The bioavailability and nonlinear pharmacokinetics of MK-679 in humans.
MK-679 (R(-)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3- (dimethylamino)-3-oxo-propyl)thio)methyl)thio)propanoic acid) is a potent and specific LTD4-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration-time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg 14C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.
Cheng
H
H
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486.
Schwartz
J I
JI
Lin
C
C
Amin
R D
RD
Seibold
J R
JR
Lasseter
K C
KC
Ebel
D L
DL
Tocco
D J
DJ
Rogers
J D
JD
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D011422:Propionates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D001993:Bronchodilator Agents; D011422:Propionates; D011804:Quinolines; C059141:verlukast