Sulfinpyrazone is soluble in alkaline solutions. Its synthesis is similar to that of phenylbutazone
(Fig. 36.33). It produces its uricosuric effect in a manner similar to that of probenecid. A dose of 35 mg produces a
uricosuric effect equivalent to that produced by 100 mg of probenecid, whereas 400 mg/day of sulfinpyrazone
produces an effect comparable to that obtained with doses of 1.5 to 2 g of probenecid. It also possesses, not
surprisingly, some of the properties of phenylbutazone. It is an inhibitor of human platelet prostaglandin synthesis at
the cyclooxygenase step, resulting in a decrease in platelet release and a reduction in platelet aggregation. This
antiplatelet effect suggests a role for sulfinpyrazone in reducing the incidence of sudden death, which can occur in
the first year following a myocardial infarction; however, it lacks the analgetic and anti-inflammatory effects of
phenylbutazone.
Sulfinpyrazone is a uricosuric agent that competitively inhibits uric acid reabsorption in kidney proximal tubules, which is a key mechanism targeted in the treatment of gout. It can also inhibit degranulation of platelets, reducing the release of ADP and thromboxane and diminishing platelet aggregation.
White or almost white powder.
Sulfinpyrazone is used in the treatment of gout acting as a uricosuric medication.
As an anti-inflammatory and uricosuric agent, its side effects were severe enough to preclude its continuous use in the treatment of chronic gout. Evaluation of several chemical congeners indicated that the phenylthioethyl analog of phenylbutazone had promising anti-inflammatory and uricosuric activity. A metabolite, the sulfoxide pyrazone, exhibited enhanced uricosuric activity. Interestingly, the corresponding sulfone does not appear to be a metabolite. Sulfinpyrazone lacks the clinically striking anti-inflammatory and analgesic properties of phenylbutazone.
Sulfinpyrazone is used upon exactly the same indications as phenylbutazone.
ChEBI: Sulfinpyrazone is a sulfoxide and a member of pyrazolidines. It has a role as a uricosuric drug.
Sulfinpyrazone (Anturane), another uricosuric agent, is
chemically related to the antiinflammatory and uricosuric
compound phenylbutazone. However, it lacks the
antiinflammatory, analgesic, and sodium-retaining properties
of phenylbutazone and possesses a number of undesirable
side effects that limit its therapeutic usefulness.
296 parts of (β-phenylmercapto-ethyl)-malonic acid diethyl ester and then 203
parts of hydrazobenzene are added while stirring to a warm sodium ethylate
solution obtained from 23 parts of sodium and 400 parts by volume of
absolute alcohol. About half the alcohol is then distilled off, after which 200
parts by volume of absolute xylene are gradually added without removing the
inclined condenser. The temperature of the oil bath is kept at about 130°C for
12 hours while continuously stirring so that the alcohol still present and that
which is liberated distills off but the xylene remains as solvent.
After cooling, 400 parts by volume of water are stirred in. The aqueous layer
is separated from the xylene, shaken out twice with 40 parts by volume of
chloroform and then made acid to Congo red paper with concentrated
hydrochloric acid. The oil which separates is taken up in ethyl acetate and the
solution obtained is washed with water. After drying over sodium sulfate the
solvent is distilled off under reduced pressure and the residue is recrystallized
from alcohol. 1,2-diphenyl-3,5-dioxo-4-(β-phenylmercapto-ethyl)-pyrazolidine
melts at 106° to 108°C.
Antiarthritic (uricosuric)
Sulfinpyrazone (Anturane) produces its uricosuric action ina similar manner to that of probenecid and is indicated forthe treatment of chronic and recurrent gouty arthritis. It iswell absorbed with approximately 50% of the administereddose excreted as unchanged drug into the renal tubules. Therest of the drug is primarily metabolized via CYP2C9 intothe corresponding sulfide and sulfone metabolites, thus itcan potentiate the anticoagulant effect of warfarin.
The mechanism of sulfinpyrazone’s uricosuric
activity is similar to that of probenecid.
Sulfinpyrazone is readily absorbed after oral administration,
with peak blood levels reached 1 to 2 hours after
ingestion. It is more highly bound to plasma protein
(98–99%) than is probenecid (84–94%) and is a more
potent uricosuric agent. Most of the drug (90%) is eliminated
through active proximal tubular secretion of the
intact parent compound. Sulfinpyrazone also undergoes
p-hydroxylation to form a uricosuric metabolite, the
formation of which undoubtedly contributes to the
drug’s prolonged activity (about 10 hours) and potency
relative to probenecid. In contrast to probenecid, the
rate of excretion of sulfinpyrazone is not enhanced by
alkalinization of the urine, since the drug is largely ionized
at all urinary pH ranges and therefore not a candidate
for passive back-diffusion.
Only the parent sulfinpyrazone and its
reduced sulfide metabolite, however, are active as COX inhibitors. Because these compounds
are reversible inhibitors, the antithrombotic activity lasts only as long as blood levels of the drug
and metabolite persist (half-life, 4–6 hours for parent sulfinpyrazone, 11–14 hours for the sulfide
metabolite). Sulfinpyrazone is not yet approved in the United States for use in acute myocardial
infarction or for transient ischemic attack prophylaxis.
Sulfinpyrazone, although less effective than allopurinol
in reducing serum uric acid levels, remains useful
for the prevention or reduction of the joint changes and
tophus deposition that would otherwise occur in
chronic gout; it has no antiinflammatory properties.
During the initial period of sulfinpyrazone use, acute attacks
of gout may increase in frequency and severity. It
is recommended, therefore, that either colchicine or a
nonsteroidal antiinflammatory agent be coadministered
during early sulfinpyrazone therapy.
Abdominal pain, nausea, and possible reactivation
of peptic ulcer have been reported.
Sulfinpyrazone is a structural derivative of the anti-inflammatory drug phenylbutazone. Unlike
phenylbutazone, however, sulfinpyrazone does not have significant anti-inflammatory activity. It
does have potent uricosuric effects and frequently is used in the treatment of gout.
The most frequent adverse
reactions are GI disturbances; however, the incidence is relatively low.
Sulfinpyrazone, 1,2-diphenyl-4,2-(phenylsulfinil)ethyl-3,5-pyrazolidinedione (3.2.8), is an analog of phenylbutazone that is synthesized in the analogous manner of
condensing hydrazobenzol with 2-(2-phenyltioethyl)malonic ester into pyrazolidinedione
(3.2.7), and the subsequent oxidation of thiol ether by hydrogen peroxide in acetic acid into
the sulfoxide, sulfinpyrazone (3.2.8) [70,71].
Potentially hazardous interactions with other drugs
Anticoagulants: increased risk of bleeding with
apixaban; enhances anticoagulant effect of
coumarins; possibly increased risk of bleeding with
dabigatran.
Antidiabetics: enhances effect of sulphonylureas.
Antiepileptics: increases concentration of
fosphenytoin and phenytoin.
Ciclosporin: may reduce ciclosporin levels.
The metabolites produced result from sulfoxide reduction, sulfur and aromatic oxidation, and C-glucuronidation of the
heterocyclic ring in a manner similar to that for phenylbutazone. The metabolite resulting from p-hydroxylation of the
aromatic ring possesses uricosuric effects in humans. The sulfide metabolite, a major metabolic product, may
contribute to the antiplatelet effects of sulfinpyrazone but not to the uricosuric effects.
[1] Patent: US4288602, 1981, A
