Related Experiment Videos
Prevention of cyclosporine-induced nephrotoxicity with pentoxifylline
L J Brunner1, K Vadiei, L V Iyer
1Department of Pharmaceutics, College of Pharmacy, University of Houston.
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 prostaglandins resulting in vasoconstriction and ischemia. The present study investigated the coadministration of CSA with a unique hemorheologic agent, pentoxifylline (PTX), in the murine model. A total of 48 rats were orally dosed with CSA 25 mg/kg for 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 microliters/min/g KW) was similar to control rats 884 +/- 185 microliters/min/g KW); both were significantly greater than CSA alone (537 +/- 211 microliters/min/g KW; p less than .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 less than .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.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Pentoxifylline (PTX) may mitigate cyclosporine (CSA) induced nephrotoxicity by preserving renal function. This study in rats suggests PTX coadministration improves kidney function without altering CSA absorption.
Area of Science:
- Nephrology
- Pharmacology
- Immunosuppression
Background:
- Cyclosporine (CSA) is vital for preventing allograft rejection but causes dose-limiting nephrotoxicity.
- The exact cause of CSA-induced acute kidney injury remains unclear, possibly involving prostaglandin inhibition and renal vasoconstriction.
Purpose of the Study:
- To investigate the potential of pentoxifylline (PTX), a hemorheologic agent, to reduce CSA-induced nephrotoxicity.
- To assess the impact of PTX on renal function and CSA pharmacokinetics in a murine model.
Main Methods:
- 48 rats received oral CSA (25 mg/kg) for 10 days, with either PTX (45 mg/kg) or saline administered every 12 hours.
- Renal function was evaluated by measuring creatinine clearance (CCR) and inulin clearance (CIN).
- Oral and intravenous CSA pharmacokinetics were compared with and without PTX coadministration.
Main Results:
- Rats coadministered CSA and PTX showed significantly higher inulin clearance compared to those receiving CSA alone.
- CSA treatment significantly reduced creatinine clearance, an effect mitigated by coadministration with PTX.
- No significant differences in electrolyte handling or CSA pharmacokinetics were observed between groups.
Conclusions:
- Pentoxifylline coadministration appears to protect against cyclosporine-induced nephrotoxicity in rats.
- PTX may improve renal function by mechanisms independent of altering cyclosporine absorption or electrolyte handling.