Pharmacokinetics and Tissue Distribution of Cisplatin and Conjugates of Cisplatin with Carboxymethyldextran and A5B7 Monoclonal Antibody in CD1 Mice

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Abstract
The plasma disposition kinetics and tissue distribution of platinum was evaluated following intravenous bolus administration to CD1 immune-competent mice of cisplatin, cisplatin conjugated to anti-CEA monoclonal antibody A5B7 via a carboxymethyl dextran (CMdextran) carrier molecule, and cisplatin coupled to the CMdextran in the absence of antibody. In addition, the in vivo characteristics of 125I-labeled A5B7 were compared with and without conjugation to CMdextran. Conjugation of cisplatin [clearance (CL = 0.62 mL/min/g, volume of distribution at steady-state (Vdss) = 16 mL/g] to CMdextran restricted its tissue distribution (Vdss = 0.43 mL/g) and reduced its systemic clearance (CL = 0.055 mL/min/g). Subsequent conjugation of the complex to A5B7 further reduced both its distribution (Vdss = 0.20 mL/g) and clearance (CL = 0.016 mL/min/g). Clearance of A5B7 (CL = 0.002 mL/min/g) was increased by conjugation to CMdextran (CL = 0.014 mL/min/g); tissue distribution was unchanged. A5B7-CMdextran-cisplatin was relatively stable in plasma and other tissues, except the liver. The extent of distribution of platinum into tissues (lung, liver, muscle, kidney) was markedly influenced by conjugation, with the influence being greatest for unmodified cisplatin and least for the A5B7-CMdextran conjugate. However, the time courses of tissue distribution, expressed in mean residence time scales, were similar, implying a common mechanism controlling tissue uptake.