Eur J Clin Pharmacol (1991) 41:501 EuropeanJournalof ( ~ ( ~ @ ~
@l e u ecei]e@ ] © Springer-Verlag 1991
Letters to the editors
Pharmacokinetics of flumazenil in fulminant hepatic failure C. C. D. van der Rijt 1, R. H. Drost 2, S. W. Schalm 1, and M. Schramel 2 Department of Internal Medicine II, University Hospital Dijkzigt, Rotterdam and 2 Netherlands Institute for Drugs and Doping Research, University of Utrecht, Utrecht, The Netherlands
Received: July 20, 1990/Acceptedin revised form: April 6, 1991
Key words: Pharmacokinetics, Flumazenil; fulminant hepatic failure
Flumazenil, the first benzodiazepine antagonist available in clinical practice, is rapidly eliminated from the body by the liver, with an elimination half-life of about 1 h and a plasma clearance rate of about 1 1/min [1-4]. Recent studies of its elimination rate in chronic liver disease showed about a 2-4 fold increase in elimination half-life and a 2-4 fold decrease in plasma clearance [5-6]. Similar results were recently obtained in 4 controls and 3 patients with severe chronic liver disease (tl/2 0.74-1.21 h and 2.08-3.16 h, respectively; CL 694-858 ml-min-1 and 218-322 m l . m i n 1, respectively). The pharmacokinetics of flumazenil was also examined in 3 patients with fulminant hepatic failure. They received 1.0 mg injected over 10 min. Blood samples were taken from the contralateral arm before injection and after 0, 2, 5,10, 20, 30, 60,120,180 and 240 min. Measurement of plasma flumazenil levels was performed by gas chromatography on a fused silica column, emplying automated splitless injection and nitrogenphosphorus sensitive detection. The individual plasma concentration-time curves were fitted to 2 exponentional terms. Elimination from the body was severely impaired,
Table 1. Patient characteristics and individual disposition kinetics of flumazenil Subject
A
B
C
sex age (y) albumin (g.1 1,N 36-48) antithrombin III (U/l, N > 85) bilirubin (gM, N < 12) ASAT (U. 1-~,N < 30)
F 18 31 0.10 196 94
M 18 31 0.01 556 330
F 18 30 457 304
2.25 261 2.98 46.5
6.56 144 9.39 81.0
5.59 122 8.08 59.1
Pharmacokinetics
tx/2(h) CL (ml.min ~) MRT (h) Vs~(1)
not detectable in plasma; tu2 half-life; CL clearance rate; MRT mean residence time; Vs~ volume of distribution calculated from the product of the MRT and the clearance a
with plasma half-lives up to 7-times normal and up to a 7fold decrease in the plasma clearance rate (table). We conclude that the pharmacokinetics of flumazenil is severely impaired in chronic liver disease as well as in fulminant hepatic failure. Flumazenil is currently under investigation for the treatment of hepatic encephalopathy [7-9]. The impaired elimination rate must be considered in evaluation of studies of the use of flumazenil for hepatic encephalopathy.
References 1. Klotz U, Ziegler G, Reimann IW (1984) Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man. Eur J Ctin Pharmaco127:115-117 2. Klotz U, Duka Th, Dorow R0 Doenicke A (1985) Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15-1788.Br J Clin Pharmacol 19:95-98 3. Klotz U, Ziegler G, Ludwig L, Reimann IW (1985) Pharmacodynamic interaction between midazolam and a specific benzodiazepine antagonist in humans. J Clin Pharmaco125: 400-406 4. Roncari G, Ziegler WH, Guentert TW (1986) Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788in man following intravenous and oral administration. Br J Clin Pharmaco122: 421-428 5. Pomier-Layrargues G, Giguhre JR Lavoie J, Willems B, Butterworth RF (1989) Pharmacokinetics of benzodiazepine antagonist Ro 15-1788in cirrhotic patients with moderate or severe liver dysfunction. Hepatology 10:969-972 6. Janssen U, Walker S, Maier K, Von Gaisberg U, Klotz U (1989) Flumazenil disposition and elimination in cirrhosis. Clin Pharmacol Ther 46:317-323 7. Scollo-LavizzariO, Steinmann E (1985) Reversal of hepatic coma by benzodiazepine antagonist Ro 15-1788.Lancet I: 1324 8. Bansky G, Meier PJ, Riederer E, Walser H, Ziegler WH, Schmid M (1989) Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology 97:44-50 9. Grimm G, Katzenschlager R, Schneeweiss Bet al. (1988) Improvement of hepatic encephalopathy treated with flumazenil. Lancet 11:1392-1394 Dr. S. W. Schalm Department of Internal Medicine II University Hospital Dijkzigt Dr. Molewaterplein 40 NL-3015 GD Rotterdam The Netherlands
