EFFECT OF PARA-AMINOBENZOIC ACID ON THE PHARMACOKINETICS AND URINARY-EXCRETION OF CIS-DIAMMINEDICHLOROPLATINUM(II) IN RATS

Pal-a-aminobenzoic acid (PABA) has been previously reported as being a n inhibitor of DDP toxicity, and its use did not result in any observa ble loss in antitumor activity of DDP. The following studies investiga ted the effect of PABA on the pharmacokinetics and urinary excretion o f cis-diammine-dichloroplatinum(II) (DDP) in male Sprague-Dawley rats. DDP was injected i.p. at the dose of 7.5 mg/kg in normal saline alone and with a concurrent i.p. injection of PABA (100 mg/kg). The combine d treatment with PABA produced a significant increase in the plasma co ncentrations of total platinum, without affecting the levels of platin um species in the plasma ultrafiltrate. Similar results were also obta ined in additional studies in rats receiving the same close of DDP plu s PABA through different routes of administration (i.e. DDP i.v. and P ABA i.p.). Both the al en under the total platinum plasma concentratio n-time curve (AUG) up to 60 min and AUC(0-120) min were increased by P ABA by an average of 113% and 66%, respectively. The administration of PABA in mts was followed by a substantial reduction in total urinary excretion of platinum (P < 0.05) and by a significant (P < 0.01) lower concentration of DDP derived platinum in the urine collected during t he first 4 h after treatment. The renal clearance of filterable platin um was reduced by PABA by an average of 67.5% from 1.11 to 0.36 ml/min /100 g body wt. Total 24-h urinary excretion of platinum was also decr eased, although not significantly, by PABA. Urine volumes from rats tr eated with DDP+PABA were similar to those from animals receiving DDP a lone. HPLC studies indicate that PABA reacts readily with the species generated from DDP in vitro, while the agent Is essentially unreactive toward he parent DDP and does not influence its decomposition rate. T he overall data of this study suggest that the protective effect evert ed by PABA on DDP toxicity may be at least partially due to its abilit y to interact with aquated DDP as well as to alter the renal excretion of platinum.