NEPHROTOXICITY STUDIES OF THE IMMUNOSUPPRESSANTS TACROLIMUS (FK506) AND ASCOMYCIN IN RAT MODELS

The nephrotoxic potential of ascomycin, the C21-ethyl analogue of FK50 6, was defined and ways explored to enhance its detection. After 14-da y dosing in the Fischer-344 rat, FK506 and ascomycin reduced creatinin e clearance by >50% at doses of 1 and 3 mg/kg, i.p., respectively. Asc omycin also had a 3-fold lower immunosuppressive potency in a poplitea l lymph node hyperplasia assay, resulting in an equivalent therapeutic index consistent with a common mechanistic dependence on calcineurin inhibition. Renal impairment with different routes of administration w as correlated with pharmacokinetics. Sensitivity of detection was not adequate with shorter dosing durations in rats with unilateral nephrec tomy or in mice using a cytochrome P-450 inhibitor, SKF-525A. In 14-da y studies, nephrotoxicity was not induced by continuous i.p. infusion of ascomycin at 10 mg/kg/day or daily oral administration (up to 50 mg /kg/day) in rats on a normal diet, nor by continuous i.v. infusion (up to 6 mg/kg/day) in rats on a low salt diet to enhance susceptibility. The lack of toxicity at high oral doses of FK506 or ascomycin, and th e finding of non-linear oral pharmacokinetics of ascomycin show that t his drug class has an oral absorption ceiling. The negative results wi th continuous infusion suggest that ascomycin nephrotoxicity is govern ed by peak drug levels. In addition to defining ways to meaningfully c ompare the nephrotoxic potential of FK506 derivatives, these results h ave implications for overall safety assessment and improved clinical u se. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.