- Email: [email protected]
Hepatic injury caused by benzbromarone
Journal of Hepatology 1994; 20:376-379 Printed in Denmark. All rights reserved Munksgaard. Copenhagen
Copyright©JournalofHepatology 1994 Journal of Hepatology
ISSN 0168-8278
Hepatic injury caused by benzbromarone Melanie M. van der K l a u w 1, Pieternella M. H o u t m a n 2, B r u n o H. Ch. Stricker 1'3 a n d Pieter Spoelstra 4 tDepartment of lnternal Medich~e 11, University Hospital Dijkzigt, Rotterdam, 2Department of Rheumatology, Medical Centre Leeuwarden, Leeuwarden, 3Netherlands Centre for Monitoring of Adverse Reactions to Drugs, Rijsw(jk, and 4Department of Gastroenterology and Hepatology, Medical Centre Leeuwarden, Leeuwarden, The Netherlands
(Received 31 August 1992)
This case study describes a woman who developed a predominantly hepatocellular injury, approximately 3 months after starting treatment with 100 mg benzbromarone daily. She had also taken 250 mg methyldopa daily for several years. Infections with hepatitis A and B were excluded serologically, no autoantibodies were demonstrated, and ultrasonography and endoscopic retrograde cholangiopancreatography did not show extrahepatic obstruction. The patient recovered after discontinuation of both drugs. Two years later, readministration of benzbromarone was followed by a relapse. Later, methyldopa was used without problems. We conclude that hepatic injury in this patient was caused by benzbromarone. © Journal of Hepatology. Key words." Adverse reactions; Drug-induced hepatic injury; Toxic hepatitis
Benzbromarone is a benzofuran derivative which is used as a uricosuric agent in the treatment of gout. Use of benzbromarone has occasionally been associated with diarrhea, rash, and renal colic due to urate and oxalate urolithiasis (1). To the best of our knowledge, however, no cases of hepatic injury caused by benzbromarone have been reported in the medical literature. We report a patient who developed hepatic injury caused by benzbromarone on two occasions.
Case
Report
A 68-year-old female had been treated for 3 years because of chronic gout with tophi on several fingers of both hands. As she was a low secretor of uric acid, and because allopurinol did not improve her condition, treatment was changed from allopurinol (up to 400 mg a day) to benzbromarone (Desuric®), 200 mg a day. In addition, she also received methyldopa (Aldomet ®) 250 mg daily for hypertension; no other drug was taken. After 6 weeks, the dose of benzbromarone was lowered to 100 mg daily. Her condition was stable at that time. Two months later she visited the outpatient clinic, having had influenza-like
complaints for several days. She had had diarrhea and her urine had been darker than usual. On presentation, there was malaise, anorexia and mild pain in the right upper abdomen when she bent forward. Her stools were looser than usual, but she did not complain of diarrhea any more and the color had not changed. She had a history of jaundice at 22 years of age. On examination, she was jaundiced, but there were no signs of chronic liver disease such as spider naevi or palmar erythema. There was mild abdominal tenderness and the liver was slightly palpable and smooth. No ascites was noticed, and there was no splenomegaly or lymphadenopathy. Laboratory examination (reference values in brackets): creatinine 91 /.tmol/l (50-80), urea 4.7 mmol/1 (3.0-7.4), serum aspartate aminotransferase (ASAT) 509 U/I (<40), serum alanine aminotransferase (ALAT) 793 U/I (<40), ?-glutamyltransferase ()GT) 145 U/1 (4-35), alkaline phosphatase 217 U/1 (30-100), total bilirubin 83 /zmol/1 (3-18), conjugated bilirubin 52 pmol/1 (<3), amylase 71 U/I (<55) (see Fig. I). Routine hematological examinations were normal, as were glucose, sodium, potassium, and uric acid. Serology showed the absence of HBsAg, anti-HBs, anti-HBc and there were no antibodies
Correspondence to: Dr B. H. Ch. Stricker, Medical Officer, Netherlands Centre for Monitoring of Adverse Reactions to Drugs, P.O. Box 5406, 2280 HK Rijswijk, The Netherlands.
