- Email: [email protected]
Sulfinpyrazone: Relationship between dose, kinetics, plasma concentrations and biological effects
THROMBOSIS RESEARCH,Supplement TV: 89-92, 1983 0049-3848183 $3.00 + .OO Printed in the USA. All rights Copyright (c) 1983 Pergamon Press Ltd.
reserved.
SULFINPYRAZONE: RELATIONSHIPBETWEEN DOSE, KINETICS, PLASMA CONCENTRATIONS AND BIOLOGICALEFFECTS
M.R. Buchanan Department of Pat ho1 ogy McMaster University Hamilton, Ontario, Canada L8N 315 INTRODUCTION Sulfinpyrazone is a metabolite of the phenylbutazone analogue, G25671 which is rapidly absorbed from the gastrointestinal tract and bound primarily to plasma proteins (2). Sulfinpyazone was initially marketed as a uricosuric agent for the treatment of gout in the early 1950’s (3,4). Thus, the early investigations of the relationship between the pharmacological properties and biological effects were performed in terms of its ability to reduce plasma concentrations of uric acid. These studies were performed in both man and animals (5-7) and showed that 48 to 54% of the administered drug was excreted as unchanged sulfinpyrazone, 10 to 13% was metabolized to hydroxy-sulfinpyrazone metabolites, and 28 to 38% was conjugated with C-glucuronic acid. These metabolites comprised at least 89 to 95% of the radiolabelled drug administered, as measured in urine O-76 hours after treatment. was found to be the most Of these, the unchanged sulfinpyrazone potent uricosuric agent. Cl),
In the mid-1960’s, Smythe and colleagues (8) reported that sulfinpyrazone had an effect on platelet function. Thus, they found that the reduced platelet half-life (3.31 days) seen in geriatric patients suffering from gout, was prolonged to 4.5 days after sulfinpyrazone treatment. This prolongation in platelet survival was associated with a reduction of the clinically apparent thromboembolic complications seen in the same patients. In rabbits,
addition, they found that normal platelet half-life, measured in was significantly prolonged with sulfinpyrazone treatment (9). This effect was time-dependent and the maximum effect was only achieved following chronic admini stration (30 days). Neither the explanation for the prolonged platelet survival nor the delayed onset of the sulfinpyrazone effect were elucidated, although these investigators did suggest that the sulfinpyrazone effect was independent of its uricosuric properties or of any effect on coagulation.
Since then, a number of investigators have performed studies to determine the possible mechanisms of action of sulfinpyrazone, and these have been reviewed by Dr. R. Wallis (13). Briefly, sulfinpyrazone is thought to be a reversible inhibitor of platelet cycle-oxygenase activity (10-12).
89
90
SULFINPYRAZONE PHARMACODYNAMICS
Suppl.
IV, 1983
In 1975, our laboratory performed a number of experiments in rabbits to determine the relationship between sulfinpyrazone plasma concentrations and inhibition of platelet function in vivo. We found that in vivo collagen-induced platelet aggregation was signficantly inhibited in a dose-related manner 30 minutes after the intravenous administration of sulfinpyrazone (11). This initial inhibitory effect was short-lived and platelet aggregation returned towards normal within 4 hours. The effect was correlated with the sulfinpyrazone plasma concentration. However, when platelet aggregation was measured 8-18 hours after treatment, platelet aggregation again became inhibited, the maximum inhibitory effect being seen at 18 hours, long after sulfinpyrazone had been cleared from the plasma. Furthermore, when platelets were collected from these rabbits, washed and resuspended, the inhibitory effect on the platelet still persisted. In contrast, when platelets were collected from rabbits 2 hours after sulfinpyrazone treatment, (at a time when _in vivo platelet aggregation was significantly inhibited), washed and resuspended, the inhibitory effect of sulfinpyrazone was lost. Based on these observations, we proposed that a previously unidentified metaboli te in vivo, and possessed was formed pharmacological properties and platelet inhibitory effects markedly different from those of its parent compound (11). Similar observations have also been reported in man. Thus, Walter and colleagues (14) examined the effects of sulfinpyrazone on collagen-induced platelet aggregation ex vivo measured in platelet-rich plasma collected from patients with cardiovascular disease. Platelet aggregation was measured upon entering the study before treatment and serially at 2 week intervals following sulfinpyrazone treatment. Platelet aggregation was significantly inhibited after 14 days of treatment and inhibited even further after 90 days of treatment. When therapy was stopped after 14 days, the platelet response to collagen returned to normal within 7-8 hours, indicating a reversible inhibitory ef feet. However, when therapy was stopped after 90 days, recovery of the platelet response was delayed indicating an for 7-14 days, irreversible effect on platelet function. This time-dependent decrease in collagen-induced platelet aggregation was associated with a time-dependent increase in drug metabolizing enzymes within the liver (14,151. The authors suggested that these enzymes needed to be activated to maximally facilitate In other the metabolism of sulfinpyrazone to its more potent metabolites. Maguire et al (19) found that the onset of the antiplatelet effect studies, of sulfinpyrazone was better achieved if sulfinpyrazone was given in 2 X 400 a critical level of mg doses daily rather than 4 x 200 mg doses, suggesting its metabolite was necessary to obtain an Optimal sulfinpyrazone and/or therapeutic effect. that sulfinpyrazone has prolonged Other investigators have confirmed function and have also demonstrated that inhibitory effects on platelet previously unidentified metabolites are formed in both man and animals The prolonged effect of sulfinpyrazone is attributed to the (16,171. Pedersen and Jakobsen (18) measured the formation of a sulfide metabolite. and its metabolites in diabetic patients plasma levels of sulfinpyrazone They found that in treated with sulfinpyrazone for 2 to 2-l/2 years. addition to the well recognized hydroxyl sulfinpyrazone and C-glucuronic acid 16% of the metabolized sulfinpyrazone circulated in the plasma metabolites, In other studies, Dietele et al (20) measured in the sulfide form. sulfinpyrazone and these metabolites in urine following the administration Of' a single 100 mg dose of sulfinpyrazone and found only minimal levels of the The difference in sulfide levels in plasma and same sulfide metabolite.
Suppl. IV, 1983
91
SULFINPYRAZONE PHARMACODYNAMICS
urine suggest that this metabolite is cleared more slowly than either its These studies thus parent compound or the other better known metabolites. suggest that the measurement of circulating sulfinpyrazone levels rather than may better facilitate an understanding of the levels of excreted products, relationship between sulfinpyrazone pharmacokinetics, pharmacodynamics and its biological effect. CONCLUSIONS function following acute The reversible inhibition of platelet sulfinpyrazone treatment appears to be due to the parent compound, whereas following a more prolonged the irreversible effect on platelet function These treatment may be due to the formation of a sulfide metabolite. observations provide us not only with an insight into some of the inconsistencies associated with the antithrombotic effects of sulfinpyrazone, but also suggest that the investigation of the pharmacological properties of potentially useful antithrombotic drugs in parallel with the study of their biological effects may be useful to clarify their relevance and clinical application.
REFERENCES 1.
BURNS, J. J., YU, T.F., RITTERBRAND, A., PAVEL, J .M., BUTMAN, A.B. new uricosuric agent, the sulfoxide metabolite BRODIE, B. B. A potent the phenylbutazone analogue G25671. J. Pharmacol. Exp. Ther. 418-426, 1957.
2.
GUTMAN, A.B., DAYTON, P.G., YU, T.F., BERGER, L., CHEN, W., SICAM, L.E. and BURNS, J.J. A study of the inverse relationship between pKa and rate of renal excretion of phenylbutazone analogs in man and dogs. Amer. J. Med. 29, 1017-1033, 1960.
3.
BRODIE, B.B., YU, T.T., BURNS, J. J., CHENKIN, T., PATON, B.C., STEELE, and GUTMAN, A.B. J.M. Observations on G-25671, a phenylbutazone analogue (4-phenyl-thioethyl)-1,2-diphenyl e 3,5,pyrazolidinedione) Proc. Exp. Biol. Med. 86, 884-888, 1954.
4.
tXiRYZL0, M.A. and chronic gout. Ann.
5.
