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Drug interactions with zileuton
THE LANCET
haemorrhage and intracerebral haematoma owing to the rupture of a middle cerebral artery aneurysm on the right side in 1995. Although a blisterlike dilatation was not observed on the first angiogram, a small aneurysmal dilatation was detected on the angiogram taken at the time of the second haemorrhage. We emphasise that this patient could develop new aneurysms4 or growth of a small blisterlike dilatation to an apparent aneurysm resulting in subarachnoid haemorrhage. Thus, a close follow-up angiography should be a mandatory examination in patients who have polycystic kidney disease with ruptured aneurysms. There might also be a possibility of recurrent subarachnoid haemorrhage due to a second or third aneurysm that might be too small to detect on the initial angiogram. We operated on a patient with polycystic kidney disease, in January, 1997, who had three aneurysms and one junctional dilatation of the posterior communicating artery. Three aneurysms were successfully obliterated. A follow-up angiography is scheduled for January, 1998, because the diameter of the junctional dilatation was about 4 mm and its wall appeared thin during surgery. Although magnetic resonance angiography and threedimensional computed tomography are non-invasive, such screening methods are not feasible in patients who have been treated with a metal clip used for obliterating the aneurysm. Susumu Wakai Dokkyo University School of Medicine, Mibu, Tochigi 321-02, Japan
1
2
3
4
Ronkainen A, Hernesniemi J, Puranen M, et al. Familial intracranial aneurysms. Lancet 1997. 349: 380–84. Wakabayashi T, Fujita S, Ohbora Y, Suyama T, Tamaki N, Matsumoto S. Polycystic kidney disease and intracranial aneurysms: early angiographic diagnosis and early operation for the unruptured aneurysm. J Neurosurg 1983; 58: 488–91. Wakai S, Okuhata S, Inoh S, Ochiai C, Watanabe K, Nagai M. Growth of cerebral aneurysms. In: Sugita K, Shibuya M, eds. Intracranial aneurysms and arteriovenous malformations. Nagoya: Nagoya University COOP Press, 1990: 11–15. Wakai S. Clinical studies of de novo aneurysms. Neurosurgery 1994; 34: 1102.
Drug interactions with zileuton SIR—In the August, 1996, issue of The Lancet, McGill and Busse stated that no drug interactions involving zileuton have been reported.1 However, there is clear evidence indicating that zileuton has important drug interactions with warfarin, theophylline, terfenadine, and propranolol.2–4 Two studies were
Vol 349 • May 17, 1997
published in Clinical Pharmacokinetics in December, 1995, reporting warfarin and theophylline drug interactions associated with zileuton.3,4 The manufacturer also warns of zileuton interactions with terfenadine and propranolol.1 I draw attention to the issue of drug interaction when zileuton is administered. In a double-blinded, placebocontrolled study, a zileuton regimen of 600 mg every 6 h or placebo was given to healthy adults.3 The volunteers also received warfarin. The prothrombin time for each volunteer was adjusted to 14–18 s with different warfarin doses. The co-administration of zileuton with warfarin reduced the clearance of warfarin by 15% and increased serum concentrations by 22%, which resulted in a significant prolongation of the prothrombin time. Warfarin is known to be a metabolic substrate for the CYP1A2 and CYP2C9 isozymes. The mechanism of the drug interaction is thought to be competitive inhibition of these isozymes by zileuton.3 When treatment requires both zileuton and warfarin, monitoring of prothrombin/INR and for signs and symptoms of bleeding is strongly recommended. A pharmacokinetic study examined zileuton and theophylline interaction.4 The randomised, placebo-controlled trial gave healthy volunteers theophylline 200 mg four times a day. The volunteers also received zileuton 800 mg twice daily, or placebo. The results showed that when zileuton and theophylline were taken at the same time, both the peak and trough levels of theophylline were increased by 75–125% compared with placebo. The estimated drop in steady-state clearance was 50%, resulting in an increase of theophylline serum half-life of about 24%. Theophylline clearance is mainly through metabolism by hepatic isozymes CYP1A and CYP3A. The mechanism of this drug interaction might be competition of substrate sites on these enzymes. Theophylline has a narrow therapeutic range of about 10–20 µg/mL. Some volunteers given theophylline and zileuton reported increases in reactions such as nausea, dyspepsia, abdominal pain, headache, and tachycardia that might have been related to the high theophylline concentrations. When zileuton and theophylline are given concomitantly, theophylline dose should be lowered by half.2 In addition, close monitoring of theophylline concentrations is warranted. The manufacturer package insert includes two reports on zileuton interactions with terfenadine and propranolol. Zileuton is reported to reduce their clearance and increase their bioavailability. Concomitant use
of zileuton and terfenadine is not recommended. Care should be taken when propranolol is used together with zileuton. Since zileuton is metabolised by the cytochrome P450 enzyme system, which metabolises many other drugs, other drugs interactions are possible. Clinicians should therefore be on alert to ensure proper clinical monitoring. Rebecca Lau University of Washington Medical Center, Seattle, WA, USA
1 2
3
4
McGill KA, Busse WW. Zileuton. Lancet 1996; 348: 519–24. ZyfloTMFilmtab (zileuton tablet) manufacturer’s package insert, Abbott Laboratories, USA. Awni WM, Hussein Z, Granneman GR, et al. Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans. Clin Pharmacokinet 1995; 29 (suppl 2): 67–76. Granneman GR, Braeckman RA, Cavanaugh JH, et al. Effect of zileuton on theophylline pharmacokinetics. Clin Pharmacokinet 1995; 29 (suppl 2): 77–83.
