Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2

Abstract

Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A2 and on systemic biosynthesis of prostacyclin in vivo. Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA2-dependent aggregation, induced ex vivo by arachidonic acid (83 +/- 11% vs. 11. 9 +/- 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB2 (-95 +/- 2% vs. -6.9 +/- 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB2 (-70 +/- 9.9% vs. -20.3 +/- 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA2-dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE2 in whole blood ex vivo) to a comparable degree (-93.3 +/- 2% vs. -83 +/- 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF1alpha. These data suggest that (i) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; (ii) comparable COX-2 inhibition is attained by celecoxib (100-800 mg) and ibuprofen (800 mg) after acute dosing; and (iii) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans.

Figure 1

Inhibition of arachidonic acid-induced platelet aggregation ex vivo in volunteers 3 hr after dosing with placebo, 800 mg ibuprofen, and various doses of celecoxib. ∗∗, P < 0.01 for comparisons with placebo.

Figure 2

(A) Inhibition of serum TxB₂, an index of COX-1 activity ex vivo in volunteers 4 hr after receiving placebo, 800 mg ibuprofen, or various doses of celecoxib. ∗, P < 0.05; ∗∗, P < 0.01 for comparisons with placebo. (B) The relationship between log plasma concentration of celecoxib taken 2, 4, 6, and 24 hr after dosing and inhibition of serum TxB₂ expressed as the percentage change from baseline values. A shallow but variable dose response effect is evident (see Results).

Figure 3

Urinary excretion of 11-dehydro TxB₂, a major TxB₂ metabolite largely derived from platelets after placebo (■—■), 800 mg of ibuprofen (▴—▴), and celecoxib at 100 (•—•), 400 (♦—♦), and 800 mg (▾—▾).

Figure 4

(A) Inhibition of LPS-stimulated plasma PGE₂, an index of COX-2 activity, ex vivo in volunteers receiving placebo, 800 mg of ibuprofen, and various doses of celecoxib. ∗∗, P < 0.01 when compared with placebo. (B) The relationship between LPS-stimulated plasma PGE₂ ex vivo, an index of COX-2 activity, and log plasma concentrations of celecoxib 2, 4, 6, and 24 hr after dosing. PGE₂ is expressed as a percentage of predosing values. A steep but variable dose-response is evident. ∗∗, P < 0.01 for comparisons with placebo.