DAYTON, P.G., SICAM, L.E., LANDRAU, M. and BURNS, J.J. Metabolism sulfinpyrazone (Anturane) and other thioanalogues of phenylbutazone man. J. Pharmacol. Exp. Ther. 132, 287-290, 1961.
6.
DIETERLE, W., FAIGLE, J.W., MORY, H., RICHTER, W.J. and Biotransformation and pharmacokinetics of sulfinpyrazone man. Europ. J. Clin. Pharmacol. 9, 135-145, 1975.
7.
ALDRIDGE, A. and JOHNSON, G.E. Can. J. Physiol. Pharmacol. 50,
8.
SMYTHE, H.A., ORGYZLO, M.A., MURPHY, E.A. and MUSTARD, J.F. The effect of sulfinpyrazone (anturan) on platelet economy and blood coagulation in man. Can. Acad. Assoc. J. 92, 818-821, 1965.
HARRISON, J. Evaluation Rheum. Dis. 16, 425-428,
Excretion 1061-1065,
of 1957.
uricosuric
of sulfinpyrazone 1972.
agents
and of 119,
in
for in
THEOBALD, W. (Anturan) in
in
the
rat.
92
SULFINPYRAZONEPHARMACODYNAMICS
Suppl.
IV,
1983
9.
MUSTARD, J.F., ROUSELL, H.C., SMYTHE, H.A., SENYI, A. and MURPHY, E.A. The effect of sulfinpyrazoneon platelet economy and thrombusformation in rabbits. Blood 29:859-867,1967.
10.
ALI, M. and MCDONALD, J.W.A. Effects of sulfinpyrazoneon platelet prostaglandin synthesis and platelet release of serotonin. J. Lab. Clin. Med. 89, 868-875, 1977.
11.
BUCHANAN, M.R., ROSENFELD, J. and HIRSH, J. The prolonged effect of sulfinpyrazone on collagen induced platelet aggregation in vivo. Thromb. Res. 13, 883-892, 1978.
12. CERSKUS, A.L., ALI, M. and MCDONALD, J.W.D. Thromboxane and B2 6-keto-prostaglandinF synthesis during infusion of collagen and arachidonicacid in rabb its: inhibitionby aspirin and sulfinpyrazone. Thromb. Res. 18, 693-705, 1980. 13.
WALLIS, R.B. Mechanisms of action of sulphinpyrazone. Thromb. Res. Suppl. 31-38, 1983.
14. WALTER, E., HOWK-LAIBACH, P., ZIMMERMANN,R. and WEBER, E. Action and interaction of sulfinpyrazone in anticoagulated patients. Thromb. Haemost. 42, 62, 1979. 15. WALTER, E., STAIGER, C.L., DE VRIES, J., ZIMMERMAN, R. and WEBER, E. Induction of drug metabolizing enzymes by sulfinpyrazone. Europ. J. Clin. Pharmaool.19, 353-358, 1981. 16.
BUTLER, K.D., DIETERLE,W., MAGUIRE, E.D., PAY, G.F., WALLIS, R.B. and WHITE, A.M. Sustained effects of sulfinpyrazone. In: Cardiovascular Actions of Sulphinpyszone:Basic and Clinical Research. M. McGregor, J.F. Mustard, M.F. Oliver and S. Sherry (Eds.1. Symposium Specialists Inc., Miami, 1980, pp.19-34.
17.
PEDERSEN, A.K. and JAKOBSEN, P. Two new metabolitesof sulfinpyrazone in vivo effect. Thromb. in the rabbit: A possible cause of prolonged-Res. 16, 871-876, 1979.
18. PEDERSEN, A.K. and JAKOBSEN, P. Sulphinpyrazonemetabolism during long-termtherapy. Brit. J. Clin. Pharmacol.11, 597-603, 1981. 19.
MAGUIRE, E.D., PAY, G.F., TURNEY, J., WALLIS, R.B., WESTON, M.J., WHITE, A.M., WILLIAMS, L.C. and WOODS, H.F. The effects of two different dosage regimens of sulphinpyrazoneon platelet function -ex vivo and blood chemistryin man. Haemostas.10, 153-164, 1981.