377
HEPATIC INJURY CAUSED BY BENZBROMARONE
800
• = SGPT (=ALAT) 700
• = Alkaline Phosphatase
600 500 400 30O 200 100
211 i
0 march 1987
-
11 3 may
i
i "; 10 31 4 july
,,
'
1 sept 26
17 jan jan may 1988 1989
,
1, 29 ,'3 july
1,
1, sept
3o april 1990
Benzbromarone Methyldopa
1 Colchicine AIIopurinol
i
l/I
may 1991
//
............ ,j~,~[
/,~i¢//
Fig. l. SGPT (ALAT), alkaline phosphatase and total bilirubin over the years, in association with the use of several drugs.
against hepatitis A. Antinuclear, antimitochondrial and anti-smooth muscle antibodies could not be demonstrated. A chest X-ray was normal. Ultrasonography showed a normal liver and gallbladder, no gallstones and no expanded intrahepatic bile ducts, but was suggestive of a mildly dilated choledochal and pancreatic duct. Subsequent endoscopic retrograde cholangiopancreatography (ERCP), however, showed normal intra- and extrahepatic bile ducts and no tumors or stones. All medication was stopped at her first visit to the outpatient clinic. Twenty-four days later, her liver function had improved, as shown by the following values: SGOT (ASAT) 43 U/l, SGPT (ALAT) 129 U/l, L D H 199 U/l, )GT 47 U/ 1, alkaline phosphatase 109 U/1 (Fig. 1). Liver function and liver enzymes normalized within 2 months after discontinuation of benzbromarone. During the following years, gout was subsequently treated with colchicine, allopurinol and sulfinpyrazone. Because these drugs were not effective, benzbromarone was started again 2 years after the episode of jaundice in a dose of 25 mg daily with regular checks of liver function. Together with the benzbromarone, she took colchicine, 500/.tg daily. After a month without any problems, the dose of benzbromarone was increased to 50 mg daily. Colchicine was continued at the same dose. Fourteen days later liver enzymes were again elevated: SGOT (ASAT) 139 U/l, SGPT (ALAT) 199 U/ 1, .?GT 34 U/l, alkaline phosphatase 102 U/I. Benzbroma-
rone was discontinued and colchicine was increased to 1500/.tg daily. Liver enzymes normalized over the next 2 months. Half a year later methyldopa was again administered, without any problems.
Discussion It is highly probable that hepatic injury was caused by benzbromarone in view of the temporal relationship, the absence of other possible causes and the relapse after readministration (2). Hepatitis A and B were excluded, and although hepatitis C was not ruled out, the patient had not received transfusions or other parenteral procedures, and there was no history of surgery. In view of the clinical picture and normal hematology, infectious mononucleosis and cytomegalovirus infection were considered unlikely causes of hepatic injury. Although ultrasonography was suggestive of a dilated choledochal duct, ERCP did not show any abnormalities. After the first episode, it was thought that methyldopa had caused the hepatic injury. Only after the recurrence of hepatic injury, was benzbromarone recognized as the cause. Although we are not aware of any reported cases of hepatic injury caused by benzbromarone, some inferences can be drawn from the striking similarity between benzbromarone, benzarone and benziodarone (Fig. 2). Benziodarone resembles amiodarone but lacks the di-
378
M.M. VAN DER KLAUW et al.
