oxypurinol and allopurinol-riboside

There are no safe and effective oral drugs to treat leishmaniasis and Chagas' disease. The safety, pharmacokinetics, and metabolism of single and multiple oral doses of allopurinol riboside, an investigational antiparasitic agent, were evaluated in a randomized, double-blinded, placebo-controlled study in 32 healthy male volunteers, at levels up to 25 mg/kg q.i.d. for 13 doses. No significant toxicity was detected. Allopurinol riboside peaks in plasma 1.6 hours after administration, has an elimination half-life of 3 hours, and steady-state concentrations in the therapeutic range. However, in contrast to preclinical studies in dogs (plasma levels proportional to oral doses up to 200 mg/kg), we found that plasma levels were unexpectedly low and did not rise with increasing dose. Furthermore, allopurinol and oxypurinol (unanticipated metabolites) were detected at levels proportional to the dose of allopurinol riboside. We present a model that includes incomplete absorption, metabolism of residual drug by enteric flora, and absorption of bacterial metabolites to explain these findings in humans.

Topics: Adolescent; Adult; Allopurinol; Antiprotozoal Agents; Double-Blind Method; Drug Evaluation; Half-Life; Humans; Least-Squares Analysis; Male; Middle Aged; Oxypurinol; Purines; Ribonucleosides

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross-sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.

Topics: Allopurinol; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cross-Sectional Studies; Humans; Oxypurinol; Ribonucleosides; Uric Acid

The anti-gout agent allopurinol is one of the most prescribed pharmaceuticals in Germany and is widely metabolized into oxypurinol (80%) as well as the corresponding riboside conjugates (10%) within the human body. To investigate the occurrence of allopurinol and oxypurinol in the urban water cycle an analytical method was developed based on solid phase extraction (SPE) and subsequent liquid chromatography electrospray-ionization tandem mass spectrometry (LC-MS/MS). In raw wastewater concentration levels of oxypurinol ranged up to 26.6 μg L(-1), whereas allopurinol was not detected at all. In wastewater treatment plant (WWTP) effluents, concentrations of allopurinol were

Topics: Allopurinol; Chromatography, Liquid; Cities; Drinking Water; Environmental Monitoring; Germany; Groundwater; Oxypurinol; Ribonucleosides; Rivers; Sewage; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Wastewater; Water Pollutants, Chemical

Topics: Adult; Allopurinol; Chromatography, High Pressure Liquid; Drug Overdose; Female; Gout; Gout Suppressants; Humans; Kidney Failure, Chronic; Oxypurinol; Ribonucleosides; Risk Factors; Transsexualism

Allopurinol-1-riboside, a major metabolite of allopurinol, is commonly thought to be directly synthesized by purine nucleoside phosphorylase (PNP) in vivo. As this enzyme is otherwise believed to function in vivo primarily in the direction of nucleoside breakdown, we have determined by high performance liquid chromatography and a conventional chromatographic method the urinary metabolites of allopurinol in a child deficient of PNP. In this patient approximately 40% of urinary allopurinol metabolites consisted of allopurinol-1-riboside, thus proving the possibility of indirect formation of allopurinol-1-riboside via allopurinol-1-ribotide in vivo, catalysed by hypoxanthine guanine phosphoribosyltransferase (HGPRT) and a phosphatase.

Topics: Allopurinol; Chromatography, Affinity; Chromatography, High Pressure Liquid; Guanine; Humans; Hypoxanthine Phosphoribosyltransferase; Infant; Male; Oxypurinol; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Purine-Pyrimidine Metabolism, Inborn Errors; Ribonucleosides

Solubility measurements, seeded crystal growth kinetics, solution depletion adsorption studies, nucleation observations, zeta potential measurements, and measurements of in vivo intrarenal crystallization all failed to show that either oxipurinol or allopurinol riboside interacts with calcium, oxalate, or whewellite (CaC2O4.H2O) at concentrations expected in therapeutic situations. We conclude that at therapeutically expected concentrations, oxipurinol and allopurinol riboside do not affect crystallization of calcium oxalate.

Topics: Allopurinol; Animals; Calcium Oxalate; Crystallization; In Vitro Techniques; Kidney Calculi; Kinetics; Oxalates; Oxypurinol; Pyrimidines; Rats; Ribonucleosides