Pharmacological and biochemical interactions of N-(phosphonacetyl)-L-aspartate and 5-fluorouracil in beagles.
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.
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004347:Drug Interactions; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000096:biosynthesis; D012313:RNA / Q000378:metabolism; D014018:Tissue Distribution
D001798:Blood Proteins; D009943:Organophosphorus Compounds; D011743:Pyrimidines; D001224:Aspartic Acid; D012313:RNA; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D005472:Fluorouracil