PHARMACOKINETICS AND TISSUE DISTRIBUTION OF CISPLATIN AND CONJUGATES OF CISPLATIN WITH CARBOXYMETHYLDEXTRAN AND A5B7 MONOCLONAL-ANTIBODY INCD1 MICE

The plasma disposition kinetics and tissue distribution of platinum wa s evaluated following intravenous bolus administration to CD1 immune-c ompetent mice of cisplatin, cisplatin conjugated to;anti-CEA monoclona l antibody A5B7 via a carboxymethyl dextran (CMdextran) carrier molecu le, and cisplatin coupled to the CMdextran in the absence of antibody. In addition, the in vivo characteristics of I-125-labeled A5B7 were c ompared with and without conjugation to CMdextran. Conjugation of cisp latin [clearance (CL = 0.62 mL/min/g, volume of distribution at steady -state (Vd(ss)) = 16 mL/g] to CMdextran restricted its tissue distribu tion (Vd(ss) = 0.43 mL/g) and reduced its systemic clearance (CL = 0.0 55 mL/min/g). Subsequent conjugation of the complex to A5B7 further re duced both its distribution (Vd(ss) = 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 plas ma and other tissues, except the liver, The extent of distribution of platinum into tissues (lung, liver, muscle, kidney) was markedly influ enced by conjugation, with the influence being greatest far unmodified cisplatin and least for the A5B7-CMdextran conjugate. However, the ti me courses of tissue distribution, expressed in mean residence time sc ales, were similar, implying a common mechanism controlling tissue upt ake.