The comparative pharmacokinetics of carboplatin and cisplatin in mice and rats

Abstract

The plasma, urinary and biliary clearances of cisplatin and its non-nephrotoxic analogue, Carboplatin ( cis-diammine-1,1-cyclobutane dicarboxylate platinum II, CBDCA, JM8) have been determined in mice and rats following intravenous administration of the compounds. The plasma concentration-time curves were biphasic during the time period studied (0–60 min), with t 1 2 α of 2–3 min for both platinum complexes and t 1 2 β of 10–15 min for cisplatin and 25–26 min for Carboplatin. The kinetic rate constants, k 12and k 21, were similar for both Carboplatin and cisplatin, indicating that there was no appreciable net accumulation of the compounds in the peripheral tissues. Immediately after administration, Carboplatin became reversibly bound to plasma proteins in vivo to the extent of about 20%. Appreciable irreversible binding appeared after the first 60 min and increased steadily, so that by 4 hr only 34% of the compound was present in the plasma as the free drug. In comparison, binding of cisplatin to plasma was exclusively irreversible and, after the first 10 min, free drug disappeared rapidly, such that by 60 min free platinum was not detectable. The plasma clearance of free cisplatin (26.1 ml/ min/kg) was significantly greater than that of either Carboplatin (10.3 ml/min/kg) or inulin (10.1 ml/ min/kg). The main route of excretion of the two platinum complexes was via the urine, with 80–90% of Carboplatin and 43–48% of cisplatin being excreted within 4 hr. In the rat, the Carboplatin excreted in the urine was predominantly as the unchanged compound. The renal clearance of cisplatin (12.3 ml/ min/kg) was significantly greater than that of either Carboplatin (9.3 ml/min/kg) or inulin (9.6 ml/min/ kg), suggesting that cisplatin was excreted by an active renal secretory mechanism whilst Carboplatin was eliminated by glomerular filtration alone. Biliary excretion of the two compounds was only 0.4-1.2% of the administered dose in 6 hr, with biliary clearance of cisplatin (0.27 ml/min/kg) being fivefold greater than that of Carboplatin (0.053 ml/min/kg). The results indicate that the major pharmacokinetic differences between Carboplatin and cisplatin relate to their renal handling and their reactivity with macromolecules. These differences may well underline the substantial lack of Carboplatin nephrotoxicity in comparison with cisplatin.