New metabolites of 20. DIETERLE, W., FAIGLE, J.W. and MOPPERT, J. Res. 30, 989-992, 1980. sulfinpyrazonein man. Arzneim.-Forsch/Drug
reserved.
SULFINPYRAZONE: RELATIONSHIPBETWEEN DOSE, KINETICS, PLASMA CONCENTRATIONS AND BIOLOGICALEFFECTS
M.R. Buchanan Department of Pat ho1 ogy McMaster University Hamilton, Ontario, Canada L8N 315 INTRODUCTION Sulfinpyrazone is a metabolite of the phenylbutazone analogue, G25671 which is rapidly absorbed from the gastrointestinal tract and bound primarily to plasma proteins (2). Sulfinpyazone was initially marketed as a uricosuric agent for the treatment of gout in the early 1950’s (3,4). Thus, the early investigations of the relationship between the pharmacological properties and biological effects were performed in terms of its ability to reduce plasma concentrations of uric acid. These studies were performed in both man and animals (5-7) and showed that 48 to 54% of the administered drug was excreted as unchanged sulfinpyrazone, 10 to 13% was metabolized to hydroxy-sulfinpyrazone metabolites, and 28 to 38% was conjugated with C-glucuronic acid. These metabolites comprised at least 89 to 95% of the radiolabelled drug administered, as measured in urine O-76 hours after treatment. was found to be the most Of these, the unchanged sulfinpyrazone potent uricosuric agent. Cl),
In the mid-1960’s, Smythe and colleagues (8) reported that sulfinpyrazone had an effect on platelet function. Thus, they found that the reduced platelet half-life (3.31 days) seen in geriatric patients suffering from gout, was prolonged to 4.5 days after sulfinpyrazone treatment. This prolongation in platelet survival was associated with a reduction of the clinically apparent thromboembolic complications seen in the same patients. In rabbits,
addition, they found that normal platelet half-life, measured in was significantly prolonged with sulfinpyrazone treatment (9). This effect was time-dependent and the maximum effect was only achieved following chronic admini stration (30 days). Neither the explanation for the prolonged platelet survival nor the delayed onset of the sulfinpyrazone effect were elucidated, although these investigators did suggest that the sulfinpyrazone effect was independent of its uricosuric properties or of any effect on coagulation.
Since then, a number of investigators have performed studies to determine the possible mechanisms of action of sulfinpyrazone, and these have been reviewed by Dr. R. Wallis (13). Briefly, sulfinpyrazone is thought to be a reversible inhibitor of platelet cycle-oxygenase activity (10-12).
89
90
SULFINPYRAZONE PHARMACODYNAMICS
Suppl.
IV, 1983
In 1975, our laboratory performed a number of experiments in rabbits to determine the relationship between sulfinpyrazone plasma concentrations and inhibition of platelet function in vivo. We found that in vivo collagen-induced platelet aggregation was signficantly inhibited in a dose-related manner 30 minutes after the intravenous administration of sulfinpyrazone (11). This initial inhibitory effect was short-lived and platelet aggregation returned towards normal within 4 hours. The effect was correlated with the sulfinpyrazone plasma concentration. However, when platelet aggregation was measured 8-18 hours after treatment, platelet aggregation again became inhibited, the maximum inhibitory effect being seen at 18 hours, long after sulfinpyrazone had been cleared from the plasma. Furthermore, when platelets were collected from these rabbits, washed and resuspended, the inhibitory effect on the platelet still persisted. In contrast, when platelets were collected from rabbits 2 hours after sulfinpyrazone treatment, (at a time when _in vivo platelet aggregation was significantly inhibited), washed and resuspended, the inhibitory effect of sulfinpyrazone was lost. Based on these observations, we proposed that a previously unidentified metaboli te in vivo, and possessed was formed pharmacological properties and platelet inhibitory effects markedly different from those of its parent compound (11). Similar observations have also been reported in man. Thus, Walter and colleagues (14) examined the effects of sulfinpyrazone on collagen-induced platelet aggregation ex vivo measured in platelet-rich plasma collected from patients with