Miller A A, Moore E C, Hurlbert R B, Benvenuto J A, Loo T L
Cancer Res. 1983 Jun;43(6):2565-70.
N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorouracil (FUra) are both antimetabolites that affect the biosynthetic pathways of pyrimidines. To determine whether these two drugs exhibit synergistic pharmacological or biochemical interactions, we determined the pharmacological and biochemical parameters of PALA and [14C]FUra in 14 beagle dogs which received i.v. bolus administrations of either the single agents or the drug combination. The pharmacokinetic parameters of PALA (four dogs, 20 mg/kg) in plasma, cerebrospinal fluid, and urine were not changed by FUra (10 mg/kg, 30 min after PALA). The pharmacokinetics of [2-(14)C]FUra (six dogs, 10 mg/kg, 20 muCi/kg) was characterized by higher FUra plasma concentrations after pretreatment with PALA (20 mg/kg, 30 min before FUra); this led to a significantly larger area under the drug concentration-time curve, a decreased volume of distribution, and a reduced clearance rate and was associated with higher cerebrospinal fluid concentrations of FUra. The FUra plasma and cerebrospinal fluid half-lives, however, were not significantly altered by PALA. The biochemical determinants of PALA and FUra activity were studied in intestinal mucosa, liver, thymus, spleen, and bone marrow of four dogs. Although the activity of the target enzyme of PALA, L-aspartate carbamoyltransferase, in tissue extracts was decreased at least 50% at 18 to 24 hr after PALA administration (50 mg/kg), the uridine nucleotide pools remained remarkably stable. Intracellular FUra concentrations were not influenced by PALA. The incorporation of 5-fluorouridine triphosphate into RNA was enhanced in intestinal mucosa and liver. In other tissues, however, fluorouridine nucleotide concentrations were not affected by PALA. Free 5-fluorodeoxyuridine monophosphate had the highest concentration in liver and was detectable in all tissues, but it was not altered by PALA treatment. Our results show that the pharmacological and biochemical events after FUra exposure are marginally modulated by PALA in normal dogs. If sensitive tumors with a higher degree of interaction between the two drugs could be identified, limited toxicity to normal tissues can be expected.
N-（膦酰乙酰基）-L-天冬氨酸（PALA）和5-氟尿嘧啶（FUra）均为影响嘧啶生物合成途径的抗代谢物。为确定这两种药物是否表现出协同药理或生化相互作用，我们测定了14只比格犬静脉推注单药或联合用药后PALA和[14C]FUra的药理和生化参数。PALA（4只犬，20mg/kg）在血浆、脑脊液和尿液中的药代动力学参数未因FUra（10mg/kg，在PALA给药30分钟后）而改变。[2-（14）C]FUra（6只犬，10mg/kg，20μCi/kg）的药代动力学特征为在用PALA（20mg/kg，在FUra给药前30分钟）预处理后血浆中FUra浓度更高；这导致药物浓度-时间曲线下面积显著增大、分布容积减小、清除率降低，并与脑脊液中更高的FUra浓度相关。然而，FUra在血浆和脑脊液中的半衰期未因PALA而显著改变。在4只犬的肠黏膜、肝脏、胸腺、脾脏和骨髓中研究了PALA和FUra活性的生化决定因素。尽管在给予PALA（50mg/kg）后18至24小时，组织提取物中PALA的靶酶L-天冬氨酸氨甲酰转移酶的活性至少降低了50%，但尿苷核苷酸池仍保持显著稳定。细胞内FUra浓度不受PALA影响。5-氟尿苷三磷酸掺入RNA在肠黏膜和肝脏中增强。然而，在其他组织中，氟尿苷核苷酸浓度不受PALA影响。游离5-氟脱氧尿苷单磷酸在肝脏中的浓度最高，在所有组织中均可检测到，但不受PALA治疗影响。我们的结果表明，在正常犬中，FUra暴露后的药理和生化事件仅受到PALA的轻微调节。如果能够识别出两种药物之间相互作用程度更高的敏感肿瘤，则有望对正常组织产生有限的毒性。
