Tacrolimus and nonsteroidal anti-inflammatory drugs: an association to be avoided.
BACKGROUND
Tacrolimus (FK) and nonsteroidal anti-inflammatory drugs (NSAIDs) can cause acute nephrotoxicity. The expanding use of tacrolimus and the intense consumption of NSAIDS increase the chances of their simultaneous use.


METHODS
Rats receiving a nonselective COX inhibitor (diclofenac, D) and FK or a selective COX-2 inhibitor (rofecoxib, RO) and FK were treated with FK (2 mg/kg/day), D (10 mg/kg/day), RO (3 mg/kg/day), FK+D, FK+RO and vehicle for 7 days on low-salt diet.


RESULTS
Both associations significantly impaired glomerular filtration rate (GFR; 0.63 +/- 0.06 ml/min/100 g in FK+D, 0.83 +/- 0.06 ml/min/100 g in FK+RO) which did not occur with single drug therapy (0.98 +/- 0.03 ml/min/100 g in D, 1.06 +/- 0.04 ml/min/100 g in RO, 0.99 +/- 0.05 ml/min/ 100 g in FK) or vehicle (1.10 +/- 0.05 ml/min/100 g). GFR decrease was significantly higher with FK+D. GFR impairment occurred without RBF or RVR major changes. Mild tubular vacuolization and dilatation and acute degenerative changes were observed in tubular cells. FK+D animals showed a marked weight loss, not observed in the other groups. FK+NSAIDs association decreased FK blood levels (1.73 +/- 0.3 ng/ml in FK+D, 1.8 +/- 0.3 ng/ml in FK+RO, 3.2 +/- 0.4 ng/ml in FK, p < 0.05).


CONCLUSIONS
The association of FK and nonselective or COX-2 selective NSAIDs in salt-depleted animals caused a significant GFR impairment and decreased FK blood levels.
Division of Nephrology, São José do Rio Preto Medical School, São Paulo, Brazil.
Rosa Maria C
RM
Soubhia
Glória Elisa F
GE
Mendes
Francine Zocoler
FZ
Mendonça
Maria Alice S
MA
Baptista
José Paulo
JP
Cipullo
Emmanuel A
EA
Burdmann
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D004008:Diclofenac / Q000009:adverse effects / Q000494:pharmacology; D004357:Drug Synergism; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007783:Lactones / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D051381:Rats; D013450:Sulfones / Q000009:adverse effects / Q000494:pharmacology; D016559:Tacrolimus / Q000009:adverse effects* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007166:Immunosuppressive Agents; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D004008:Diclofenac; D016559:Tacrolimus