Benefit of theophylline administration in tacrolimus-induced nephrotoxicity in rats

Tacrolimus (TAC), a widely used nephrotoxic calcineurin inhibitor, is associated with renal vasoconstriction possibly through adenosine receptor activation. Theophylline (THEO), an adenosine receptor inhibitor, protects against the nephrotoxicity of drugs associated with renal vasoconstriction. We hypothesized that coadministration of low dose THEO in rats would prevent TAC-induced nephrotoxicity. Sprague-Dawley rats pair-fed a low-sodium diet were randomized into three groups ( n=10/group): the control (CONTROL) group received the vehicle for both medications; the TAC group received TAC 6 mg/kg/day and vehicle; and the TAC+THEO group received TAC and THEO 17 mg/kg/day. On day 21, a timed urine collection was obtained for creatinine clearance. On day 22, serum creatinine, THEO and whole blood TAC concentrations were determined. One kidney was removed for formalin fixation and histological assessment. In the TAC group, serum creatinine increased while creatinine clearance decreased compared to CONTROL (0.3+/-0.0 vs. 0.4+/-0.0 mg/dl and 0.53+/-0.06 vs. 0.34+/-0.04 ml/min/100 g body weight respectively, p<0.05), while TAC+THEO did not differ from control. There were no significant differences in renal histology. Concurrent administration of low-dose THEO prevented the TAC-induced decline in renal function, consistent with a role for adenosine in TAC-induced nephrotoxicity.