CIS-DIAMMINEDICHLOROPLATINUM(II) - PROCAINE PHARMACOKINETIC INTERACTION IN MICE BEARING P388 LEUKEMIA

The distribution and elimination kinetics of cis-diamminedichloroplati num (II) (DDP) in female BDF1 mice bearing 6-day P388 leukemia were in vestigated in the presence and absence of procaine hydrochloride (P.HC l) exposure. DDP was administered as a single i.p. dose of 8 mg/kg in a 0.9% NaCl solution 6 days after tumor inoculum. P.HCl was administer ed as a single i.v. dose of 40 mg/kg immediately after DDP. The combin ed treatment with P.HCI produced marked changes in the plasma concentr ation-time profile of Pt. The unbound fraction of Pt was significantly increased both in the ascites fluid and plasma following DDP+P.HCl ad ministration. P.HCl treatment induced a significant reduction (P<0.01) in the rate constant of the protein-bound of Pt in plasma of tumored mice. Urinary excretion of Pt was unaffected by P.HCI, and there was n o significant P.HCl-induced modification in the concentrations of Pt i n the P388 leukemic cells. A statistically significant reduction of ki dney and spleen Pt content was observed in female mice exposed to a do se of 8 mg/kg DDP+P.HCl. A similar reduction was observed in kidneys a nd testes of tumored mice receiving 16 mg/kg DDP along with 40 mg/kg P .HCl, which also showed lower renal and testicular cisplatin-DNA adduc ts after DDP+P.HCl than after DDP treatment. Potential explanations fo r the ability of P.HCl to interfere with the pharmacokinetics and biod istribution of DDP are discussed.