: Wong
authors.forename: T
authors.initials: T
authors.lastname: Prueksaritanont
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004353:Drug Evaluation, Preclinical; D007093:Imidazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007421:Intestine, Small / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; C525458:telcagepant