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Pharmacological and biochemical interactions of N-(phosphonacetyl)-L-aspartate and 5-fluorouracil in beagles


, : Pharmacological and biochemical interactions of N-(phosphonacetyl)-L-aspartate and 5-fluorouracil in beagles. Cancer Research 43(6): 2565-2570

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.

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PMID: 6189583


Other references

Tuunanen, M.; Aalto, M.; Seppä, K., 2013: Mean-weekly alcohol questions are not recommended for clinical work. The aim of this study was to evaluate middle-aged men's willingness to answer short, clinically feasible alcohol-related questions and to discuss changing their drinking habits. All 45-year-old male inhabitants of the city of Tampere, Finland...

Buser H., 1987: Paleostructures. Pages 14-15 1987

Bishop, P.M.; Whittingham, C.P., 1963: Emerson effect in isolated chloroplasts. Nature 197(4873): 1225-1226

Rivallan, A., 2013: The informal meeting place. Soins. Psychiatrie: 11-11

Lasar, L.; Maros, T.; Kreps, I., 1960: Structural changes of the nerve fibers and endings under the influence of roentgen rays. Revue des Sciences Medicales 5: 195-198

Powis, L.; Oliver, C., 2014: The prevalence of aggression in genetic syndromes: a review. Research into behavioural phenotypes identifies both environmental and organic factors as influencing aggression in children and adults with genetic disorders associated with intellectual disability. However, in contrast to self-injury there is a...

Tolor, A., 1970: Fallacy of schizophrenic deficit in the interpersonal sphere. Journal of Consulting and Clinical Psychology 35(2): 278-282

Anonymous, 1980: 7th International conference on cacao research, Douala, 4-12 November, 1979. In the disease section of this conference at Douala, Cameroon, summaries are given of papers on Phytophthora; diseases other than P. (Thielaviopsis, Colletotrichum, Botryodiplodia and diebacks due to Calonectria); and cacao swollen shoot virus.

Zimmerman, K.D.; Burton, T.E., 1994: A single-armed manta-board as a new diver-controlled planing board and its use for underwater surveys. ine Fisheries Review 56(2 ): 16

Berg, G.; Köberl, M.; Rybakova, D.; Müller, H.; Grosch, R.; Smalla, K., 2017: Plant microbial diversity is suggested as the key to future biocontrol and health trends. The microbiome of plants plays a crucial role in both plant and ecosystem health. Rapid advances in multi-omics tools are dramatically increasing access to the plant microbiome and consequently to the identification of its links with diseases and...