Amiodarone O
I / CH2 -
j
"
~
~
C
-
~ 0
CH3
O - CH2CH2 N "~ CH2 - CH3
-#~-C4H9
Benziodarone O
I OH
mH5 --q
Benzbromarone
i
Br
oJ, o2H
OH
Benzarone
o
C2H5 Fig. 2. Comparison of the structure of amiodarone, benziodarone, benzbromarone and benzarone.
ethylamino group. In 1964, benziodarone was withdrawn in the United Kingdom because of 14 cases of jaundice, which appeared 8-16 weeks after the start of treatment. These cases were reported from January to August 1964 to the Committee on Safety of Medicines (3,4). Few details were given and a causal relationship with the drug was debated. Benzarone has been associated with acute hepatocellular injury (5,6) and with chronic active hepatitis (7). Onset of symptoms, such as arthralgia, myalgia and jaundice was approximately 1 month after starting treatment (5,6) but in the other case, hepatic injury was discovered 6 months after starting treatment (7). In all cases, a relapse followed readministration within 10 days to 2~/,_ months (5-7). In two cases, antismooth muscle antibodies were present (6,7). Biopsies showed confluent hepatocellular necrosis (5,7) with portal fibrosis and ~. pattern suggestive of chronic
active hepatitis (7). Recently, the Federal Health Office in Germany suspended the marketing authorization for benzarone because of several reports of hepatic injury (8). The mechanism of hepatic injury caused by benzbromarone is unknown. It was initially thought that benzbromarone was metabolized to bromobenzarone and benzarone (9,10). This metabolic pathway was disputed, however, by others (11), who could not find any bromobenzarone or benzarone after oral administration of 100 mg benzbromarone to 10 healthy volunteers. A totally different metabolic pathway, in which benzbromarone was hydroxylated, was reported in 1988. Two other compounds, suggestive of metabolites, were found, one of them being monohydroxylated benzbromarone (12). Benzbromarone was found to undergo oxidation of the ethyl side chain and hydroxylation of the benzofuran ring, followed by methylation of one of the hydroxy groups (13). Earlier studies were said to have misinterpreted the chromatographic data. In 1991 seven metabolites were identified (14), several of which had structures which were different from those identified earlier (13). In view of the structural resemblance it is possible that benzbromarone, benzarone and benziodarone cause hepatic injury by a common mechanism, either by direct damage to the hepatocyte or indirectly by an immunoallergic reaction, secondary to the binding of reactive intermediates to cell constituents. The hypothesis of a common mechanism of hepatic injury may find some support in the fact that both benzarone and benzbromarone are hydroxylated in the benzofuran ring and in the ethyl side chain (14, 15). How far hepatic injury is related to the recently discovered different human elimination phenotypes (16) remains to be determined. The apparent rarity of the reaction at therapeutic doses suggests that individual susceptibility plays an important role. The absence of hypersensitivity symptoms and the delayed reaction to rechallenge are not suggestive of an immunoallergic reaction but could be compatible with metabolic idiosyncrasy. Although benziodarone also resembles amiodarone, hepatic injury caused by the latter is at least partly explained by lysosomal accumulation of the amphiphilic molecules amiodarone and desethylamiodarone. As benziodarone lacks the polar diethylamino moiety of amiodarone, its effect on the liver is probably different from amiodarone. Although the incidence of hepatic injury caused by benzbromarone is unknown, it is probably uncommon. Even so, medical practitioners should be aware of the possibility that the currently available benzofurans benzbromarone, benzarone and benziodarone may cause hepatocellular damage.
HEPATIC INJURY CAUSED BY BENZBROMARONE
References 1. Masbernard A, Giudicelli CP. Ten years experience with benzbromarone in the management of gout and hyperuricemia. S Afr Med J 1981; 59: 701-6. 2. Stricker BHCh. Diagnosis and causality assessment of drug-induced hepatic injury. In: Stricker BHCh ed. Drug-induced Hepatic Injury, 2nd Edn. Amsterdam, New York: Elsevier, 1992. 3. Lee H, Devey GF. Jaundice associated with benziodarone. Lancet 1964; i: 1280. 4. Cahal DA. Jaundice and 'Cardivix'. Lancet 1964; ii: 754. 5. Nakad A, Azzouzi K, Gerbaux A, et al. H6patite fi la benzarone: un deuxi~me cas. Gastroenterol Clin Biol 1990; 14: 782-4. 6. Sepulchre D, De Plaen JL, Geubel AP. H6patite m6dicamenteuse lice ~_la benzarone (Fragivix): ~ propos d'une observation clinique. Acta Gastro-Enterol Belg 1990; 53: 499-503. 7. Babany G, Larrey D, Pessayre D, Degott C, Rueff B, Benhamou JP. Chronic active hepatitis caused by benzarone. J Hepatol 1987; 5: 332-5. 8. Press release 45/1992 from the Federal Health Office, Berlin, October 20, 1992. 9. Broekhuysen J, Pacco M, Sion R, Demeulenaere L, Van Hee M. Metabolism of benzbromarone in man. Eur J Clin Pharmacol 1972; 4: 125-30.
