Pharmacokinetics of cisplatin in analbuminemic rats

Abstract

The effect of protein binding on the pharmacokinetics of cisplatin (cis-diamminedichloroplatinum (II); CDDP) has been studied in analbuminemic rats, which genetically lack albumins, in comparison with normal rats. CDDP was reported to highly bind to serum components, and the major binder was thought to be an albumin. However, there were no significant differences in the serum disappearance profiles of platinum after intravenous (iv) bolus injection of CDDP to analbuminemic rats as compared with normal rats. The total body clearance, Cl(tot), of platinum in normal rats was 48.7+/-22.0 mL h(-1) (5 mg kg(-1)), 55.9+/-4.04 mL h(-1) (10 mg kg(-1)) and 49.0+/-3.57 mL h(-1) (20 mg kg(-1)), whereas Cl(tot) in analbuminemic rats was 52.0+/-8.48 mL h(-1) (5 mg kg(-1)), 62.9+/-10. 8 mL h(-1) (10 mg kg(-1)) and 62.8+/-6.81 mL h(-1) (20 mg kg(-1)). The serum blood urea nitrogen (BUN) and creatinine levels at 6 h after iv injection were higher in both groups of rats who received CDDP than those of pre-dose level. However, there were no significant differences in the renal function tests between analbuminemic rats and normal rats. The binding of CDDP to the serum samples obtained from analbuminemic rats and normal rats was measured by a centrifuging filtration method. The binding percentages were 68.0+/-5.9% (2.0 microg mL(-1)), 56.8+/-4.1% (5.0 microg mL(-1)) and 64.6+/-4.4% (10.0 microg mL(-1)) in analbuminemic rats and 52.9+/-3.5% (2.0 microg mL(-1)), 52.2+/-3.4% (5.0 microg mL(-1)), 56.9+/-1.9% (10.0 microg mL(-1)) in normal rats. Higher binding percentages were obtained in analbuminemic rats than in normal rats. In vitro binding studies under the two incubation conditions (5 min and 2 h) showed that the binding percentages of CDDP to serum proteins were 59.2+/-3.2% (5 min) and 72.3+/-6.5% (2 h) for albumin, 42.3+/-1.9% (5 min) and 39.5+/-2.5% (2 h) for alpha(1)-acid glycoprotein (AAG) and 51.7+/-5.3% (5 min) and 49. 2+/-1.9% (2 h) for gamma-globulin. From these studies, it was elucidated that albumin is not the major ligand in the rat serum and that other proteins also have important roles in the pharmacokinetics of CDDP.