Pharmacokinetics and tissue distribution of novel traditional Chinese medicine-platinum anticancer agents in rats

The pharmacokinetics and tissue distribution profiles of a novel series of traditional Chinese medicine-platinum (TCM-Pt) compounds [Pt(C8H8O5)(NH2R)(2)]: 1 (where R = H), 3 (R = CH3) and 5 (R = C6H10), were studied in Sprague-Dawley rats following a single bolus intravenous (i.v.) injection. Platinum concentrations in total plasma, plasma ultrafiltrate, urine and tissues were measured by flameless atomic absorption spectroscopy. Pharmacokinetic studies showed that plasma concentrations of total and free platinum for the novel TCM-Pt compounds as well as cisplatin and carboplatin declined in a biexponential manner with a short distribution half-life (t(1/2 alpha): 0.12-0.34 h). Compared with cisplatin, the novel TCM-Pt compounds had a longer elimination half-life (t(1/2 beta)), larger dose normalized area under the curve (AUC/D), larger volume of distribution at steady-state (V-ss), slower clearance (CL) of free platinum and higher percentage of cumulative urinary excretion (CUE), which can be attributed to their lower chemical reactivities. In tissues, the highest Pt concentrations were found in the kidney, followed by the liver and the lowest in the heart; no Pt was detected in the brain. Twenty-four hours after drug administration, platinum concentrations in tissues were significantly lower for the novel TCM-Pt compounds. These findings suggest that the novel compounds might afford higher clinical efficacy and reduced systemic side effects, when compared with cisplatin. (c) 2007 Elsevier Inc. All rights reserved.