Tacrolimus and Nonsteroidal Anti-Inflammatory Drugs: An Association to Be Avoided

Abstract

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.

Interaction of the Anti-Inflammatory Annexin A1 Protein and Tacrolimus Immunosuppressant in the Renal Function of Rats

“…After that, the rats were submitted to GFR (inulin clearance) or hemodynamic studies as previously described [20]. Briefly, rats were anesthetized with sodium pentobarbital (50 mg/ml/kg i.p.…”

Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: Role of endothelin signaling

“…Diclofenac does not affect blood levels of CSA, but the diclofenac level is nearly doubled and reversible decreases in renal function occasionally occur (Olyaei et al, 1999). The use of tacrolimus, another immunosuppressant with calcineurin inhibitory activity, and nonselective or cyclooxygenase-2 (COX-2) selective NSAIDs in salt-depleted rats impairs the glomerular filtration rate and reduces tacrolimus blood levels (Soubhia et al, 2005). By contrast, in a recent study we established evidence of a renoprotective effect for celecoxib, selective COX-2 inhibitor, against functional, inflammatory, and structural manifestations of CSA nephrotoxicity (El-Gowelli et al, 2014).…”

Calcineurin Inhibitor Nephrotoxicity

“…This effect can be explained by the role of cyclo-oxygenase in the vascular effects of calcineurin inhibition (see above). However, although these studies demonstrate an additive pharmacodynamic effect, certain NSAIDs like diclofenac also interact with CNI pharmacokinetics and augment cyclosporine but decrease tacrolimus blood levels (330,331). Whether chronic use of NSAIDs in combination with CNIs would also lead to more rapid progression of chronic CNI nephrotoxicity is currently not known.…”