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

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 microM.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 beta-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 beta-glucuronidase. BAU had equivalent potency against UrdPase in liver extracts from the three species, with Ki values of about 0.17 microM. 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 microM from a control level of 1.8 microM. In the rat, a 30 mg/kg i.v. dose of BAU increased plasma uridine to 2.1 from 1.1 microM control levels, and a 300 mg/kg oral dose resulted in a peak plasma uridine concentration of only 6 microM. In the monkey, BAU (30 mg/kg, i.v.) had no effect on plasma uridine despite the presence of 10-100 microM 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.

Disposition and metabolism of triprolidine in mice.

The disposition of the antihistamine, triprolidine, was studied in male and female CD-1 mice after a single oral 50 mg/kg dose of [14C]triprolidine HCl. Urine and feces collected over 72 hr postdosing were analyzed for total radiocarbon, and for parent drug and metabolites by radiochromatography. Structures of metabolites were determined by GC/MS, direct probe MS, FAB/MS, LC/MS, NMR, and IR techniques. More than 80% of the dose was recovered in the urine, with the remainder recovered in the feces. The carboxylic acid analog of triprolidine (219C69) was found to be the major metabolite in urine and feces, accounting for an average of 57.6% of the administered dose. Three minor metabolites were identified as a gamma-aminobutyric acid analog of triprolidine, a pyrrolidinone analog of 219C69, and a pyridine-ring hydroxylated derivative of triprolidine. Parent drug could only be detected in urine and accounted for 0.3% (females) to 1.1% (males) of the dose. The results of this study showed that triprolidine was absorbed well but extensively metabolized when administered orally to mice.

Disposition of triprolidine in the male beagle dog.

Three male beagle dogs were given 2.5 mg/kg doses of [14C]triprolidine HCl monohydrate (2.09 mg/kg of the free base) by intravenous and oral routes, in a nonrandomized cross-over experiment. After either route of administration, approximately 75% of the dose was excreted in the urine, and the remainder was excreted in the feces. Triprolidine was extensively metabolized, with less than 1% of the parent drug recovered in the excreta after either route of administration. Three metabolites were isolated from excreta and identified, including the major metabolite (metabolite 1, 219C69), in which the toluene ring methyl group was oxidized to a carboxylic acid, a metabolite (metabolite 2) in which the pyrrolidine ring was opened with oxidation of the terminal carbon to a carboxylic acid (a gamma-aminobutyric acid), and a metabolite (metabolite 3) that was a pyrrolidinone derivative of 219C69. Other metabolites in urine and feces were present in amounts too small for quantitation or identification. Route of administration had little effect on the metabolic pattern of triprolidine. Thus, after oral administration of triprolidine, a mean of 49.1% of the dose was excreted as 219C69, 12.0% as metabolite 2, 3.4% as metabolite 3, and 0.6% as triprolidine, while after intravenous administration, a mean of 50.8% of the dose was excreted as 219C69, 11.1% as metabolite 2, 4.2% as metabolite 3, and 0.8% as triprolidine. Plasma contained triprolidine, 219C69, and metabolite 2, as well as other apparent metabolites that were present at levels too low for quantitation. Mean pharmacokinetic parameters calculated for triprolidine after intravenous dosing were: CL = 24.4 ml/min/kg, Vdss = 5.8 liters/kg, and Vc = 1.6 liters/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of acrivastine in the male beagle dog.

Three male beagle dogs were given 10 mg/kg iv and oral doses of [14C]acrivastine, a novel nonsedating antihistaminic agent, in a nonrandomized crossover experiment. Urine and feces were collected for 72 hr after dosing. After iv dosing, a mean of 34% was recovered in the urine, and 63% was recovered in the feces. After po dosing, a mean of 29% of the radiocarbon was recovered in the urine, and 63% was recovered in the feces (dose adjusted for 14% lost in vomitus). Acrivastine and three major metabolites were detected in the excreta. The metabolites were identified as a side-chain-reduced analog of acrivastine (metabolite 3, 270C81), a gamma-aminobutyric acid analog of 270C81 (metabolite 2), and a benzoic acid analog of 270C81 (metabolite 1). After iv dosing, 34% of the dose was excreted as parent drug, 21% as metabolite 3, 15% as metabolite 2, and 6% as metabolite 1, while after po dosing, 35% of the dose was excreted as parent drug, 18% as metabolite 3, 11% as metabolite 2, and 7% as metabolite 1. Pharmacokinetic analysis of acrivastine plasma concentration-time curves after both routes of administration indicated a mean total body clearance of 17.3 ml/min/kg, a Vss of 0.93 liter/kg, a terminal half-life of 0.7 hr, and an oral bioavailability of 40%. The apparent plasma half-life of the metabolite, 270C81, was 1.5 hr. Analysis of AUC values indicated that greater amounts of 270C81 than acrivastine circulated in plasma after both iv and po dosing, and that first-pass metabolism of acrivastine to 270C81 occurred. The results indicated that acrivastine was extensively metabolized in the dog to 270C81 and suggested that 270C81 itself underwent further metabolism to metabolites 1 and 2.

The C-6 proton of tetrahydrobiopterin is acquired from water, not NADPH, during de novo biosynthesis.

Tetrahydrobiopterin, the cofactor for the aromatic amino acid hydroxylases, is synthesized in mammals from GTP via a pathway involving both dihydropterin and tetrahydropterin intermediates. In this work, we have investigated the mechanism of conversion of the product formed from GTP, 7,8-dihydroneopterin triphosphate, into the tetrahydropterin intermediates. Tetrahydrobiopterin can be oxidized under conditions which yield pterin or pterin 6-carboxylate without exchange of the C-6 and C-7 protons. Using these techniques, a gas chromatography/mass spectrometry method was developed to determine that in the biosynthesis of tetrahydrobiopterin de novo, in preparations of bovine adrenal medulla, the C-6 proton of tetrahydrobiopterin is derived from water and not from NADPH. In contrast, the C-6 proton of tetrahydrobiopterin produced from sepiapterin (6-lactoyl-7,8-dihydropterin) comes from NADPH. The results are consistent with evidence for the formation of the first tetrahydropterin intermediate by a tautomerization without any requirement for NADPH.

The formation of diarachidonyl diglyceride by rat neutrophils.

Neutrophils isolated from the pleural cavity of rats 3 hr after the intrapleural injection of carrageenan metabolize exogenously added arachidonic acid via cyclooxygenase and lipoxygenase. In addition, these cells esterify arachidonic acid to produce diarachidonyl diglyceride. The structure of the diglyceride was determined with the use of various chemical and enzymatic digestions, gas chromatography-mass spectrometry, and 252Cf plasma-desorption mass spectrometry. The formation of this unique diglyceride is stimulated by the presence of nonsteroidal anti-inflammatory drugs. Some of the possible consequences of diarachidonyl diglyceride production are discussed.

Rearrangement of chloramphenicol-3-monosuccinate.

The equilibrium mixture of chloramphenicol-3-monosuccinate and its alternate form at neutral pH in aqueous solution was reexamined. The structure of the alternate form was shown by mass specxtrometry and NMR spectroscopy to be chloramphenicol-1-monosuccinate and not the cyclic hemi-ortho ester reported previously.