Authors’ reply SIR—At the time our drug profile was submitted for consideration to The Lancet, there were no published reports of drug interactions involving zileuton, a selective 5-lipoxygenase inhibitor. In our review, we stated that because zileuton is hepatically metabolised, clinicians should remain alert for possible drug interactions. Lau correctly states that since the review was published important drug interactions with zileuton have been described. In fact, because of zileuton’s metabolism by the cytochrome P450 enzyme system, one can anticipate that other interactions will be identified. In addition to the drug interactions described by Lau between zileuton and warfarin, theophylline, terfenadine, and propranolol, other pharmacokinetic studies have been conducted examining the potential for interactions between zileuton and digoxin, salicylate, phenytoin, and prednisone.1–4 Zileuton has been shown to substantially decrease the mean time to maximum digoxin plasma concentrations (0·95 vs 1·43 h) over 13 days in a placebocontrolled, crossover study in volunteers.1 However, there was no evidence that zileuton had any large overall effect on the plasma concentration-time profile of digoxin; thus co-administration of zileuton and digoxin does not require increased clinical monitoring of digoxin.1 Concomitant administration of sulphasalazine with zileuton over 8 days in volunteers had no significant effects on the pharmacokinetics of sulphasalazine or its metabolites, sulphapyridine, and N-acetylsulphapyridine.2 A randomised, double-blind, cross-
1479
haemorrhage and intracerebral haematoma owing to the rupture of a middle cerebral artery aneurysm on the right side in 1995. Although a blisterlike dilatation was not observed on the first angiogram, a small aneurysmal dilatation was detected on the angiogram taken at the time of the second haemorrhage. We emphasise that this patient could develop new aneurysms4 or growth of a small blisterlike dilatation to an apparent aneurysm resulting in subarachnoid haemorrhage. Thus, a close follow-up angiography should be a mandatory examination in patients who have polycystic kidney disease with ruptured aneurysms. There might also be a possibility of recurrent subarachnoid haemorrhage due to a second or third aneurysm that might be too small to detect on the initial angiogram. We operated on a patient with polycystic kidney disease, in January, 1997, who had three aneurysms and one junctional dilatation of the posterior communicating artery. Three aneurysms were successfully obliterated. A follow-up angiography is scheduled for January, 1998, because the diameter of the junctional dilatation was about 4 mm and its wall appeared thin during surgery. Although magnetic resonance angiography and threedimensional computed tomography are non-invasive, such screening methods are not feasible in patients who have been treated with a metal clip used for obliterating the aneurysm. Susumu Wakai Dokkyo University School of Medicine, Mibu, Tochigi 321-02, Japan
1
2
3
4
Ronkainen A, Hernesniemi J, Puranen M, et al. Familial intracranial aneurysms. Lancet 1997. 349: 380–84. Wakabayashi T, Fujita S, Ohbora Y, Suyama T, Tamaki N, Matsumoto S. Polycystic kidney disease and intracranial aneurysms: early angiographic diagnosis and early operation for the unruptured aneurysm. J Neurosurg 1983; 58: 488–91. Wakai S, Okuhata S, Inoh S, Ochiai C, Watanabe K, Nagai M. Growth of cerebral aneurysms. In: Sugita K, Shibuya M, eds. Intracranial aneurysms and arteriovenous malformations. Nagoya: Nagoya University COOP Press, 1990: 11–15. Wakai S. Clinical studies of de novo aneurysms. Neurosurgery 1994; 34: 1102.
