A comparative study on the hypouricemic activity and potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase inhibitors: TEI-6720 and allopurinol in rats.
In this study, the hypouricemic efficacy of a novel xanthine oxidase/xanthine dehydrogenase inhibitor, TEI-6720, was compared with that of allopurinol in a hyperuricemic rat model established by feeding the animals oxonate, a uricase inhibitor. In addition, using normal rats, the changes in xanthine concentration in plasma and the concentrations and absolute quantities of uric acid, allantoin and xanthine in urine were analyzed during a 28-day period of repeated administration of TEI-6720 to determine the changes occurring during this period and the conditions required for the formation of xanthine crystals and calculi in comparison with allopurinol. TEI-6720 and allopurinol caused a significant dose-dependent decrease in plasma uric acid levels in the hyperuricemic rat model and the ED50 of TEI-6720 was lower than that of allopurinol, indicating that in terms of hypouricemic efficacy TEI-6720 is more potent than allopurinol. TEI-6720 also showed more potent activity than allopurinol in decreasing urinary uric acid and allantoin levels in normal rats. In addition, TEI-6720 and allopurinol showed similar dose-response curves for the decrease in uric acid or allantoin concentration, and the associated increase in xanthine concentration, indicating that TEI-6720 and allopurinol have similar pharmacological characteristics although the dosage required differs. The efficacy of TEI-6720 in increasing plasma and urinary xanthine levels in normal rats was approximately 10- to 30-fold greater than that of allopurinol. However, with respect to renal xanthine calculus formation, there was only about a 3-fold difference in dosage comparing TEI-6720 and allopurinol. This difference suggests that there may be another factor independent of xanthine, and dependent on the drug itself, involved in renal calculus formation caused by allopurinol. The daily excretion of purine metabolites per body weight was about 20-fold higher in rats than in humans. From these results, it is concluded that TEI-6720 has potent hypouricemic activity and that, compared to allopurinol, administration of TEI-6720 is not likely to result in a higher incidence of calculus formation.
Horiuchi
H
H
Pharmaceuticals Development Research Laboratories, Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan. h.horiuchi@teijin.co.jp
Ota
M
M
Kobayashi
M
M
Kaneko
H
H
Kasahara
Y
Y
Nishimura
S
S
Kondo
S
S
Komoriya
K
K
D000481:Allantoin / Q000652:urine; D000493:Allopurinol / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000069465:Febuxostat; D007669:Kidney Calculi / Q000139:chemically induced* / Q000737:chemistry; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology*; D014527:Uric Acid / Q000097:blood* / Q000652:urine; D019820:Xanthine / Q000097:blood* / Q000737:chemistry / Q000652:urine; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D013844:Thiazoles; D000069465:Febuxostat; D019820:Xanthine; D014527:Uric Acid; D000481:Allantoin; D000493:Allopurinol; D014969:Xanthine Oxidase