Pharmacokinetics of c/s-Diammine-1,1-cyclobutane Dicarboxylate Platinum(ll) in Patients with Normal and Impaired Renal Function1

c/s-Diammine-1,1-cyclobutane dicarboxylate platinum(ll) (CBDCA, JM8) is a nonnephrotoxic analogue of cisplatin cur rently undergoing clinical evaluation. Pharmacokinetic studies have been performed in patients receiving CBDCA (20 to 520 mg/sq m) as a 1-hr infusion without hydration or diuresis. Follow ing the end of the infusion, plasma levels of total platinum and ultrafilterable (M, < 50,000) platinum (free platinum) decayed biphasically with first-order kinetics (total platinum fà ̄/2= 98 min; f?/2range, 399 to >1440 min; free platinum f?/2= 87 min; f?/2= 354 min). During the first four hr, binding of platinum to plasma protein was limited (24%), with most of the free platinum in the form of unchanged CBDCA (94%). However, by 24 hr, the majority of platinum was protein bound (87%). The major route of elimination was renal, 65% of the platinum administered being excreted in the urine within 24 hr, with 32% of the dose excreted as unchanged CBDCA. No evidence was found from studies on the renal clearance of free platinum to indicate renal tubular secretion (mean free platinum renal clearance, 69 ml/min). How ever, the plasma clearance of free platinum did correlate posi tively with glomerular filtration rates (p = 0.005). None of the pharmacokinetic parameters determined were dose dependent. In vitro studies with plasma and urine demonstrated that, in contrast to cisplatin, CBDCA is a stable complex [f1/2 37°; plasma, 30 hr, and urine (range), 20 to 460 hr]. The differences in the pharmacokinetics of cisplatin and CBDCA may explain why the latter complex is not nephrotoxic.