Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females.
OBJECTIVE
The safety, tolerability, and pharmacokinetics of intravenous *i.v.) montelukast sodium (Singulair, MK-0476), and the oral bioavailability of montelukast sodium in healthy males and healthy females were studied.


METHODS
This was a two-part study. Part I was a four-period study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as 15-minute constant-rate i.v. infusions (Periods 1-3), followed by a 10-mg oral tablet dose of montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females of i.v. montelukast sodium (9 mg) infused over 15 and 5 minutes (Periods 5 and 6, respectively) or injected as a bolus over 2 minutes (Period 7), followed by a 10-mg oral tablet dose of montelukast sodium (Period 8). Plasma samples were collected and analyzed by HPLC.


RESULTS
In males (N = 6), as the i.v. dose of montelukast sodium increased from 3 to 18 mg, the area under the plasma concentration-time curve of montelukast sodium from time 0 to infinity (AUC) increased proportionately. The mean values of plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/12), and mean residence time in the body (MRTi.v.) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and remained essentially constant over the i.v. dosage range. Following oral administration of a 10-mg tablet of montelukast sodium, the AUC, maximum plasma concentration (Cmax), time when Cmax occurred (Tmax), apparent t1/12, mean absorption time (MAT), and bioavailability (F) of montelukast sodium averaged 2441 ng.hr/ml, 385 ng/ml. 3.7 hr, 4.9 hr, 3.4 hr, and 66%, respectively. Following i.v. administration of 9 mg of montelukast sodium to females (N = 6), the values of CL, Vss, t1/2, and MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respectively. Following oral administration of a 10-mg tablet to females, the mean AUC, Cmax, Tmax, apparent t1/2, MAT and F were 2270 ng.hr/ml, 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively. These parameter values were similar to or slightly smaller than those in healthy males receiving the same i.v. and oral doses.


CONCLUSIONS
The disposition kinetics of montelukast sodium were linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral dose are well tolerated.
Cheng
H
H
Merck Research Laboratories, Department of Drug Metabolism, West Point, Pennsylvania 19486, USA.
Leff
J A
JA
Amin
R
R
Gertz
B J
BJ
De Smet
M
M
Noonan
N
N
Rogers
J D
JD
Malbecq
W
W
Meisner
D
D
Somers
G
G
D000085:Acetates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000328:Adult; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D020024:Leukotriene Antagonists; D008297:Male; D008565:Membrane Proteins; D010919:Placebos; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018077:Receptors, Leukotriene; D012737:Sex Factors; D013440:Sulfides
D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D010919:Placebos; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor; C093875:montelukast