Esposito M, Vannozzi M, Viale M, Pellecchia C, Civalleri D, Gogioso L
Servizio di Farmacologia Tossicologica, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Anticancer Res. 1995 Nov-Dec;15(6B):2541-7.
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.
对氨基苯甲酸（PABA）先前已被报道为顺铂毒性的抑制剂，并且其使用并未导致顺铂的抗肿瘤活性出现任何可观察到的损失。以下研究调查了PABA对雄性Sprague-Dawley大鼠体内顺二氯二氨铂（II）（DDP）的药代动力学和尿排泄的影响。DDP以7.5mg/kg的剂量腹腔注射于单独的生理盐水中以及同时腹腔注射PABA（100mg/kg）的情况下。PABA的联合治疗使总铂的血浆浓度显著升高，而不影响血浆超滤液中铂物种的水平。在通过不同给药途径（即DDP静脉注射和PABA腹腔注射）接受相同剂量DDP加PABA的大鼠的额外研究中也获得了类似结果。PABA使总铂血浆浓度-时间曲线（AUC）直至60分钟以及AUC0-120分钟分别平均增加了113%和66%。给大鼠施用PABA后，铂的总尿排泄量大幅降低（P<0.05），并且在治疗后最初4小时收集的尿液中，DDP衍生铂的浓度显著降低（P<0.01）。PABA使可滤过铂的肾清除率平均降低67.5%，从1.11降至0.36ml/min/100g体重。PABA也使铂的24小时总尿排泄量有所降低，尽管不显著。用DDP+PABA治疗的大鼠的尿量与单独接受DDP的动物的尿量相似。高效液相色谱研究表明，PABA在体外很容易与DDP产生的物种发生反应，而该试剂对母体DDP基本无反应，并且不影响其分解速率。本研究的总体数据表明，PABA对DDP毒性的保护作用可能至少部分归因于其与水合DDP相互作用以及改变铂肾排泄的能力。
