CONCOMITANT DOSING WITH ANTAGONISTS IMPROVED TACROLIMUS (FK506)-INDUCED NEPHROTOXICITY IN RATS

FK506-induced nephrotoxicity has been reported to occur by arteriolar constriction of the renal cortex, which is induced through the production of such vasoactive factors as thromboxane A2 (TX A2), renin, etc. In the present study, we investigated whether FK506-induced nephrotoxicity is improved by concomitant antagonists for TX A2, angiotensin II, endothelin, adenosine, adrenergic α2 receptor, platelet activating factor, and calcium channel, and found that some showed a potentiality of being antidotes to FK506-induced nephrotoxicity. A calcium antagonist showed the best improving effects and was followed by a TXA2 dual inhibitor and an angiotensin II antagonist. An α2 blocked showed a slight improvement, but endothelin, adenosine, and platelet activating factor (PAF) antagonists had no effects on the nephrotoxicity. The results suggested that FK506-induced nephrotoxicity occurs by constriction of the renal artery, and that various vasoactive factors are involved. In the present study, FK506 and antagonists for vasoconstrictive factors were dosed to rats and the parameters of nephrotoxicity were examined. In this kind of study, antidotes need not only improve the toxicity of the main drug ; they must not diminish its pharmacological action. Accordingly, both toxic and pharmacological parameters must be investigated in a study aimed at finding an antidote to side effects of medicine. Thus, in the present paper we put forth our opinions about estimation of concomitant dosing. (J Toxicol Pathol 9 : 277 ～284, 1996)