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.

Pharmacokinetics of Oltipraz in Mutant Nagase Analbuminemic Rats

“…This indicated that oltipraz is considerably bound to globulins in plasma of NARs. The considerable binding of azosemide,8 bumetanide,29 torasemide,30 cisplatin,31 and methotrexate (our unpublished data) in globulins in plasma of NARs were also reported.…”

Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

“…This is a much smaller difference than with furosemide (98.9 versus 12%) (Inoue et al, 1987), and probably reflects the extensive binding of azosemide to ␣-and ␤-globulins whereas binding to albumin is more important for furosemide. Like azosemide, the binding of bumetanide (approximately 30 -40%) to rat ␣-and ␤-globulins (Kim and Lee, 2001) and cisplatin (approximately 50%) to 1% rat ␥-globulin (Takada et al, 1999) has also been reported.…”

Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats

“…Thawed serum and the filtrate of serum samples were diluted with double-distilled deionized water containing 0.05% (v/v) Triton X-100 and 0.4 N HCl (Takada et al, 1999). The furnace temperature program consisted of drying at 100°C for 60 s and at 120°C for 60 s, ashing at 700°C for 60 s and at 2000°C for 10 s, atomizing at 2800°C for 5 s and cooling for 5 s.…”