PLASMA DRUG PROFILES AND TOLERABILITY OF MK-571 (L-660,711), A LEUKOTRIENE D4 RECEPTOR ANTAGONIST, IN MAN

We have studied the tolerability and plasma drug profiles of a leukotriene D4 receptor antagonist, MK-571, given intravenously and as an oral solution in two separate trials. Study I (i.v.) involved 2 panels of 6 healthy men in a double-blind, alternating, incrementally increasing dose study with single doses up to 1500 mg. There was good tolerability at all doses. Plasma was assayed stereospecifically by HPLC for the S(+) and R(-) enantiomers of MK-571. For each enantiomer AUC values increased more than proportionately with increasing dose, suggesting nonlinear kinetics. The S(+) enantiomer was cleared more rapidly than the R(-) enantiomer. The apparent initial volume of distribution was less than 10 l for both enantiomers. Study II (oral) involved 18 healthy subjects in 3 parallel groups who took multiple oral doses of 100, 300, and 600 mg t.i.d. for 31 doses. MK-571 administration was well tolerated, with only mild to moderate gastrointestinal discomfort at the highest dose. Total MK-571 (plasma samples assayed nonstereoselectively) was rapidly absorbed after oral administration, reaching peak concentrations at 1-2 h. Mean 8 h AUC increased from dose 1 to dose 31 in all subjects at all doses, suggesting a modest extent of accumulation (about 50%) of total MK-571 in plasma with a t.i.d. dosage regimen.