Use of microdialysis to study platinum anticancer agent pharmacokinetics in preclinical models

Microdialysis sampling of blood and extracellular fluid (ECF) of living tissue offers unique advantages for studying anticancer drug distribution, metabolism, and mechanisms of tumor drug resistance. We applied microdialysis sampling in a rat model to describe the pharmacokinetics of cisplatin and carboplatin simultaneously in blood and several peripheral tissues, including tumor tissue. After i.v. bolus drug administration, samples were collected every 10 min for 4-6 h using microdialysis probes implanted into the jugular vein, kidney, and either liver or subcutaneously growing breast tumor tissue in anesthetized Fisher 344 rats. Analyte concentrations are expressed as absolute extracellular concentrations obtained by correction of the data for in vivo recovery. For cisplatin, peak renal concentrations (mean, 36.7 and 80.1 micrograms/mL) always exceeded peak plasma (8.4 and 13.2 micrograms/mL) and hepatic (6.3 and 10.4 micrograms/mL) concentrations following 5 and 10 mg/kg doses, respectively. For carboplatin, doses of 20 and 30 mg/kg also resulted in high peak renal concentrations, which were similar at both dose levels (mean, 87.9 and 89.3 micrograms/mL). However, at 30 mg/kg peak hepatic carboplatin concentrations were increased significantly, resulting in a disproportionate 3.5-fold increase in mean AUC at the higher dose level. Tumor cisplatin and carboplatin AUCs were similar to that in the circulation, but variable, ranging from 52 to 109% of the corresponding plasma AUCs. Microdialysis was determined to be a reliable methodology for examining the in vivo disposition of platinum anticancer agents in multiple tissue types. Our results revealed expected large renal exposures following i.v. administration, and variable tumor exposure with dose. Significant increases in hepatic carboplatin exposure with increasing dose suggest a possible mechanism for high-dose carboplatin-induced hepatic toxicity.