Effects of nephrectomy on the pharmacokinetics of various cloned human interferons in the rat

SA Tokazewski-Chen, BJ Marafino and N Stebbing

The pharmacokinetics of two human leukocyte interferon (IFN) subtypes (IFN-alpha A and IFN-alpha D) and two molecular hybrids [IFN-alpha AD(Bgl) and IFN-alpha AD(Pvu)] was studied in rats receiving single i.v. injections, 5.0 X 10(6) I.U./kg, of these materials. All four preparations were highly purified and resulted in plasma decay curves with similar elimination half-lives of 95.3 +/- 13.5 min. The four IFN- alpha subtypes investigated showed differences when their clearances are compared, suggesting that the 13 residue differences between amino acids 92 and 165 affect the clearance. The fact that only IFN-alpha D has an apparent volume of distribution (Vd beta) of 12.9 +/- 3.4 liters/kg whereas the other three IFN-alpha subtypes have Vd beta of 5.7 +/- 1.0 liters/kg suggests that the amino acid differences between residues 1 and 61 affect the Vd beta. Only in the case of IFN-alpha D did functional nephrectomy significantly (P = .02) increase the apparent volume of distribution at steady state. Functional nephrectomy before i.v. injection resulted in a 4-fold decrease in IFN-alpha AD(Bgl) and IFN-alpha AD(Pvu) clearance, an 8-fold decrease in IFN- alpha A clearance and a 10-fold decrease in IFN-alpha D clearance. The elimination half-life of each interferon was unchanged after nephrectomy. Intramuscular administration of the IFN-alpha subtypes in rats produced low plasma concentrations. IFN-alpha D peaks at 39 +/- 10 I.U./ml of plasma, whereas IFN-alpha A reaches 201 +/- 53 I.U./ml, IFN- alpha AD(Bgl) reaches 396 +/- 47 I.U./ml and IFN-alpha AD(Pvu) results in a maximum plasma concentration of 747 +/- 66 I.U./ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 227, Issue 1, pp. 9-15, 10/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics