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Lack of evidence for reduction of theophylline clearance by ranitidine
I i CORRESPONDENCE
IDIOPATHIC HYPERAMMONEMIA AFTER HIGH-DOSE CHEMOTHERAPY
LACK OF EVIDENCE FOR REDUCTION OF THEOPHYLLINE CLEARANCE BY RANITIDINE
To the Editor: A syndrome of idiopathic hyperammonemia in patients with hematologic malignancy has recently been described by Mitchell et al (Am J Med 1988; 85: 662-667). Central to their description of the syndrome is the appearance of elevated plasma ammonia levels following cytoreductive chemotherapy. We report a patient with idiopathic hyperammonemia in the setting of untreated multiple myeloma. A 67-year-old white man was admitted with a two-week history of increasing lethargy, hallucinations, and back pain. Results of initial neurologic examination were nonfocal, but the patient had alternating periods of lucidity and delirium. Findings on laboratory studies were as follows: blood urea nitrogen 46 mg/dL; creatinine 8.5 mg/ dL; serum calcium 16.8 mg/dL; ammonia 67 mg/dL; normal bilirubin, alkaline phosphatase, and hepatic transaminases. Multiple myeloma (IgG-kappa) was diagnosed based on urine and serum immunoelectrophoretic studies and bone marrow aspiration. The patient’s level of consciousness varied widely, and ammonia levels remained persistently elevated despite lactulose therapy. On two occasions, the patient developed acute hypoventilation, requiring intubation. Despite initiation of aggressive chemotherapy, the patient died on the 27th hospital day. We believe that this patient demonstrated the syndrome of idiopathic hyperammonemia in the setting of hematologic malignancy, and suggest that the syndrome be considered in patients with the appropriate clinical presentation, even in the absence of cytoreductive chemotherapy. PAUL FINE, M.D. KENNETH ADLER, M.D. DAVID GERSTENFELD,M.D. Morristown Memorial Hospital Morristown, New Jersey
To the Editor: Roy et al (Am J Med 1988; 85: 525527) recently reported three patients who had elevated theophylline levels and symptoms of theophylline toxicity associated with ranitidine administration. The authors concluded from their findings that the increase in serum theophylline levels in their patients was a result of inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism, producing a decreased theophylline clearance. The authors make this claim without sufficient documentation in their patients and despite the fact that eight controlled clinical studies in more than 70 subjects have shown no effect of ranitidine on theophylline clearance [l]. However, the authors do raise a series of interesting questions in defense of their assumption. These include: (1) Do singledose intravenous studies reflect what is seen with oral administration at steady state in patients? (2) Do elderly patients or patients with chronic obstructive pulmonary disease (COPD) respond differently from healthy volunteers in studies?, and (3) Studies, even with large numbers, may not detect interindividual sensitivity to the drug effect. An extensive review of the existing literature on cimetidine, a proven inhibitor of the cytochrome P-450 enzymes, reveals the answers to these questions. Utilizing a single intravenous dose of aminophylline, Powell et al [2] showed that cimetidine at 300 mg four times daily produced a 36% (range, 22% to 49%) decrease in theophylline clearance in 12 healthy adult volunteers. Hsu et al [3] found the same degree of inhibition of theophylline clearance in 19 elderly COPD patients at steady state using rapid-release theophylline (37.80/o, 26.2% to 46.7%) or sustained-release theophylline (33.4%, 22.2% to 45%). Furthermore, using stable isotope methodology, Vestal et al [4] confirmed that elderly
Submitted January 20, 1989, and accepted January 27, 1989
May 1989
COPD patients receiving steadystate oral sustained-release theophylline do not respond differently (33% decrease) from healthy volunteers. In a comparative study designed specifically to determine the influence of age, Adebayo and Coker [5] found no difference between the effect of cimetidine on theophylline disposition in the elderly versus young adults. In regard to ranitidine, Roy et al did not note in their discussion that single intravenous aminophylline studies in elderly COPD patients [6] and multiple-dose oral sustained-release theophylline studies at steady state in asthmatic patients [7] and elderly COPD patients [B] have also failed to demonstrate an effect of ranitidine on theophylline clearance. As pointed out by the authors, the possibility of interindividual sensitivity to an effect is difficult to assess by studies designed to determine the predominant response in the population However, when that logic is used, 21 of 41 subjects from studies in which individual data are available had apparent decreases in theophylline