title: Renal effects of nabumetone, a COX-2 antagonist: impairment of function in isolated perfused rat kidneys contrasts with preserved renal function in vivo.
abstract: The constitutive cyclooxygenase (COX)-1 enzyme has been considered the physiologically important isoform for prostaglandin synthesis in the normal kidney. It has, therefore, been suggested that selective inhibitors of the 'inducible' isoform (COX-2) may be free from renal adverse effects. We studied the renal effects of the predominantly COX-2 antagonist nabumetone in isolated perfused kidneys. As compared with controls, kidneys removed after in vivo administration of oral nabumetone (15 mg/kg) disclosed altered renal function with reduced glomerular filtration rate, filtration fraction, and urine volume and enhanced hypoxic outer medullary tubular damage. By contrast, renal function and morphology were not affected in vivo by nabumetone or its active metabolite 6-methoxy-2-naphthylacetic acid. The latter agent (10-20 mg/kg i.v.) did not significantly alter renal microcirculation, as opposed to a selective substantial reduction in medullary blood flow noted with the nonselective COX inhibitor indomethacin (5 mg/kg i.v.). In a rat model of acute renal failure, induced by concomitant administration of radiocontrast, nitric oxide synthase, and COX inhibitors, the decline in kidney function and the extent of hypoxic medullary damage with oral nabumetone (80 mg/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. Both nabumetone and 6-methoxy-2-naphthylacetic acid reduced renal parenchymal prostaglandin E2 to the same extent as indomethacin. It is concluded that while nabumetone adversely affects renal function and may intensify hypoxic medullary damage ex vivo, rat kidneys are not affected by this agent in vivo, both in acute and chronic studies. COX selectivity may not explain the renal safety of nabumetone.
authors.affiliation: Department of Medicine, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Reichman
authors.forename: S
authors.initials: S
authors.lastname: Cohen
authors.forename: M
authors.initials: M
authors.lastname: Goldfarb
authors.forename: A
authors.initials: A
authors.lastname: Shina
authors.forename: S
authors.initials: S
authors.lastname: Rosen
authors.forename: M
authors.initials: M
authors.lastname: Brezis
authors.forename: F
authors.initials: F
authors.lastname: Karmeli
authors.forename: S N
authors.initials: SN
authors.lastname: Heyman
mesh_terms: D058186:Acute Kidney Injury / Q000503:physiopathology; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000502:physiology / Q000503:physiopathology*; D008297:Male; D009280:Naphthaleneacetic Acids / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013997:Time Factors
chemical_list: D016861:Cyclooxygenase Inhibitors; D009280:Naphthaleneacetic Acids; C044612:6-methoxy-2-naphthylacetic acid; D015232:Dinoprostone