cardiovascular disease. Platelet aggregation was measured upon entering the study before treatment and serially at 2 week intervals following sulfinpyrazone treatment. Platelet aggregation was significantly inhibited after 14 days of treatment and inhibited even further after 90 days of treatment. When therapy was stopped after 14 days, the platelet response to collagen returned to normal within 7-8 hours, indicating a reversible inhibitory ef feet. However, when therapy was stopped after 90 days, recovery of the platelet response was delayed indicating an for 7-14 days, irreversible effect on platelet function. This time-dependent decrease in collagen-induced platelet aggregation was associated with a time-dependent increase in drug metabolizing enzymes within the liver (14,151. The authors suggested that these enzymes needed to be activated to maximally facilitate In other the metabolism of sulfinpyrazone to its more potent metabolites. Maguire et al (19) found that the onset of the antiplatelet effect studies, of sulfinpyrazone was better achieved if sulfinpyrazone was given in 2 X 400 a critical level of mg doses daily rather than 4 x 200 mg doses, suggesting its metabolite was necessary to obtain an Optimal sulfinpyrazone and/or therapeutic effect. that sulfinpyrazone has prolonged Other investigators have confirmed function and have also demonstrated that inhibitory effects on platelet previously unidentified metabolites are formed in both man and animals The prolonged effect of sulfinpyrazone is attributed to the (16,171. Pedersen and Jakobsen (18) measured the formation of a sulfide metabolite. and its metabolites in diabetic patients plasma levels of sulfinpyrazone They found that in treated with sulfinpyrazone for 2 to 2-l/2 years. addition to the well recognized hydroxyl sulfinpyrazone and C-glucuronic acid 16% of the metabolized sulfinpyrazone circulated in the plasma metabolites, In other studies, Dietele et al (20) measured in the sulfide form. sulfinpyrazone and these metabolites in urine following the administration Of' a single 100 mg dose of sulfinpyrazone and found only minimal levels of the The difference in sulfide levels in plasma and same sulfide metabolite.
Suppl. IV, 1983
91
SULFINPYRAZONE PHARMACODYNAMICS
urine suggest that this metabolite is cleared more slowly than either its These studies thus parent compound or the other better known metabolites. suggest that the measurement of circulating sulfinpyrazone levels rather than may better facilitate an understanding of the levels of excreted products, relationship between sulfinpyrazone pharmacokinetics, pharmacodynamics and its biological effect. CONCLUSIONS function following acute The reversible inhibition of platelet sulfinpyrazone treatment appears to be due to the parent compound, whereas following a more prolonged the irreversible effect on platelet function These treatment may be due to the formation of a sulfide metabolite. observations provide us not only with an insight into some of the inconsistencies associated with the antithrombotic effects of sulfinpyrazone, but also suggest that the investigation of the pharmacological properties of potentially useful antithrombotic drugs in parallel with the study of their biological effects may be useful to clarify their relevance and clinical application.
REFERENCES 1.
BURNS, J. J., YU, T.F., RITTERBRAND, A., PAVEL, J .M., BUTMAN, A.B. new uricosuric agent, the sulfoxide metabolite BRODIE, B. B. A potent the phenylbutazone analogue G25671. J. Pharmacol. Exp. Ther. 418-426, 1957.
2.
GUTMAN, A.B., DAYTON, P.G., YU, T.F., BERGER, L., CHEN, W., SICAM, L.E. and BURNS, J.J. A study of the inverse relationship between pKa and rate of renal excretion of phenylbutazone analogs in man and dogs. Amer. J. Med. 29, 1017-1033, 1960.
3.
BRODIE, B.B., YU, T.T., BURNS, J. J., CHENKIN, T., PATON, B.C., STEELE, and GUTMAN, A.B. J.M. Observations on G-25671, a phenylbutazone analogue (4-phenyl-thioethyl)-1,2-diphenyl e 3,5,pyrazolidinedione) Proc. Exp. Biol. Med. 86, 884-888, 1954.
4.
tXiRYZL0, M.A. and chronic gout. Ann.
5.
DAYTON, P.G., SICAM, L.E., LANDRAU, M. and BURNS, J.J. Metabolism sulfinpyrazone (Anturane) and other thioanalogues of phenylbutazone man. J. Pharmacol. Exp. Ther. 132, 287-290, 1961.