Drug interactions with zileuton SIR—In the August, 1996, issue of The Lancet, McGill and Busse stated that no drug interactions involving zileuton have been reported.1 However, there is clear evidence indicating that zileuton has important drug interactions with warfarin, theophylline, terfenadine, and propranolol.2–4 Two studies were
Vol 349 • May 17, 1997
published in Clinical Pharmacokinetics in December, 1995, reporting warfarin and theophylline drug interactions associated with zileuton.3,4 The manufacturer also warns of zileuton interactions with terfenadine and propranolol.1 I draw attention to the issue of drug interaction when zileuton is administered. In a double-blinded, placebocontrolled study, a zileuton regimen of 600 mg every 6 h or placebo was given to healthy adults.3 The volunteers also received warfarin. The prothrombin time for each volunteer was adjusted to 14–18 s with different warfarin doses. The co-administration of zileuton with warfarin reduced the clearance of warfarin by 15% and increased serum concentrations by 22%, which resulted in a significant prolongation of the prothrombin time. Warfarin is known to be a metabolic substrate for the CYP1A2 and CYP2C9 isozymes. The mechanism of the drug interaction is thought to be competitive inhibition of these isozymes by zileuton.3 When treatment requires both zileuton and warfarin, monitoring of prothrombin/INR and for signs and symptoms of bleeding is strongly recommended. A pharmacokinetic study examined zileuton and theophylline interaction.4 The randomised, placebo-controlled trial gave healthy volunteers theophylline 200 mg four times a day. The volunteers also received zileuton 800 mg twice daily, or placebo. The results showed that when zileuton and theophylline were taken at the same time, both the peak and trough levels of theophylline were increased by 75–125% compared with placebo. The estimated drop in steady-state clearance was 50%, resulting in an increase of theophylline serum half-life of about 24%. Theophylline clearance is mainly through metabolism by hepatic isozymes CYP1A and CYP3A. The mechanism of this drug interaction might be competition of substrate sites on these enzymes. Theophylline has a narrow therapeutic range of about 10–20 µg/mL. Some volunteers given theophylline and zileuton reported increases in reactions such as nausea, dyspepsia, abdominal pain, headache, and tachycardia that might have been related to the high theophylline concentrations. When zileuton and theophylline are given concomitantly, theophylline dose should be lowered by half.2 In addition, close monitoring of theophylline concentrations is warranted. The manufacturer package insert includes two reports on zileuton interactions with terfenadine and propranolol. Zileuton is reported to reduce their clearance and increase their bioavailability. Concomitant use
of zileuton and terfenadine is not recommended. Care should be taken when propranolol is used together with zileuton. Since zileuton is metabolised by the cytochrome P450 enzyme system, which metabolises many other drugs, other drugs interactions are possible. Clinicians should therefore be on alert to ensure proper clinical monitoring. Rebecca Lau University of Washington Medical Center, Seattle, WA, USA
1 2
3
4
McGill KA, Busse WW. Zileuton. Lancet 1996; 348: 519–24. ZyfloTMFilmtab (zileuton tablet) manufacturer’s package insert, Abbott Laboratories, USA. Awni WM, Hussein Z, Granneman GR, et al. Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans. Clin Pharmacokinet 1995; 29 (suppl 2): 67–76. Granneman GR, Braeckman RA, Cavanaugh JH, et al. Effect of zileuton on theophylline pharmacokinetics. Clin Pharmacokinet 1995; 29 (suppl 2): 77–83.
Authors’ reply SIR—At the time our drug profile was submitted for consideration to The Lancet, there were no published reports of drug interactions involving zileuton, a selective 5-lipoxygenase inhibitor. In our review, we stated that because zileuton is hepatically metabolised, clinicians should remain alert for possible drug interactions. Lau correctly states that since the review was published important drug interactions with zileuton have been described. In fact, because of zileuton’s metabolism by the cytochrome P450 enzyme system, one can anticipate that other interactions will be identified. In addition to the drug interactions described by Lau between zileuton and warfarin, theophylline, terfenadine, and propranolol, other pharmacokinetic studies have been conducted examining the potential for interactions between zileuton and digoxin, salicylate, phenytoin, and prednisone.1–4 Zileuton has been shown to substantially decrease the mean time to maximum digoxin plasma concentrations (0·95 vs 1·43 h) over 13 days in a placebocontrolled, crossover study in volunteers.1 However, there was no evidence that zileuton had any large overall effect on the plasma concentration-time profile of digoxin; thus co-administration of zileuton and digoxin does not require increased clinical monitoring of digoxin.1 Concomitant administration of sulphasalazine with zileuton over 8 days in volunteers had no significant effects on the pharmacokinetics of sulphasalazine or its metabolites, sulphapyridine, and N-acetylsulphapyridine.2 A randomised, double-blind, cross-
1479