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Allopurinol and Other Inhibitors of Urate Synthesis

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Allopurinol and Other Inhibitors of Urate Synthesis CHAPTER 21 Allopurinol and Other Inhibitors of Urate Synthesis GERTRUDE B. ELION A. Introduction The ideal drug for the treatment of hyperuricemia would be one which reduces uric acid synthesis without interfering with important anabolic pathways or normal regu­ latory functions. In theory, uric acid production may be inhibited at a number of different enzymatic steps, either those involved in the de novo pathway of purine biosynthesis or those concerned with the final stages of purine catabolism. Com­ pounds such as azaserine and diazo-oxo-norleucine which block the early steps of purine biosynthesis reduce uric acid synthesis but also interfere with nucleic acid synthesis and are therefore cytotoxic (GRAYZEL et aI., 1960; ZUCKERMAN et aI., 1959). Inhibition of xanthine oxidase, on the other hand, has proven to be a clinically safe and effective method of reducing uric acid formation. Although xanthine oxidase has long been known to oxidize hypoxanthine and xanthine to uric acid, it has not always been apparent that the bulk of uric acid production in man involves this enzyme. Indeed, the discovery that inosinate was the first purine synthesized de novo (BUCHANAN et aI., 1957) suggested the possibility that the conversion of hypoxanthine to xanthine to uric acid might occur at the ribonucleoside or ribonucleotide level (GREENBERG, 1957). The finding that patients with congenital xanthinuria lacked xanthine oxidase (WATTS et aI., 1964), although they apparently could convert inosinate to xanthylate via the enzyme inosinate dehydrogenase, focused attention on the importance of xanthine oxidase in uric acid production. It was open to question, however, whether or not xanthine oxidase inhibi­ tion could be achieved in vivo. WESTERFELD et ai. (1959) had succeeded in inhibiting xanthine oxidase in rats only with toxic levels of carbonyl reagents. Moreover, a pteridine which was a potent xanthine oxidase inhibitor in vitro failed to give any inhibition in vivo (BYERS, 1952). Allopurinol (4-hydroxypyrazolo(3,4-d}pyrimidine) was chosen for in vivo studies of xanthine oxidase inhibition because it was a potent inhibitor of the enzyme in vitro, was relatively nontoxic, and did not appear to interfere with anabolic processes within the cell, as judged by its lack of inhibition of the growth of bacteria or tumors (ELION et aI., 1963). In this chapter allopurinol and its oxidation product, oxipurinol, will be discussed together for reasons which will be apparent. Other xanthine oxidase inhibitors will be discussed as well. B. Inhibition of Xanthine Oxidase In Vitro Allopurinol, a structural analog of hypoxanthine (Fig. 1), is both a substrate for and a potent inhibitor of xanthine oxidase in vitro. The binding of allopurinol to xanthine W. N. Kelley et al. (eds.), Uric Acid © Springer-Verlag Berlin Heidelberg 1978 486 GERTRUDE B. ELION OH OH N~ I N) X.O. (x) ~:tN I }-OH N HO N N H HO~3c H H Hypoxanthine Xanthine Uric acid Allopurinol Oxipurinol Fig. 1. Structural formulas of oxypurines, uric acid, allopurinol, and oxipurinol oxidase is about ten- to fortyfold greater than the binding of xanthine to the enzyme and the inhibition appears to be competitive when initial reaction kinetics are con­ sidered (ELlON, 1966). The K j of allopurinol depends on the source of xanthine oxidase and the pH at which the kinetics are measured. For the bovine cream enzyme the K j = 7 X 10- 7 M at pH 7.4 (ELlON, 1966), for the human liver enzyme it is 1.9 x 10- 7 M at pH 7.4 (ELlON, 1966), and for the human small intestinal enzyme it 9 has been reported to be K j =7.6 x 10- M (WATTS et aI., 1965). However, it was recognized in early studies that the enzyme kinetics of allopurinol were not simple and that preincubation of the enzyme for several minutes with allopurinol led to inactivation of the enzyme (ELlON, 1966). The product of the enzymatic oxidation of allopurinol is the xanthine analog oxipurinol (Fig. 1) (4,6-dihydroxypyrazolo(3,4-d)pyrimidine; alloxanthine; oxoallo­ purinol; DHPP). Although the apparent K j of this compound initially appeared to be higher than that of allopurinol (ELlON, 1966), rapid inactivation of the enzyme occurred in the presence of a substrate, e.g. xanthine. Preincubation of the enzyme with oxipurinol alone did not inactivate the enzyme. The explanation for these observations was soon forthcoming from experiments performed anaerobically (MASSEY et aI., 1970; EDMONDSON et aI., 1972) or in the presence of a chemical reductant (SPECTOR and JOHNS, 1970). Oxipurinol complexes very tightly (K j = 5 x 10- 10 M) with partially reduced xanthine oxidase in which the molybdenum is in the Mo(IV) state (MASSEY et aI., 1970, 1970a; SPECTOR and JOHNS, 1970, 1970 a). This binding is stoichiometric, mole for mole, to functional enzyme, i.e., only to enzyme which is turning over. The binding is not