6.
DIETERLE, W., FAIGLE, J.W., MORY, H., RICHTER, W.J. and Biotransformation and pharmacokinetics of sulfinpyrazone man. Europ. J. Clin. Pharmacol. 9, 135-145, 1975.
7.
ALDRIDGE, A. and JOHNSON, G.E. Can. J. Physiol. Pharmacol. 50,
8.
SMYTHE, H.A., ORGYZLO, M.A., MURPHY, E.A. and MUSTARD, J.F. The effect of sulfinpyrazone (anturan) on platelet economy and blood coagulation in man. Can. Acad. Assoc. J. 92, 818-821, 1965.
HARRISON, J. Evaluation Rheum. Dis. 16, 425-428,
Excretion 1061-1065,
of 1957.
uricosuric
of sulfinpyrazone 1972.
agents
and of 119,
in
for in
THEOBALD, W. (Anturan) in
in
the
rat.
92
SULFINPYRAZONEPHARMACODYNAMICS
Suppl.
IV,
1983
9.
MUSTARD, J.F., ROUSELL, H.C., SMYTHE, H.A., SENYI, A. and MURPHY, E.A. The effect of sulfinpyrazoneon platelet economy and thrombusformation in rabbits. Blood 29:859-867,1967.
10.
ALI, M. and MCDONALD, J.W.A. Effects of sulfinpyrazoneon platelet prostaglandin synthesis and platelet release of serotonin. J. Lab. Clin. Med. 89, 868-875, 1977.
11.
BUCHANAN, M.R., ROSENFELD, J. and HIRSH, J. The prolonged effect of sulfinpyrazone on collagen induced platelet aggregation in vivo. Thromb. Res. 13, 883-892, 1978.
12. CERSKUS, A.L., ALI, M. and MCDONALD, J.W.D. Thromboxane and B2 6-keto-prostaglandinF synthesis during infusion of collagen and arachidonicacid in rabb its: inhibitionby aspirin and sulfinpyrazone. Thromb. Res. 18, 693-705, 1980. 13.
WALLIS, R.B. Mechanisms of action of sulphinpyrazone. Thromb. Res. Suppl. 31-38, 1983.
14. WALTER, E., HOWK-LAIBACH, P., ZIMMERMANN,R. and WEBER, E. Action and interaction of sulfinpyrazone in anticoagulated patients. Thromb. Haemost. 42, 62, 1979. 15. WALTER, E., STAIGER, C.L., DE VRIES, J., ZIMMERMAN, R. and WEBER, E. Induction of drug metabolizing enzymes by sulfinpyrazone. Europ. J. Clin. Pharmaool.19, 353-358, 1981. 16.
BUTLER, K.D., DIETERLE,W., MAGUIRE, E.D., PAY, G.F., WALLIS, R.B. and WHITE, A.M. Sustained effects of sulfinpyrazone. In: Cardiovascular Actions of Sulphinpyszone:Basic and Clinical Research. M. McGregor, J.F. Mustard, M.F. Oliver and S. Sherry (Eds.1. Symposium Specialists Inc., Miami, 1980, pp.19-34.
17.
PEDERSEN, A.K. and JAKOBSEN, P. Two new metabolitesof sulfinpyrazone in vivo effect. Thromb. in the rabbit: A possible cause of prolonged-Res. 16, 871-876, 1979.
18. PEDERSEN, A.K. and JAKOBSEN, P. Sulphinpyrazonemetabolism during long-termtherapy. Brit. J. Clin. Pharmacol.11, 597-603, 1981. 19.
MAGUIRE, E.D., PAY, G.F., TURNEY, J., WALLIS, R.B., WESTON, M.J., WHITE, A.M., WILLIAMS, L.C. and WOODS, H.F. The effects of two different dosage regimens of sulphinpyrazoneon platelet function -ex vivo and blood chemistryin man. Haemostas.10, 153-164, 1981.
New metabolites of 20. DIETERLE, W., FAIGLE, J.W. and MOPPERT, J. Res. 30, 989-992, 1980. sulfinpyrazonein man. Arzneim.-Forsch/Drug