Species-dependent differences in the biochemical effects and metabolism of 5-benzylacyclouridine

• Published in: Biochemical pharmacology Vol. 45; no. 1; pp. 173 - 181
• Main Authors: Davis, Stephen T., Joyner, Suzanne S., Chandrasurin, Pisal, Baccanari, David P.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 07.01.1993; Elsevier Science
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Female; Half-Life; Kinetics; Liver - enzymology; Macaca fascicularis; Male; Medical sciences; Mice; Pharmacology. Drug treatments; Rats; Species Specificity; Tissue Extracts - metabolism; Uracil - analogs & derivatives; Uracil - pharmacokinetics; Uridine - blood; Uridine Phosphorylase - antagonists & inhibitors; 5-FU, 5-fluorouracil; LC/MS, liquid chromatography/mass spectrum; 5-FdUrd, 5-fluoro-2'-deoxyuridine; RT, retention time; BAU, 5-benzylacyclouridine, [5-benzyl-1-(2'-hydroxyethoxymethyl)uracil]; BBAU, 5-benzyloxybenzylacyclouridine, [5-( m-benzyloxybenzyl)-1-(2'-hydroxyethoxymethyl)uracil]; UrdPase, uridine phosphorylase; AZT, 3'-azido-3'-deoxythymidine (zidovudine); and T 1 2 , half-life; Antineoplastic agent; Acyclic nucleoside; Intraperitoneal administration; Intravenous administration; Rat; Enzyme; Rodentia; Monkey; Enzyme inhibitor; Species specificity; Metabolism; Vertebrata; Mammalia; Mouse; Uridine phosphorylase; Animal; Primates; Pharmacokinetics; Pyrimidine nucleoside; Uracil
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/0006-2952(93)90390-I

The pharmacokinetics and biochemical effects of the uridine phosphorylase (UrdPase) inhibitor 5-benzylacyclouridine (BAU) were investigated in the mouse, rat and monkey. Following i.p. administration of BAU (30 mg kg ) in the mouse and i.v. administration in the rat and monkey, initial BAU plasma half-life values were 36, 36 and 25 min, and the areas under the plasma BAU concentration versus time curves (AUC) were 127, 80 and 76 μM·hr, respectively. Rats were also dosed p.o. and i.v. with BAU at 90 mg kg , and a comparison of the AUC values showed an oral bioavailability of 70%. Analyses of plasma samples by HPLC indicated that the metabolism of BAU differed in these species. A major BAU metabolite was observed in monkeys. Its concentration was greater than or equal to that of BAU in almost every plasma sample, and its elimination paralleled that of BAU. Urinary recovery of the metabolite was 10-fold higher than the recovery of unchanged drug. The compound was identified as the ether glucuronide of BAU by its UV absorption spectrum, its co-elution with BAU after incubation with β-glucuronidase, and liquid chromatography/mass spectrum analysis. A different metabolite was detected in rat plasma; its maximum concentration was 15% of the BAU level, and its elution position on the HPLC chromatogram was not affected by the action of β-glucuronidase. BAU had equivalent potency against UrdPase in liver extracts from the three species, with K i values of about 0.17 μM. However, the in vivo effects of BAU on plasma uridine concentrations were species dependent. In mice, a 30 mg/kg i.p. dose of BAU increased the plasma uridine concentration to 11 μM from a control level of 1.8 μM. In the rat, a 30 mg/kg i.v. dose of BAU increased plasma uridine to 2.1 from 1.1 μM control levels, and a 300 mg/kg oral dose resulted in a peak plasma uridine concentration of only 6 μM. In the monkey, BAU (30 mg/kg, i.v.) had no effect on plasma uridine despite the presence of 10–100 μM BAU levels in plasma for 1.5 hr. These data show that there are significant differences in the biochemical effects and metabolism of BAU in CD-1 mice, CD rats and cynomolgus monkeys.