Clinical pharmacokinetics of the cyclooxygenase inhibiting nitric oxide donator (CINOD) AZD3582

Abstract

Abstract The clinical pharmacokinetics of the COX-inhibiting nitric oxide donator (CINOD) AZD3582 and its metabolites, including naproxen, nitric oxide and nitrate, are summarized. AZD3582 has low aqueous solubility, moderate and passive intestinal permeability and is degraded by intestinal esterases. Its oral bioavailability (F) appears to be maximally a few per cent, and increases by several-fold after food intake. Ninety-four per cent or more of an AZD3582 dose is absorbed, of which at least 9–20% appears to be taken up as intact substance. AZD3582 has a predicted plasma protein binding degree of ∼ 0.1%, a half-life (t½) of 3 to 10 h and does not accumulate after repeated once- and twice-daily dosing. In patients AZD3582 does not provide a significantly better gastrointestinal (GI) side-effect profile than the highly permeable and locally irritating naproxen. Possible reasons for this include considerable GI uptake as naproxen, limited duration and extent of nitric oxide donation in the GI mucosa and the circulation, tolerance development (involving auto-inhibition of nitric oxide catalysing enzymes) and mucosal damage caused by nitric oxide. Blood pressure data suggest that nitric oxide is mainly donated within 3h. The uptake of naproxen is slightly slower and lower (≥ 94% relative GI uptake and 80–85% relative F) after AZD3582 administration compared with naproxen dosing. The naproxen t½ and trough steady-state concentrations after AZD3582 and naproxen dosing are similar. The average systemic nitrate exposure is approximately doubled after dosing of 375 to 750 mg AZD3582 twice daily.