Alleviation of experimental cyclosporin A toxicity by substitution of fish muscle oil as drug vehicle

Abstract

The toxicity of cyclosporin A (CsA) formulated in either olive oil (OO) or fish muscle oil (FO) was investigated in groups of normal Sprague-Dawley rats or in animals which had undergone laparotomy or unilateral nephrectomy. CsA (25 mg/kg/day for 14 days) was administered by gavage from the time of operation, and indices of renal and hepatic function were determined at regular intervals. Urinary thromboxane B2 (TxB2) excretion and whole blood CsA concentrations were determined on day 14, when renal histology was also examined. Compared to CsA/OO treatment, and observed only in normal animals, body weight was significantly increased following administration of CsA/FO, to values similar to those observed following treatment with FO alone. Although there was evidence of renal dysfunction in all CsA-treated animals, irrespective of drug vehicle, elevations in plasma urea and urinary N-acetyl-β-D-glucosaminidase activity were significantly more pronounced in rats given CsA/OO compared with CsA/FO. Indeed, compared with pretreatment values, no significant changes in these parameters were observed in CsA/FO-treated nephrectomized animals. Whilst there were no great differences in plasma creatinine or creatinine clearance rates between CsA/OO- and CsA/FO-treated groups, animals given CsA/FO showed less evidence of renal structural change as assessed by proximal tubular cell vacuolation, basophilia and microcalcification. The extent of hepatic impairment was also significantly less pronounced when FO was used as drug vehicle. Groups of CsA/FO-treated animals also demonstrated significantly lower whole blood CsA levels compared with CsA/OO groups; moreover, TxB2 excretion was significantly lower in the former group. These data show that the less marked impairment of renal and hepatic function observed when CsA is administered in FO compared with OO is associated with both reduced CsA blood levels and urinary TxB2 excretion.