Uricosuric activity

Oxyphenbutazone (712), y-hydroxyphenylbutazone and kebuzone (715) are metabolites of phenylbutazone in liver. The first cited is an equally potent antiinflammatory agent but slightly less toxic. Compounds (711) and (712) are rarely used as analgesics and antipyretics because of their toxicities. The first one is used in therapy of rheumatoid disorders characterized by a lack of detectable antiglobulin and antinuclear antibodies in the serum. The y-hydroxyphenylbutazone has marked uricosuric activity but little antirheumatic effect. Kebuzone (715) is an antiinflammatory agent still widely used in Europe. 

Acetohexamide (Dymelor) is the only sulfonylurea with uricosuric activity, an action that may be of benefit in diabetic patients who also have gout. 

Some saluretic-diuretic agents, like ethacrynic acid, are inactive in the rat, when given orally. Moreover, uricosuric activity in mice is less reliable than that in primates. 

Phenol red (= phenolsulfonphthalein) excretion is an indirect test for uricosuric activity. After intravenous injection phenol red is mainly eliminated by active secretion in the proximal tubulus of the kidney. Treatment with uricosuric agents decreases the secretory activity of tubulus cells resulting in a delayed excretion of phenol red. Plasma values of phenol red are increased in treated animals as compared to controls. 

Suprofen-induced AKI is characterized by acute flank and/or abdominal pain. In series of 16 patients. Hart et al. [114] described that the mean peak serum creatinine was 3.6 mg/dl (range 2 to 8 mg/dl), which returned to normal limits at follow-up. Suprofen is know to have uricosuric activity leading Hart and colleagues [114] to suggest that this renal syndrome may have resulted from ureteral or tubular precipitation of uric acid. 

Notwithstanding its obsolescence in the treatment of infectious diseases, probenecid found a very important place in the physician s armamentarium because of its uricosuric activity. Its interference with the reabsorption of uric acid through the renal tubular membrane was an unexpected observation. Probenecid is the first useful synthetic compound for the control of uric acid excretion and the age-old disease, gout. 

When metabolized, phenylbutazone yields two hydroxylated derivatives . The first is oxyphenbutazonc, the properties of which are described above the second contains an alcoholic hydroxyl group in the butyl side-chain XXVIII, R = (GH2)2-CHOHMe, R = Ph). This compound is devoid of anti-inflammatory activity but has enhanced uricosuric potency. Other derivatives with a modified side-chain show increased uricosuric activity associated with anti-inflammatory action. The most important are the phenylthioethyl analogue (G25671, XXVIII, R = (CH2)2-SPh, R = Ph) and its metabolite sulphinpyrazone (Anturan, XXVII, R = (CH2)2-SOPh, R = Ph). 

It belongs to the class of a pyrazone structural analogue having potent uricosuric activity together with some antirhombotic and platelet inhibitory activity. It is invariably employed to minimise the serum-urate concentration in the specific instances of chronic and intermittent gouty arthritis. It is ob-... 

Sulfinpyrazone is a strong acid (enolic OH pKa = 2.8), a factor that is important in the production of the uricosuric effect, because within a series of pyrazolidinedione derivatives, the stronger the acid, the more potent the uricosuric effect. Polar substitution on the side chain also influences uricosuric activity, as discussed previously with regard to the pyrazolidinediones. 

In a study of structure-activity relationships, it was found that the (-l-)-enantiomer of (370) was responsible for its uricosuric activity <87CPB3195>. Alcohol (371) and acid (372) are also diuretics <89JAP(K)01246277, 92CPB2597). Ketone (373) was developed for the treatment of brain injury <87USP4654365>, while lactone (374) is a drug for the treatment of hypoxia <87USP4654365>. 

Acetohexamide is used as an oral antidiabetic agent for the treatment of ketoacidosis-resistant diabetes. It is an intermediate acting sulfonylurea derivative. The clinical effects of lowering elevated blood glucose levels Is similar for all of the sulfonylurea derivatives. Acetohexamide, however. Is the only one to also possess uricosuric activity and therefore Is a preferable agent to treat diabetic patients with gout. 

In the case of the related compound 6,7-dichloro-2,3-dihydro-5-(2-thienylcarbonyl)-2-benzofurancarboxylic acid (Fig. 10), the diuretic and uricosuric properties are essentially completely separated. The (+)-5 -enan-tiomer, possessing the natriuretic activity, is twice as active as the racemate, with the uricosuric activity residing in the (—)-i -enantiomer [75,76]. It was postulated that a mixture of the two enantiomers could be prepared to yield an appropriate balance between the two actions [76]. Examination of nonracemic mixtures of the individual enantiomers in the chimpanzee resulted in the conclusion that the racemate possesses the optimal therapeutic ratio of the diuretic and uricosuric properties [75]. However, compared to humans the chimpanzee is a hyperresponder to uricosuric compounds and thus it may not be possible to extend this observation to man. A similar differentiation in enantiomeric activity has also been observed for the related compound 5-dimethylsulphamyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA) (Fig. 10), the uricosuric and diuretic activities being associated with the (+)-7 - and (—)-5-enantiomers, respectively [77]. 

Fanelli, G.M. Watson, L.S. Bohn, D.L. Russo, H.F. Diuretic and uricosuric activity of 6,7-dichloro-2,3-dihydro-5-(2-thienylcarbonyl)-2-benzofuran-carboxylic acid and stereoisomers in chimpanzee, dog and rat. J. Pharmacol. Exp. Ther. 1980, 212, 190-197. 

The pharmacodynamic properties of the natriuretic/uricosuric agent indacrinone have been studied in subjects given varying ratios of the (-b) and (—) enantiomers [68]. With respect to stereoselectivity in pharmacodynamic properties, (—)-indacrinone is a more potent natriuretic agent than the (-b) enantiomer. On the other hand, both enantiomers are equipotent with respect to uricosuric activity. The complexities of the pharmacodynamics of indacrinone and the merits of using different ratios of the enantiomers of indacrinone (instead of 1 1 in the racemate) are discussed in Chap. 5 (Sec. 3.3). 

Diflunisal 375 mg twice daily caused the plasma levels ofhydrochlorothiazide to rise by 25 to 30%, but this does not appear to be clinically significant. Diflunisal also has uricosuric activity, which counteracts the uric acid retention that occurs with hydrochlorothiazide. 

Giachetti, D., E. Taddei, and I. Taddei. 1986. Diuretic and uricosuric activity of Parietaria judaica L. Boll. Soc. Ital. Biol. Sper. 62(2) 197-202. 

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