379 10. Ferber H, Vergin H, Hitzenberger G. Pharmacokinetics and biotransformation of benzbromarone in man. Eur J Clin Pharmacol 1981; 19: 431-5. 11. De Vries JX, Walter-Sack I, Ittensohn A. Analysis of benzbromarone in human plasma and urine by high-performance liquid chromatography and gas chromatography-mass spectrometry. J Chromatogr 1987; 417: 420-7. 12. Walter-Sack I, De Vries JX, Ittensohn A, Kohlmeier M, Weber E. Benzbromarone disposition and uricosuric action; evidence for hydroxylation instead of debromination to benzarone. Klin Wochenschr 1988; 66: 160-6. 13. Maurer H, Wollenberg P. Urinary metabolites of benzbromarone in man. Arzneimittel-Forsch 1990; 40: 460-2. 14. Arnold PJ, Guserle R, Luckow V, Hemmer R, Grote H. Liquid chromatography-mass spectrometry in metabolic research: (I) metabolites of benzbromarone in human plasma and urine..I Chromatogr 1991; 544: 267-80. 15. Wood SG, John BA, Chasseaud LF, et al. Metabolic fate of the thrombolytic agent benzarone in man: comparison with the rat and dog. Xenobiotica 1987; 17: 881-96. 16. Walter-Sack I, De Vries JX, lttensohn A, Weber E. Rapid and slow benzbromarone elimination phenotypes in man: benzbromarone and metabolite profiles. Eur J Clin Pharmacol 1990; 39: 577-81.
Copyright©JournalofHepatology 1994 Journal of Hepatology
ISSN 0168-8278
Hepatic injury caused by benzbromarone Melanie M. van der K l a u w 1, Pieternella M. H o u t m a n 2, B r u n o H. Ch. Stricker 1'3 a n d Pieter Spoelstra 4 tDepartment of lnternal Medich~e 11, University Hospital Dijkzigt, Rotterdam, 2Department of Rheumatology, Medical Centre Leeuwarden, Leeuwarden, 3Netherlands Centre for Monitoring of Adverse Reactions to Drugs, Rijsw(jk, and 4Department of Gastroenterology and Hepatology, Medical Centre Leeuwarden, Leeuwarden, The Netherlands
(Received 31 August 1992)
This case study describes a woman who developed a predominantly hepatocellular injury, approximately 3 months after starting treatment with 100 mg benzbromarone daily. She had also taken 250 mg methyldopa daily for several years. Infections with hepatitis A and B were excluded serologically, no autoantibodies were demonstrated, and ultrasonography and endoscopic retrograde cholangiopancreatography did not show extrahepatic obstruction. The patient recovered after discontinuation of both drugs. Two years later, readministration of benzbromarone was followed by a relapse. Later, methyldopa was used without problems. We conclude that hepatic injury in this patient was caused by benzbromarone. © Journal of Hepatology. Key words." Adverse reactions; Drug-induced hepatic injury; Toxic hepatitis
Benzbromarone is a benzofuran derivative which is used as a uricosuric agent in the treatment of gout. Use of benzbromarone has occasionally been associated with diarrhea, rash, and renal colic due to urate and oxalate urolithiasis (1). To the best of our knowledge, however, no cases of hepatic injury caused by benzbromarone have been reported in the medical literature. We report a patient who developed hepatic injury caused by benzbromarone on two occasions.