clearance during ranitidine administration when compared with control subjects [2,7,9,10]. In contrast, 20 of 41 subjects had an increase or no change in theophylline clearance, which provides as much evidence for induction of metabolism as inhibition. However, this probably represents the well-documented intraindividual variation of theophylline clearance over time, which can fluctuate as much as 30% [ 111. Case reports are important to alert clinicians and researchers to the possibility of adverse effects of drugs and deleterious drug interactions; however, when they are in direct contradiction with established findings of well-controlled studies, it is essential that they be well documented. It is my opinion that Roy et al provided insufficient data and documentation to warrant their conclusions. It is probably no coincidence that the authors’ three patients and the previous two other patients reported in the literature
The American
Journal
of Medicine
Volume
86
629
CORRESPONDENCE
H. WILLIAMKELLY,
TABLE I Theophylline
Clearance
Values in Patient 1 of Roy et a/
were taking sustained-release oral theophylline preparations, and the changes in apparent theophylline clearance were based on single theophylline level determinations. Sustained-release theophylline preparations have well-documented inconsistent absorption characteristics that can be affected by food, gastric pH changes, and diurnal variation, as well as being randomly inconsistent [12]. Data from two patients in an excellent study by Rogers et al [13] illustrate this problem: In Patient 1, two 6 A.M. theophylline levels obtained within 48 hours of each other were 10 pg/ mL and 13.5 pg/mL, a 35% difference, and a 6 P.M. level was 16 pg/ mL (60%), producing a 37.5% alteration in apparent clearance if calculated in the manner of Roy et al; Patient 2 would have a 68% change in apparent theophylline clearance if the minimum and maximum theophylline levels recorded over the 48-hour interval were used to calculate the clearance. Although the authors stated the theophylline levels were all obtained 12 hours following the last dose of theophylline, they did not state whether they were drawn at the same time of day. In addition, using the data supplied by the authors and their method of calculations, I came up with totally different clearance values (Table I). There are other unanswered questions as well. When were the first levels obtained that were used to calculate the initial clearance values? How long before ranitidine administration was started? Was it at the time the patients initially presented with gastrointestinal complaints of gastric pain or hematemesis, or both, which are documented toxicities of theophylline [14]? At that time, the patients may have had increasing theophylline levels producing theophylline toxicity before initiation of ranitidine. The readers, however, are unable to determine that. In addition, an estimate of the apparent half630
May 1989
The American
Journal
lives for the patients’ clearance rates (Patient 1, 35.4 hours and 39.5 hours; Patient 2, 36.2 hours; Patient 3, three to 17 hours) during ranitidine administration would indicate that only Patient 3 had truly reached steady state (five half-lives) and that the authors’ estimated change is an underestimate if there was a change in clearance. The question of compliance should also be raised if the levels obtained while ranitidine was discontinued were during outpatient visits and the levels drawn when ranitidine was being administered were during hospitalization, when compliance could be assured. One reason for noncompliance are side effects from the drug (e.g., gastric pain). The authors have already stated that Patient 3 was not at steady state for the first determination, and the difference in theophylline levels seen is consistent with the variability in absorption or the intrapatient variability in clearance, or both. Finally, Patient 2 was taking a sustained-release preparation that has a documented increased rate of dissolution and absorption with antacids and elevated gastric pH [15]. That leaves only Patient 1 with an unexplained increase in serum theophylline concentrations and an apparently phenomenal decrease in theophylline clearance (68% or greater) compared to even the known potent inhibitor cimetidine, which produces a 5% to 50% inhibition. Could this be an individual sensitivity of this patient to competitive inhibition of P-450 isozymes responsible for theophylline metabolism by ranitidine, as suggested? It is unlikely, in that ranitidine does not impair the metabolism of antipyrine, a compound that shares metabolic isozymes with theophylline [1,9]. Also, despite the authors’ last statement in the discussion, there is no evidence that ranitidine and theophylline share the same isozymes for their respective metabolic conversion.
of Medicine
Volume
86
Pharm.~.
