title: Pharmacokinetics and food interaction of MK-462 in healthy males.
abstract: A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5-90 micrograms kg-1 of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 micrograms kg-1 are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 micrograms kg-1. The values of the plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/2), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min-1, 140 L, 1.8 h, and 1.7 h, respectively, and remained essentially constant over the dosage range of 10-60 micrograms kg-1 of IV MK-462. However, as the dose increased from 60 to 90 micrograms kg-1, the mean value of the apparent CL decreased from 1376 to 807 mL min-1. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the Vss value of MK-462 remained essentially constant over the dosage range of 10-90 micrograms kg-1 of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CLd) = 2028 mL min-1, and mean transit time in the peripheral tissues (MTTT) = 0.74 h. The mean values of AUC, Cmax, tmax, and apparent t1/2 of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng.h mL-1, 77 ng mL-1, 1.6 h, and 1.8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by approximately 20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of Cmax and apparent t1/2 of MK-462.
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: H
authors.initials: H
authors.lastname: Cheng
authors.forename: W J
authors.initials: WJ
authors.lastname: Polvino
authors.forename: D
authors.initials: D
authors.lastname: Sciberras
authors.forename: L
authors.initials: L
authors.lastname: Yogendran
authors.forename: K A
authors.initials: KA
authors.lastname: Cerchio
authors.forename: K
authors.initials: K
authors.lastname: Christie
authors.forename: T V
authors.initials: TV
authors.lastname: Olah
authors.forename: D
authors.initials: D
authors.lastname: McLoughlin
authors.forename: I
authors.initials: I
authors.lastname: James
authors.forename: J D
authors.initials: JD
authors.lastname: Rogers
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005069:Evaluation Studies as Topic; D005502:Food; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010919:Placebos; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014230:Triazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014363:Tryptamines
chemical_list: D010919:Placebos; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D014363:Tryptamines; C093622:rizatriptan