Effect of para-aminobenzoic acid on the pharmacokinetics and urinary excretion of cis-diamminedichloroplatinum(II) in rats.
Para-aminobenzoic acid (PABA) has been previously reported as being an inhibitor of DDP toxicity, and its use did not result in any observable loss in antitumor activity of DDP. The following studies investigated the effect of PABA on the pharmacokinetics and urinary excretion of cis-diamminedichloroplatinum(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 combined treatment with PABA produced a significant increase in the plasma concentrations of total platinum, without affecting the levels of platinum species in the plasma ultrafiltrate. Similar results were also obtained in additional studies in rats receiving the same dose of DDP plus PABA through different routes of administration (i.e. DDP i.v. and PABA i.p.). Both the area under the total platinum plasma concentration-time curve (AUC) up to 60 min and AUC0-120 min were increased by PABA by an average of 113% and 66% respectively. The administration of PABA in rats 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 the first 4 h after treatment. The renal clearance of filterable platinum 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 decreased, although not significantly, by PABA. Urine volumes from rats treated with DDP+PABA were similar to those from animals receiving DDP alone. HPLC studies indicate that PABA reacts readily with the species generated from DDP in vitro, while the agent is essentially unreactive toward the parent DDP and does not influence its decomposition rate. The overall data of this study suggest that the protective effect exerted by PABA on DDP toxicity may be at least partially due to its ability to interact with aquated DDP as well as to alter the renal excretion of platinum.
Esposito
M
M
Servizio di Farmacologia Tossicologica, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Vannozzi
M
M
Viale
M
M
Pellecchia
C
C
Civalleri
D
D
Gogioso
L
L
D010129:4-Aminobenzoic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D000970:Antineoplastic Agents; D002945:Cisplatin; D010129:4-Aminobenzoic Acid