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The bioavailability and nonlinear pharmacokinetics of MK‐679 in humans
Author(s) -
Cheng Haiyung,
Schwartz Jules I.,
Lin Charles,
Amin Raju D.,
Seibold James R.,
Lasseter Kenneth C.,
Ebel David L.,
Tocco Dominick J.,
Rogers J. Douglas
Publication year - 1994
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510150507
Subject(s) - bioavailability , pharmacokinetics , chemistry , thio , pharmacology , antagonist , propanoic acid , oral administration , disposition , distribution (mathematics) , stereochemistry , receptor , biochemistry , medicine , psychology , social psychology , mathematical analysis , mathematics
MK‐679 (R(−)‐3‐((3‐(2‐(7‐chloro‐2‐quinolinyl)ethenyl)phenyl)(3‐(dimethylamino)‐3‐oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD 4 ‐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 14 C‐MK‐679. Results of this study indicate that the oral bioavailability of MK‐679 is nearly quantitative.