Prevention of cyclosporine-induced nephrotoxicity with pentoxifylline.
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)
Brunner
L J
LJ
Department of Pharmaceutics, College of Pharmacy, University of Houston.
Vadiei
K
K
Iyer
L V
LV
Luke
D R
DR
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D001682:Biological Availability; D003524:Cyclosporins / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects; D008297:Male; D010431:Pentoxifylline / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D013805:Theobromine / Q000031:analogs & derivatives*
D003524:Cyclosporins; D011464:Epoprostenol; D013805:Theobromine; D010431:Pentoxifylline