Pharmacokinetic and pharmacodynamic interaction between the lipoxygenase inhibitor MK-0591 and the cyclooxygenase inhibitor ibuprofen in man.
Twelve healthy male subjects participated in a double-blind, placebo-controlled, randomized, three-period, crossover study to investigate the safety, tolerability, biochemical activity and pharmacokinetics of ibuprofen, a cyclooxygenase inhibitor and MK-0591, a 5-lipoxygenase inhibitor, given as single entities and in combination. Each subject received for three consecutive 8-day periods, separated by 1 week washout, each of the following treatments: ibuprofen 600 mg three times a day with 125 mg MK-0591 twice a day, ibuprofen 600 mg three times a day with placebo for MK-0591 and MK-0591 125 mg twice a day with placebo for ibuprofen. Cyclooxygenase inhibition was measured by platelet thromboxane (TxB2) generation test, and 5-lipoxygenase inhibition was measured by urinary leukotriene E4 excretion and ex vivo LTB4 generation in calcium-ionophore-stimulated blood. TxB2 suppression on day 8 by ibuprofen was not affected by concomitant treatment with MK-0591. MK-0591 alone had no effect on TxB2 generation. Leukotriene biosynthesis was inhibited by more than 90% by MK-0591 alone and by combined treatment, while ibuprofen alone had no effect. Coadministration appears to affect the pharmacokinetics of MK-0591 (decrease of area under the plasma concentration-vs-time curve [AUC] and maximum plasma concentrations [Cmax]) and of ibuprofen (increase of AUC and half-lives of elimination (t1/2) of the (S)-enantiomer, increase of t1/2 the (R)-enantiomer). Combined treatment had no effect on creatinine clearance nor on the number and intensity of the reported adverse experiences.
Centre of Clinical Pharmacology, Catholic University of Leuven, Belgium.
M
M
Depré
A
A
Van Hecken
R
R
Verbesselt
I
I
De Lepeleire
J
J
Schwartz
A
A
Porras
P
P
Larson
C
C
Lin
P J
PJ
De Schepper
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics*; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism*; D004311:Double-Blind Method; D004347:Drug Interactions; D004361:Drug Tolerance; D006801:Humans; D007052:Ibuprofen / Q000493:pharmacokinetics*; D007211:Indoles / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007975:Leukotriene B4 / Q000097:blood / Q000378:metabolism; D017999:Leukotriene E4 / Q000378:metabolism / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics*; D008297:Male; D011804:Quinolines / Q000493:pharmacokinetics*; D013929:Thromboxane B2 / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C078266:MK 0591; D007975:Leukotriene B4; D013929:Thromboxane B2; D017999:Leukotriene E4; D007052:Ibuprofen