Case
Report
A 68-year-old female had been treated for 3 years because of chronic gout with tophi on several fingers of both hands. As she was a low secretor of uric acid, and because allopurinol did not improve her condition, treatment was changed from allopurinol (up to 400 mg a day) to benzbromarone (Desuric®), 200 mg a day. In addition, she also received methyldopa (Aldomet ®) 250 mg daily for hypertension; no other drug was taken. After 6 weeks, the dose of benzbromarone was lowered to 100 mg daily. Her condition was stable at that time. Two months later she visited the outpatient clinic, having had influenza-like
complaints for several days. She had had diarrhea and her urine had been darker than usual. On presentation, there was malaise, anorexia and mild pain in the right upper abdomen when she bent forward. Her stools were looser than usual, but she did not complain of diarrhea any more and the color had not changed. She had a history of jaundice at 22 years of age. On examination, she was jaundiced, but there were no signs of chronic liver disease such as spider naevi or palmar erythema. There was mild abdominal tenderness and the liver was slightly palpable and smooth. No ascites was noticed, and there was no splenomegaly or lymphadenopathy. Laboratory examination (reference values in brackets): creatinine 91 /.tmol/l (50-80), urea 4.7 mmol/1 (3.0-7.4), serum aspartate aminotransferase (ASAT) 509 U/I (<40), serum alanine aminotransferase (ALAT) 793 U/I (<40), ?-glutamyltransferase ()GT) 145 U/1 (4-35), alkaline phosphatase 217 U/1 (30-100), total bilirubin 83 /zmol/1 (3-18), conjugated bilirubin 52 pmol/1 (<3), amylase 71 U/I (<55) (see Fig. I). Routine hematological examinations were normal, as were glucose, sodium, potassium, and uric acid. Serology showed the absence of HBsAg, anti-HBs, anti-HBc and there were no antibodies
Correspondence to: Dr B. H. Ch. Stricker, Medical Officer, Netherlands Centre for Monitoring of Adverse Reactions to Drugs, P.O. Box 5406, 2280 HK Rijswijk, The Netherlands.
377
HEPATIC INJURY CAUSED BY BENZBROMARONE
800
• = SGPT (=ALAT) 700
• = Alkaline Phosphatase
600 500 400 30O 200 100
211 i
0 march 1987
-
11 3 may
i
i "; 10 31 4 july
,,
'
1 sept 26
17 jan jan may 1988 1989
,
1, 29 ,'3 july
1,
1, sept
3o april 1990
Benzbromarone Methyldopa
1 Colchicine AIIopurinol
i
l/I
may 1991
//
............ ,j~,~[
/,~i¢//
Fig. l. SGPT (ALAT), alkaline phosphatase and total bilirubin over the years, in association with the use of several drugs.
against hepatitis A. Antinuclear, antimitochondrial and anti-smooth muscle antibodies could not be demonstrated. A chest X-ray was normal. Ultrasonography showed a normal liver and gallbladder, no gallstones and no expanded intrahepatic bile ducts, but was suggestive of a mildly dilated choledochal and pancreatic duct. Subsequent endoscopic retrograde cholangiopancreatography (ERCP), however, showed normal intra- and extrahepatic bile ducts and no tumors or stones. All medication was stopped at her first visit to the outpatient clinic. Twenty-four days later, her liver function had improved, as shown by the following values: SGOT (ASAT) 43 U/l, SGPT (ALAT) 129 U/l, L D H 199 U/l, )GT 47 U/ 1, alkaline phosphatase 109 U/1 (Fig. 1). Liver function and liver enzymes normalized within 2 months after discontinuation of benzbromarone. During the following years, gout was subsequently treated with colchicine, allopurinol and sulfinpyrazone. Because these drugs were not effective, benzbromarone was started again 2 years after the episode of jaundice in a dose of 25 mg daily with regular checks of liver function. Together with the benzbromarone, she took colchicine, 500/.tg daily. After a month without any problems, the dose of benzbromarone was increased to 50 mg daily. Colchicine was continued at the same dose. Fourteen days later liver enzymes were again elevated: SGOT (ASAT) 139 U/l, SGPT (ALAT) 199 U/ 1, .?GT 34 U/l, alkaline phosphatase 102 U/I. Benzbroma-
rone was discontinued and colchicine was increased to 1500/.tg daily. Liver enzymes normalized over the next 2 months. Half a year later methyldopa was again administered, without any problems.
