Prevention of Cyclosporine-Induced Nephrotoxicity with Pentoxifylline

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Abstract
Although cyclosporine (CSA) is established in the prevention of allograft rejection, its use has been associated with dose-limiting toxicities, most notably to the kidney and liver. To date, the pathogenesis of the acute form of nephrotoxicity is unclear but may be related to inhibition of vasodilatory prostagiandins resulting in vasoconstriction and ischemia. The present study investigated the coadministration of CSA with a unique hemorheologic agent, pentoxifylline (PTX), in the marine model. A total of 48 rats were orally dosed with CSA 25 mg/kgfor 10 days with either PTX 45 mg/kg i.p. or saline every 12 hr. Posttreatment renal function, assessed by creatinine (CCR) and inulin (CIN) clearances and renal electrolyte handling, was compared with baseline data and between groups. In an attempt to assess prostaglandin-mediated changes in enteral absorption, oral CSA pharmacokinetics with and without PTX were compared to the pharmacokinetics of similar groups (N = 8) administered i. v. CSA. Mean CIN of rats coadministered CSA and PTX (942 ′ 214 μl/min/g KW) was similar to control rats 884 ′ 185 μl/min/g KW); both were significantly greater than CSA alone (537 ′211 μd/min/g KW; p <. 01). Likewise, percent of baseline CCR was significantly reduced in rats treated CSA (61 ′ 24%) compared to controls 113 ′ 41 %) and rats coadministered PTX (117 ′ 75%; p <. 05). No differences in percent change from baseline electrolyte handling were observed among groups. Further, no differences in CSA pharmacokinetics with or without PTX were found. Bioavailability, when compared to the i.v. data, was not significantly different with PTX compared to saline controls (78.9 ′ 24.9% vs 93.3 ′ 19.7%; NS). These data suggest the potential benefit of PTX in the prevention of CSA-induced nephrotoxicity, most likely mediated by prostagiandins or vascular decongestion.