Allopurinol
Bioavailability and pharmacokinetics of intravenously and orally administered allopurinol in healthy beagles.

Bartges JW, Osborne CA, Felice LJ, Koehler LA, Ulrich LK, Bird KA, Chen M, Sawchuk RJ.

Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul 55108, USA.

OBJECTIVES: To determine bioavailability and pharmacokinetic parameters for allopurinol and its active metabolite, oxypurinol. ANIMALS: 6 healthy, reproductively intact female Beagles, 4.9 to 5.2 years old, and weighing 9.5 to 11.5 kg. PROCEDURE: In the first part of the study, allopurinol was administered IV at a dosage of 10 mg/kg of body weight to 3 dogs and 5 mg/kg to 3 dogs; the sequence was then reversed. In the second part of the study, allopurinol was administered orally at a dosage of 15 mg/kg to 3 dogs and 7.5 mg/kg to 3 dogs; the sequence was then reversed. In the third part of the study, allopurinol was administered IV (10 mg/kg), orally (15 mg/kg) with food, and orally (15 mg/kg) without food. Plasma samples were obtained at timed intervals, and concentrations of allopurinol and oxypurinol were determined. RESULTS: Maximal plasma allopurinol concentration and area under plasma allopurinol and oxypurinol concentration-time curves were 2 times greater when dogs were given 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs were given 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. Allopurinol elimination half-life, time to reach maximal plasma oxypurinol concentration, and oxypurinol elimination half-life were significantly greater when dogs received 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs received 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. CONCLUSIONS: Elimination of allopurinol is dependent on nonlinear enzyme kinetics. The bioavailability of allopurinol, and pharmacokinetic parameters of allopurinol and oxypurinol after oral administration of allopurinol, are not affected by administration with food. CLINICAL RELEVANCE: A dose threshold exists beyond which additional allopurinol would not substantially further inhibit xanthine oxidase activity. Oral administration of > 15 mg of allopurinol/kg to dogs would not be expected to result in greater reduction of plasma and urine uric acid concentrations. Also, allopurinol may be administered to dogs for dissolution or prevention of urate uroliths without regard to time of feeding.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9140559&dopt=Abstract allopurinol Zyloprim



Allopurinol
Influence of two diets on pharmacokinetic parameters of allopurinol and oxypurinol in healthy beagles.

Bartges JW, Osborne CA, Felice LJ, Koehler LA, Ulrich LK, Bird KA, Chen M.

Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul 55108, USA.

OBJECTIVES: To determine whether diet influences the metabolism of IV administered allopurinol in healthy dogs. ANIMALS: 6 healthy female Beagles, 4.9 to 5.2 years old and weighing 9.6 to 11.5 kg. PROCEDURES: Allopurinol was administered IV (10 mg/kg) while dogs consumed a 10.4% protein (dry weight), casein-based diet or a 31.4% (dry weight), meat-based diet. After each dose, plasma samples were obtained at timed intervals, and concentrations of allopurinol and its active metabolite, oxypurinol, were determined by high-performance liquid chromatography. An iterative, nonlinear regression analytical program was used to determine the weighted least-squares, best-fit curves for plasma allopurinol and oxypurinol concentration-time data. From these data, pharmacokinetic parameters were calculated. RESULTS: Pharmacokinetic parameters for allopurinol and oxypurinol were not different when comparing the effect of diet. CONCLUSION: There is no influence of diet on pharmacokinetic parameters of allopurinol or oxypurinol. CLINICAL RELEVANCE: In contrast to observations in human beings, allopurinol metabolism is not influenced by diet. Therefore, formation of xanthine-containing calculi in dogs consuming a high-protein diet and receiving allopurinol is probably not attributable to alteration of allopurinol metabolism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9140560&dopt=Abstract allopurinol Zyloprim



Allopurinol
Immunomodulating activity of allopurinol in experimental lens-induced uveitis.

Grus FH, Augustin AJ, Zimmermann CW, Spitznas M, Sekundo W, Lutz J.

Department of Ophthalmology, University of Bonn, Germany.

PURPOSE: The aim of this study was to evaluate the immunomodulating activity of allopurinol using a model of lens-induced uveitis (LIU) and to compare these effects to those of steroids. METHODS: We tested the sera of both LIU and control rats against western blots (WB) of SDS-PAGE separations of protein fractions from normal and LIU rat lenses. These blots were scanned using digital image analysis. A newly developed technique was used to compare the complex autoantibody (AAB) repertoires. Five groups of LIU rats were investigated: no treatment; single doses of methylprednisolone (MPR; 7.5 mg/kg body wt.i.v.); allopurinol (AL; 50 mg/kg body wt. i.v.); a combination of both drugs (AL and MPR); repeated application of AL (ALFR; 50 mg/kg body wt.i.v. every 2 weeks during the immunization period and a daily dose of approx. 25 mg/kg body wt. orally). RESULTS: Immunization induced complex antibody repertoires against lens proteins. Antibody repertoires of LIU rats were identical, regardless of whether the proteins were obtained from control, uveitis eyes, or corresponding healthy eyes of the same individual. AL showed a dose-dependent immunological effect in LIU treatment. Given as a single dose, AL revealed no significant change in the AAB repertoire; however, ALFR showed very clear modification of the AAB repertoires compared to both controls and rats receiving steroids. CONCLUSIONS: These results suggest dose-dependent effects of allopurinol in LIU treatment. Repeated application during the immunization period induced a strong immunomodulating effect of AL that was not observed after single doses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9147951&dopt=Abstract allopurinol Zyloprim



Allopurinol
Role of free radicals in the mechanism of the hydrazine-induced formation of megamitochondria.

