Renal effects of the cyclooxygenase-inhibiting nitric oxide donator AZD3582 compared with rofecoxib and naproxen during normal and low sodium intake.
BACKGROUND
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) and can thereby reduce renal function, especially with respect to solute excretion and renal perfusion. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donator. Donation of nitric oxide by AZD3582 could preserve blood flow and thereby counteract the deleterious effects of COX inhibition in the gastrointestinal tract and possibly in other organ systems, including the kidney. The aim of this single-dose study was to assess the hypothesis that AZD3582 would not adversely affect renal function compared with NSAIDs.


METHODS
In a parallel, randomized, double-blind fashion, a total of 60 healthy subjects (age range, 20-44 years) received 2 single doses of 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, 500 mg naproxen, or placebo (n = 12 per group). The first dose was given after a 5-day normal-sodium diet (150 mmol/d), and the second was given after a consecutive 3-day low-sodium diet (10 mmol/d). Urinary sodium excretion during normal sodium intake and glomerular filtration rate (GFR) (assessed by iohexol clearance) during sodium depletion were the primary variables measured.


RESULTS
Urinary sodium excretion was reduced in all active treatment groups (maximal reduction of approximately 11 mmol/h during normal sodium intake, P < .05 versus placebo for all groups). GFR was also reduced in all active treatment groups. In sodium-depleted subjects, the mean (SD) maximal reduction in GFR during 0 to 6 hours for 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, and 500 mg naproxen was 28.1 mL/min (13.5 mL/min), 33.7 mL/min (23.3 mL/min), 25.2 mL/min (29.2 mL/min), and 41.7 mL/min (30.7 mL/min), respectively, with a statistically significant difference between 500 mg naproxen and placebo. Relative changes in sodium excretion and GFR were similar during normal sodium intake and sodium depletion during active treatment.


CONCLUSIONS
The renal effects of 750 mg and 1500 mg AZD3582 were similar to those of 500 mg naproxen and 50 mg rofecoxib. Thus the potential for nitric oxide donation to create a renal-sparing agent was not found for AZD3582.
Huledal
Gunilla
G
Experimental Medicine, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden. gunilla.huledal@astrazeneca.com
Jonzon
Bror
B
Malmenäs
Maria
M
Hedman
Ann
A
Andersson
Lars I
LI
Odlind
Bo
B
Brater
D Craig
DC
D000328:Adult; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004039:Diet, Sodium-Restricted; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007472:Iohexol; D007783:Lactones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009288:Naproxen / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000031:analogs & derivatives; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011188:Potassium / Q000652:urine; D012083:Renin / Q000097:blood / Q000187:drug effects; D012964:Sodium / Q000097:blood / Q000652:urine; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D009281:Naphthalenes; D020030:Nitric Oxide Donors; D013450:Sulfones; C111751:naproxen-n-butyl nitrate; C116926:rofecoxib; D007472:Iohexol; D009288:Naproxen; D012964:Sodium; D012083:Renin; D011188:Potassium