@l e u ecei]e@ ] © Springer-Verlag 1991
Letters to the editors
Pharmacokinetics of flumazenil in fulminant hepatic failure C. C. D. van der Rijt 1, R. H. Drost 2, S. W. Schalm 1, and M. Schramel 2 Department of Internal Medicine II, University Hospital Dijkzigt, Rotterdam and 2 Netherlands Institute for Drugs and Doping Research, University of Utrecht, Utrecht, The Netherlands
Received: July 20, 1990/Acceptedin revised form: April 6, 1991
Key words: Pharmacokinetics, Flumazenil; fulminant hepatic failure
Flumazenil, the first benzodiazepine antagonist available in clinical practice, is rapidly eliminated from the body by the liver, with an elimination half-life of about 1 h and a plasma clearance rate of about 1 1/min [1-4]. Recent studies of its elimination rate in chronic liver disease showed about a 2-4 fold increase in elimination half-life and a 2-4 fold decrease in plasma clearance [5-6]. Similar results were recently obtained in 4 controls and 3 patients with severe chronic liver disease (tl/2 0.74-1.21 h and 2.08-3.16 h, respectively; CL 694-858 ml-min-1 and 218-322 m l . m i n 1, respectively). The pharmacokinetics of flumazenil was also examined in 3 patients with fulminant hepatic failure. They received 1.0 mg injected over 10 min. Blood samples were taken from the contralateral arm before injection and after 0, 2, 5,10, 20, 30, 60,120,180 and 240 min. Measurement of plasma flumazenil levels was performed by gas chromatography on a fused silica column, emplying automated splitless injection and nitrogenphosphorus sensitive detection. The individual plasma concentration-time curves were fitted to 2 exponentional terms. Elimination from the body was severely impaired,
Table 1. Patient characteristics and individual disposition kinetics of flumazenil Subject
A
B
C
sex age (y) albumin (g.1 1,N 36-48) antithrombin III (U/l, N > 85) bilirubin (gM, N < 12) ASAT (U. 1-~,N < 30)
F 18 31 0.10 196 94
M 18 31 0.01 556 330
F 18 30 457 304
2.25 261 2.98 46.5
6.56 144 9.39 81.0
5.59 122 8.08 59.1
Pharmacokinetics
tx/2(h) CL (ml.min ~) MRT (h) Vs~(1)
not detectable in plasma; tu2 half-life; CL clearance rate; MRT mean residence time; Vs~ volume of distribution calculated from the product of the MRT and the clearance a
with plasma half-lives up to 7-times normal and up to a 7fold decrease in the plasma clearance rate (table). We conclude that the pharmacokinetics of flumazenil is severely impaired in chronic liver disease as well as in fulminant hepatic failure. Flumazenil is currently under investigation for the treatment of hepatic encephalopathy [7-9]. The impaired elimination rate must be considered in evaluation of studies of the use of flumazenil for hepatic encephalopathy.
References 1. Klotz U, Ziegler G, Reimann IW (1984) Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man. Eur J Ctin Pharmaco127:115-117 2. Klotz U, Duka Th, Dorow R0 Doenicke A (1985) Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15-1788.Br J Clin Pharmacol 19:95-98 3. Klotz U, Ziegler G, Ludwig L, Reimann IW (1985) Pharmacodynamic interaction between midazolam and a specific benzodiazepine antagonist in humans. J Clin Pharmaco125: 400-406 4. Roncari G, Ziegler WH, Guentert TW (1986) Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788in man following intravenous and oral administration. Br J Clin Pharmaco122: 421-428 5. Pomier-Layrargues G, Giguhre JR Lavoie J, Willems B, Butterworth RF (1989) Pharmacokinetics of benzodiazepine antagonist Ro 15-1788in cirrhotic patients with moderate or severe liver dysfunction. Hepatology 10:969-972 6. Janssen U, Walker S, Maier K, Von Gaisberg U, Klotz U (1989) Flumazenil disposition and elimination in cirrhosis. Clin Pharmacol Ther 46:317-323 7. Scollo-LavizzariO, Steinmann E (1985) Reversal of hepatic coma by benzodiazepine antagonist Ro 15-1788.Lancet I: 1324 8. Bansky G, Meier PJ, Riederer E, Walser H, Ziegler WH, Schmid M (1989) Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology 97:44-50 9. Grimm G, Katzenschlager R, Schneeweiss Bet al. (1988) Improvement of hepatic encephalopathy treated with flumazenil. Lancet 11:1392-1394 Dr. S. W. Schalm Department of Internal Medicine II University Hospital Dijkzigt Dr. Molewaterplein 40 NL-3015 GD Rotterdam The Netherlands