Matsuhashi T, Liu X, Karbowski M, Wozniak M, Antosiewicz J, Wakabayashi T.

Department of Cell Biology and Molecular Pathology, Nagoya University School of Medicine, Japan.

The effect of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl(4-OH-TEMPO), a scavenger for free radicals, and 4-hydroxypyrazolo [3,4-d(pyrimidine)allopurinol], a xanthine oxidase inhibitor, on the hydrazine-induced changes of mitochondrial ultrastructure and those in the antioxidant system of the liver were investigated using rats as experimental animals. Animals were placed on a powdered diet containing 0.5% hydrazine for 7 d in the presence and absence of a combined treatment with 4-OH-TEMPO or allopurinol. Results obtained were as follows. 4-OH-TEMPO completely prevented the hydrazine-induced formation of megamitochondria in the liver, while it was partly prevented by allopurinol. The following changes observed in hydrazine-treated animals were improved almost completely by 4-OH-TEMPO:decreases in the body weight and liver weight; lowered rates of ADP-stimulated respiration and coupling efficiency of hepatic mitochondria; remarkable elevation of the level of lipid peroxidation. Improving effects of allopurinol were incomplete. The present results suggest that free radicals may play a key role in the mechanism of the hydrazine-induced formation of megamitochondria and that a part of free radicals generated during the hydrazine intoxication is ascribed to the degradation of purine nucleotides via xanthine oxidase. A general mechanism of the megamitochondria formation induced in various pathological conditions besides the case of hydrazine are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9199891&dopt=Abstract allopurinol Zyloprim



Allopurinol
Antioxidant activity of allopurinol on copper-catalysed human lipoprotein oxidation.

Lapenna D, de Gioia S, Ciofani G, Cuccurullo F.

Istituto di Fisiopatologia Medica, Universita degli Studi G. D'Annunzio, Facolta di Medicina e Chirurgia, Chieti, Italy.

We found that allopurinol, at therapeutically relevant concentrations (9-58 microM), significantly counteracted copper-catalysed human non-HDL lipoprotein oxidation, as assessed by thiobarbituric acid reactant content and kinetics of conjugated diene formation. Oxypurinol was ineffectual. Both drugs had no activity on metal-independent, peroxyl radical-induced lipoprotein oxidation. Specific fluorescence-quenching experiments revealed that only allopurinol could interact with copper antagonizing metal binding to lipoproteins. Thus, therapeutic allopurinol concentrations can inhibit copper-catalysed lipoprotein oxidation through metal complexation, suggesting some antioxidant-antiatherogenic activity of the drug in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9202158&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effect of dietary selenium, zinc and allopurinol supplements on plasma and tissue manganese levels in rats with thioacetamide [correction of thiocetamide]-induced liver cirrhosis.

Al-Bader AA, Mosawi MH, Hussain TA, Dashti HM.

Department of Pathology, Faculty of Medicine, Kuwait University Health Sciences Center, Safat.

The effect of thioacetamide-induced liver cirrhosis on plasma and tissue manganese levels and the protective role of selenium, zinc and allopurinol supplements was investigated in rats. Control plasma and liver manganese (Mn) levels were found to be (mean +/- SD): 8.4 +/- 2.4 mg/L and 5.7 +/- 1.5 mg/g wet weight respectively. Plasma manganese levels were significantly increased (p < 0.001) whereas liver manganese levels were significantly reduced (p < 0.05) in the cirrhotic rats. Treatment with selenium, zinc and allopurinol reversed this trend and restored the manganese levels close to the normal values. Lung, spleen, and kidney manganese levels under control conditions were considerably lower than that of the liver tissue. However, these levels registered a significant increase (p < 0.05) in cirrhotic rats and this change was normalized after selenium, zinc and allopurinol treatment. There were no significant differences in the comparative efficacy of each of these protective agents. Zinc supplement considerably increased the plasma zinc levels and plasma Zn/Mn ratio had a good correlation with plasma zinc concentration. This ratio was significantly reduced in cirrhotic rats, but returned to the control level after zinc, selenium and allopurinol treatment. The results of this study indicate that the trace element, manganese, plays an important role in stabilizing cell structure and that this effect is mediated possibly by preserving the antioxidant activity of the tissues.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9278262&dopt=Abstract allopurinol Zyloprim