covalent, and oxipurinol can be removed by prolonged dialysis or by oxidation of the enzyme, the latter either on prolonged standing in air or by electron acceptors such as ferricyanide or 2,6- dichlorophenolindophenoI. The halftime for reactivation of the oxipurinol-xanthine- Allopurinol and Other Inhibitors of Urate Synthesis 487 oxidase complex under aerobic conditions is about 5 h (MASSEY et aI., 1970). These studies on the enzyme inhibition have been recently reviewed (SPECTOR, 1977). The success of allopurinol as a xanthine oxidase inhibitor in vivo is undoubtedly due in large measure to the properties of oxipurinol as an enzyme inhibitor and to its persistence in body fluids (cf. Section IV). C. Inhibition of Xanthine Oxidase In Vivo I. Exogenous Purines The first evidence that allopurinol was an inhibitor of xanthine oxidase in vivo was its ability to prevent the oxidation of 6-mercaptopurine (6-MP) to 6-thiouric acid (TU) in mice (ELION et aI., 1962; EUON et aI., 1963). The conversion of 6-MP to TU is mediated by xanthine oxidase (ELION et aI., 1954; ELION et aI., 1959) and is a major catabolic pathway in the metabolism of 6-MP in man as well as in lower animals (ELION et aI., 1954, 1959, 1963, 1963a; HAMILTON and ELION, 1954). The inhibition of the oxidation of 6-MP by allopurinol in mice is accompanied by an equivalent potentiation of the antitumor and immunosuppressive properties of 6-MP and with some (unproportional) increase in toxicity (ELION et aI., 1963). The biological activi­ ties of other 6-substituted purines, e.g. 6-chloropurine, 6-methylthiopurine, and 6-propylthiopurine, all of which are substrates for xanthine oxidase, are potentiated by allopurinol in a similar manner. In man the oxidation of 6-MP to TU is inhibited by relatively low doses of allopurinol, as evidenced by the reduction in urinary thiouric acid and the increase in the excretion of6-MP (ELION et aI., 1963, 1963a; RUNDLES et aI., 1963; VOGLER et aI., 1966). The antileukemic activity of 6-MP is also potentiated (RUNDLES et aI., 1963; VOGLER et aI., 1966). The more efficient utilization of 6-MP for the synthesis of thiopurine nucleotides when conversion to thiouric acid is blocked undoubtedly accounts for this potentiation (ELION, 1975). II. Inhibition of Uric Acid Production The ability of allopurinol to inhibit the oxidation of endogenous purines by xanthine oxidase results in a reduction of uric acid levels in both serum and urine and in an increase in the urinary excretion of hypoxanthine and xanthine (RUNDLES et aI., 1963, 1966; HITCHINGS, 1966; YO and GUTMAN, 1964). This has made the drug an extremely useful therapeutic agent for the treatment of the primary hyperuricemia of goUt(RUNDLES et aI., 1963, 1966, 1966a, 1969; YO and GUTMAN, 1964; KLINENBERG et aI., 1965; SCOTT, 1966) as well as for the secondary hyperuricemias associated with malignancies (KRAKOFF and MEYER, 1965; KRAKOFF and MURPHY, 1968; RUNDLES et aI., 1963, 1969; SCOTT, 1966). The decrease in uric acid production is dose-related, and serum urate levels can be regulated to the desired level by dose adjustment (HITCHINGS, 1966; RUNDLES et al., 1966) unless there is serious impairment of renal function (LEVIN and ABRAHAMS, 1966). When serum urate levels are maintained below the saturation level of sodium urate, crystalline deposits of urate dissolve and tophi decrease in size. The rate of disappearance of such deposits is dependent on the level of serum urate maintained. Some acute attacks of gout have been reported to 488 GERTRUDE B. EUON occur at the beginning of therapy, as they do with uricosuric agents, probably as the result of the mobilization of urate deposits. With the maintenance of serum urate levels below the saturation point, destructive arthritis improves, acute attacks be­ come less frequent and severe, and gouty nephropathy appear to halt in most pa­ tients (SCOTT, 1966; RUNDLES et aI., 1969). In lower mammals which oxidize uric acid to allantoin via uricase, the effect of allopurinol is to reduce allantoin production and increase oxypurine excretion (HITCHINGS, 1966; EUON et aI., 1968). Longterm animal studies have shown that the degree of inhibition of xanthine oxidase remains constant at a constant dose of allopurinol, indicating that no induction of enzyme occurs as a consequence of prolonged inhibition (HITCHINGS, 1966). This is also true in man. Gout patients do not require increased amounts of allopurinol after years of treatment; indeed, the dose may often be reduced once tophi have disappeared. Because allopurinol reduces urinary uric acid as well as serum urate, it is used to prevent the hyperuricosuria, uric acid crystals, urinary stone formation, and urinary tract obstruction that often result from the rapid lysis of cells in patients with malignancies who are undergoing intensive chemotherapy or radiation (RUNDLES et aI., 1969). It is similarly possible to prevent the overproduction of uric acid in patients with chronic myeloproliferative diseases, e.g.
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