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.