Influence of the Rate of Infusion on Cyclosporine Nephrotoxicity in the Rat

Abstract

The effect of the rate of infusion of single and multiple doses of cyclosporine (CsA) on renal Junction was evaluated in Sprague-Dawley rats. CsA was dissolved in cremophore (Crem) or Tween 80 (Tween) and infused over consecutive 10-min periods at doses of 10, 20, 30 and 40 mg/kg. CsA-Crem and CsA-Tween produced similar and progressive changes in MAP, RBF, and RVR. By the end of the infusion, the mean values (% of control) of MAP (122 ′ 16% and 131 ′ 22%), RBF (56 ′ 11% and 66 ′ 20%), and RVR (222 ′ 38% and 232 ′ 134%) were significantly different from their respective preinfusion values. Infusion of Crem alone resulted in renal vasodilation at low doses and renal vasoconstriction at high doses. Vasoconstriction was not produced by infusion of Tween alone. In addition, animals were treated with vehicle alone (Gp 1), CsA 10 mg/kg/day by injection (Gp 2), or CsA 20 mg/kg/day by i. v. infusion over 4 hr (Gp 3), and were studied at 1 week. Systemic toxicity was greater with the 4-hr infusion as judged by an increase in MAP. The mean values of MAP were 107 ′ 8 (Gp 1), 101 ′ 13 (Gp 2), and 135 ′ 5 mm Hg (Gp 3; p < 0.05). However, renal function was less severely affected with the 4-hr infusion. The mean values of C<_In were 434 ′ 99 (Gp 1), 298 + 101 (Gp 2; p < 0.05), and 425 ′ 114 μ;L/min/100 g BW (Gp 3); and the mean values for RBF were 2.72 ′ 0.74 (Gp 1), 2.08 ′ 0.17 (Gp 2; p < 0.05), and 3.35 ′ 0.61 mL/min/100 g BW (Gp 3), respectively. Microangiograms showed marked abnormalities in the intrarenal perfusion pattern in the rats injected with CsA, 10 mg/kg BW.

In rats infused over 4 hr with CsA, 20 mg/kg BW, the microangiographic pattern was normal. These studies demonstrate that the acute hemodynamic effects of CsA are directly related to the rate of infusion. Furthermore, the renal toxicity which follows repetitive injection of CsA can be minimized or avoided by administering CsA as a slow infusion. In addition to the total dose administered, the rate of infusion is an important determinant of nephrotoxicity.

Pharmacological Association, Orlando, Florida, March 26, 1987; and at the 20th Annual Meeting of the American Society of Nephrology, Washington, DC, December 15, 1987.