Discussion It is highly probable that hepatic injury was caused by benzbromarone in view of the temporal relationship, the absence of other possible causes and the relapse after readministration (2). Hepatitis A and B were excluded, and although hepatitis C was not ruled out, the patient had not received transfusions or other parenteral procedures, and there was no history of surgery. In view of the clinical picture and normal hematology, infectious mononucleosis and cytomegalovirus infection were considered unlikely causes of hepatic injury. Although ultrasonography was suggestive of a dilated choledochal duct, ERCP did not show any abnormalities. After the first episode, it was thought that methyldopa had caused the hepatic injury. Only after the recurrence of hepatic injury, was benzbromarone recognized as the cause. Although we are not aware of any reported cases of hepatic injury caused by benzbromarone, some inferences can be drawn from the striking similarity between benzbromarone, benzarone and benziodarone (Fig. 2). Benziodarone resembles amiodarone but lacks the di-
378
M.M. VAN DER KLAUW et al.
Amiodarone O
I / CH2 -
j
"
~
~
C
-
~ 0
CH3
O - CH2CH2 N "~ CH2 - CH3
-#~-C4H9
Benziodarone O
I OH
mH5 --q
Benzbromarone
i
Br
oJ, o2H
OH
Benzarone
o
C2H5 Fig. 2. Comparison of the structure of amiodarone, benziodarone, benzbromarone and benzarone.
ethylamino group. In 1964, benziodarone was withdrawn in the United Kingdom because of 14 cases of jaundice, which appeared 8-16 weeks after the start of treatment. These cases were reported from January to August 1964 to the Committee on Safety of Medicines (3,4). Few details were given and a causal relationship with the drug was debated. Benzarone has been associated with acute hepatocellular injury (5,6) and with chronic active hepatitis (7). Onset of symptoms, such as arthralgia, myalgia and jaundice was approximately 1 month after starting treatment (5,6) but in the other case, hepatic injury was discovered 6 months after starting treatment (7). In all cases, a relapse followed readministration within 10 days to 2~/,_ months (5-7). In two cases, antismooth muscle antibodies were present (6,7). Biopsies showed confluent hepatocellular necrosis (5,7) with portal fibrosis and ~. pattern suggestive of chronic
active hepatitis (7). Recently, the Federal Health Office in Germany suspended the marketing authorization for benzarone because of several reports of hepatic injury (8). The mechanism of hepatic injury caused by benzbromarone is unknown. It was initially thought that benzbromarone was metabolized to bromobenzarone and benzarone (9,10). This metabolic pathway was disputed, however, by others (11), who could not find any bromobenzarone or benzarone after oral administration of 100 mg benzbromarone to 10 healthy volunteers. A totally different metabolic pathway, in which benzbromarone was hydroxylated, was reported in 1988. Two other compounds, suggestive of metabolites, were found, one of them being monohydroxylated benzbromarone (12). Benzbromarone was found to undergo oxidation of the ethyl side chain and hydroxylation of the benzofuran ring, followed by methylation of one of the hydroxy groups (13). Earlier studies were said to have misinterpreted the chromatographic data. In 1991 seven metabolites were identified (14), several of which had structures which were different from those identified earlier (13). In view of the structural resemblance it is possible that benzbromarone, benzarone and benziodarone cause hepatic injury by a common mechanism, either by direct damage to the hepatocyte or indirectly by an immunoallergic reaction, secondary to the binding of reactive intermediates to cell constituents. The hypothesis of a common mechanism of hepatic injury may find some support in the fact that both benzarone and benzbromarone are hydroxylated in the benzofuran ring and in the ethyl side chain (14, 15). How far hepatic injury is related to the recently discovered different human elimination phenotypes (16) remains to be determined. The apparent rarity of the reaction at therapeutic doses suggests that individual susceptibility plays an important role. The absence of hypersensitivity symptoms and the delayed reaction to rechallenge are not suggestive of an immunoallergic reaction but could be compatible with metabolic idiosyncrasy. Although benziodarone also resembles amiodarone, hepatic injury caused by the latter is at least partly explained by lysosomal accumulation of the amphiphilic molecules amiodarone and desethylamiodarone. As benziodarone lacks the polar diethylamino moiety of amiodarone, its effect on the liver is probably different from amiodarone. Although the incidence of hepatic injury caused by benzbromarone is unknown, it is probably uncommon. Even so, medical practitioners should be aware of the possibility that the currently available benzofurans benzbromarone, benzarone and benziodarone may cause hepatocellular damage.
