Renal effects of nabumetone, a COX-2 antagonist: Impairment of function inisolated perfused rat kidneys contrasts with preserved renal function in vivo

The constitutive cyclooxygenase (COX)-1 enzyme has been considered the phys iologically important isoform for prostaglandin synthesis in the normal kid ney. It has, therefore, been suggested that selective inhibitors of the 'in ducible' isoform (COX-2) may be free from renal adverse effects. We studied the renal effects of the predominantly COX-2 antagonist nabumetone in isol ated perfused kidneys. As compared with controls, kidneys removed after in vivo administration of oral nabumetone (15 mg/kg) disclosed altered renal f unction with reduced glomerular filtration rate, filtration fraction, and u rine volume and enhanced hypoxic outer medullary tubular damage. By contras t, renal function and morphology were not affected in vivo by nabumetone or its active metabolite 6-methoxy-2-naphthylacetic acid. The latter agent (1 0-20 mg/kg i.v.) did not significantly alter renal microcirculation, as opp osed to a selective substantial reduction in medullary blood flow noted wit h the nonselective COX inhibitor indomethacin (5 mg/kg i.v.). In a rat mode l of acute renal failure, induced by concomitant administration of radiocon trast, nitric oxide synthase, and COX inhibitors, the decline in kidney fun ction and the extent of hypoxic medullary damage with oral nabumetone (80 m g/kg) were comparable to a control group, and significantly less than those induced by indomethacin. In rats subjected to daily oral nabumetone for 3 consecutive weeks, renal function and morphology were preserved as well. Bo th nabumetone and 6-methoxy-2-naphthylacetic acid reduced renal parenchymal prostaglandin E-2 to the same extent as indomethacin. It is concluded that while nabumetone adversely affects renal function and may intensify hypoxi c medullary damage ex vivo, rat kidneys are not affected by this agent in v ivo, both in acute and chronic studies. COX selectivity may not explain the renal safety of nabumetone. Copyright (C) 2001 S. Karger AG, Basel.