Biochemical activity, pharmacokinetics and tolerability of tepoxalin, a cyclooxygenase/5-lipoxygenase inhibitor, in man

Tepoxalin, a novel inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5-LO), was investigated for biochemical activity and pharmacokinetics in two studies. Study I was a 4-period, double-blind, randomized, single rising dose using 2 alternating panels (A, B) with interspersed placebo design (A : 25, 100, 400mg, B : 50, 200, 800 mg p.o.). Study II was a 3-panel, randomized, placebo-controlled, double-blind, multiple dose study (A : 100mg, B : 200 mg, C : 400mg). In both studies, CO inhibition was assessed by generation of serum thromboxane (TxB 2 ), 5-LO activity by LTB 4 production ex vivo in Ca-ionophore-stimulated blood. Plasma drug concentrations were assayed by HPLC for tepoxalin and its identified acid metabolite. It was found in both studies that at all dose levels the TxB 2 generation was markedly suppressed (>95% 2 h postdose). In study I, at 2 h postdose, % inhibition of LTB 4 biosynthesis was marginal for the 3 lower doses but significant at 200 (14%), 400 (25%) and 800 mg (43%). In study II, the only significant inhibition occurred at the 400 mg dose at 6 h postdose on day 1 (17%) and on day 8 at 4, 6 and 8h postdose (32, 42 and 32% respectively). In both studies and at all doses, plasma concentrations of tepoxalin varied widely between subjects. Linearity between plasma concentrations and dose could not be ascertained, and correlation between drug plasma levels and effect on LTB 4 synthesis was poor. Single doses up to 800 mg and multiple doses up to 400mg of tepoxalin were generally well tolerated.