HEPATIC INJURY CAUSED BY BENZBROMARONE
References 1. Masbernard A, Giudicelli CP. Ten years experience with benzbromarone in the management of gout and hyperuricemia. S Afr Med J 1981; 59: 701-6. 2. Stricker BHCh. Diagnosis and causality assessment of drug-induced hepatic injury. In: Stricker BHCh ed. Drug-induced Hepatic Injury, 2nd Edn. Amsterdam, New York: Elsevier, 1992. 3. Lee H, Devey GF. Jaundice associated with benziodarone. Lancet 1964; i: 1280. 4. Cahal DA. Jaundice and 'Cardivix'. Lancet 1964; ii: 754. 5. Nakad A, Azzouzi K, Gerbaux A, et al. H6patite fi la benzarone: un deuxi~me cas. Gastroenterol Clin Biol 1990; 14: 782-4. 6. Sepulchre D, De Plaen JL, Geubel AP. H6patite m6dicamenteuse lice ~_la benzarone (Fragivix): ~ propos d'une observation clinique. Acta Gastro-Enterol Belg 1990; 53: 499-503. 7. Babany G, Larrey D, Pessayre D, Degott C, Rueff B, Benhamou JP. Chronic active hepatitis caused by benzarone. J Hepatol 1987; 5: 332-5. 8. Press release 45/1992 from the Federal Health Office, Berlin, October 20, 1992. 9. Broekhuysen J, Pacco M, Sion R, Demeulenaere L, Van Hee M. Metabolism of benzbromarone in man. Eur J Clin Pharmacol 1972; 4: 125-30.
379 10. Ferber H, Vergin H, Hitzenberger G. Pharmacokinetics and biotransformation of benzbromarone in man. Eur J Clin Pharmacol 1981; 19: 431-5. 11. De Vries JX, Walter-Sack I, Ittensohn A. Analysis of benzbromarone in human plasma and urine by high-performance liquid chromatography and gas chromatography-mass spectrometry. J Chromatogr 1987; 417: 420-7. 12. Walter-Sack I, De Vries JX, Ittensohn A, Kohlmeier M, Weber E. Benzbromarone disposition and uricosuric action; evidence for hydroxylation instead of debromination to benzarone. Klin Wochenschr 1988; 66: 160-6. 13. Maurer H, Wollenberg P. Urinary metabolites of benzbromarone in man. Arzneimittel-Forsch 1990; 40: 460-2. 14. Arnold PJ, Guserle R, Luckow V, Hemmer R, Grote H. Liquid chromatography-mass spectrometry in metabolic research: (I) metabolites of benzbromarone in human plasma and urine..I Chromatogr 1991; 544: 267-80. 15. Wood SG, John BA, Chasseaud LF, et al. Metabolic fate of the thrombolytic agent benzarone in man: comparison with the rat and dog. Xenobiotica 1987; 17: 881-96. 16. Walter-Sack I, De Vries JX, lttensohn A, Weber E. Rapid and slow benzbromarone elimination phenotypes in man: benzbromarone and metabolite profiles. Eur J Clin Pharmacol 1990; 39: 577-81.