Pre-clinical pharmacokinetics of the cyclooxygenase-inhibiting nitric oxide donor (CINOD) AZD3582

The pre-clinical pharmacokinetics of AZD3582 (4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate) and its primary metabolites (naproxen and nitrate) were evaluated. AZD3582 had intermediate and passive intestinal permeability (40 times lower than for naproxen), high systemic plasma clearance (CL), substantial gastrointestinal hydrolysis, intermediate volume of distribution (Vss; >or=3.4 L kg-1) and half-life (t1/2; 7 h), negligible plasma protein binding (approximately 0.1%), low/intermediate oral uptake (>or=13% as intact substance) and low and varying oral bioavailability (mean 1.4% in minipigs and 3.9% in dogs). Following administration of therapeutically relevant oral doses, plasma concentrations of AZD3582 were very low (40 h in rats, minipigs and dogs, respectively. The Vss and CL for naproxen were small. Plasma protein binding was extensive, and saturation was observed within the therapeutic dose and concentration range. Intake of food prolonged the systemic absorption of naproxen in the minipig. The pharmacokinetics of naproxen did not show apparent time- or gender-related dependency. Following oral dosing of [3H]-, [14C]- and [15N]-AZD3582, most [14C]- and [3H]-activity was excreted in urine and expired air, respectively. Seventeen per cent of [15N] was recovered in minipig urine as [15N]-nitrate. About 30% of [3H]-activity (naproxen and/or naproxen-related metabolites) was excreted in bile and re-absorbed. Concentrations of [14C]-activity (nitrooxy-butyl group and/or its metabolites) in milk were higher than in plasma and [3H]-activity in milk. [3H]- and [14C]-excretion data indicated that intact AZD3582 was not excreted in urine, bile or milk to a significant extent. There was no apparent consistency between tissue distribution of [14C]- and [3H]-activity in the rat, which suggests rapid and extensive metabolism of extravascularly distributed AZD3582. A substantial increase of plasma nitrate levels was found after single and repeated oral doses of AZD3582 in the minipig. No inhibition or induction of CYP450 was found.