Uniuersitv of New Mexico Albuquerque, Ngw’Merico 87131 1. Mitchard M, Harris A, Mullinger BM: Ranitidine drug interactions-a literature review. Pharmacol Ther 1987; 32: 293-325. 2. Powell JR, Rogers JF. Wargin WA, eta/: Inhibition of theophylline clearance by cimetidine but not ranitidine. Arch Intern Med 1984; 144: 484-486. 3. Hsu K, Garton A, Spoule BJ. et a/:The influence of orally administered cimetidine and theophylline on the elimination of each drug in patients with chronic airways obstruction. Am Rev Respir Dis 1984; 130: 740-743. 4.Vestal RE, Thummel KE. Musser B, Mercer GD: Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonarv disease: a studv using stable isotope methodology during multiple oral dose administration. Br J Clin Pharmacol 1983; 15: 411-418. 5. Adebayo GI, Coker HAB: Cimetidine inhibition of theophylline elimination: the influence of adult age and the time course. Biopharm Drug Dispos 1987; 8: 149-158. 6. Dal Negro R. Pomari C, Zoccatelli 0, et a6 Pharmacokinetics of theophylline and the He-antagonist drugs cimetidine and ranitidine. Int J Clin Pharmacol Ther Toxicol 1984; 22: 221-226. 7. Seggev JS, Barzilay M, Schey G: No evidence for interaction between ranitidine and theophylline. Arch Intern Med 1987; 147: 179-180. 8. Dal Nearo R. Turco P. Zoccatelli 0. eta/: HP-antaeonist derangement of the kinetics of sustained-release oral theophylline. Int J Clin Pharmacol Ther Toxicol 1985; 23: 329-332. 9. Breen KJ, Bury R. Desmond PV, et al: Effects of cimetidine and ranitidine on heoatic drue metabolism. Clin Pharmacol Ther 1982: 31: 2971300. 10. Kelly HW, Powell RJ, Donohue JF: Ranitidine at very large doses does not inhibit theophylline elimination. Clin Pharmacol Ther 1986; 39: 577-581. 11. Uoton RA. Thiercelin J-F. Guentert TW. et al: Intraindividual variability in theophylline pharmacokinetics: statistical verification in 39 of 60 healthy young adults. J Pharmacokinet Biopharm 1982; 10: 123-133. 12. Szefler SJ: Theoohvlline and its fickle unoredictability of absorption.‘Ann Allergy 1985; 55: 5iO-583. 13. Rogers RJ, Kalisker A, Wiener MB, et al: Inconsistent absorption from a sustained-release theophylline preparation during continuous therapy in asthmatic children. J Pediatr 1985; 106: 496-501. 14. Kelly HW: Theophylline toxicity. In: Jenne JW, Murphy S, eds. Drug therapy for asthma. New York: Marcel Dekker. 1987: 925-951. 15. Myhre KI, Walstad RA: The influence of antacid on the absorotion of two different sustained-release formulationsof theophylline. Br J Clin Pharmacol 1983; 15: 683-687. I
-
L
Submitted January 23, 1989, and accepted February 21. 1989
The Reply:
Dr. Kelly asks some “unanswered” questions relating to our patients, which I am pleased to answer since the data further document ranitidine-theophylline interactions. Some of the questions he raises have been answered earlier in a letter to the editor in the previous issue of this journal (Am J Med 1989; 86: 513). Dr. Kelly also speculates on issues that cannot be answered definitively from the available literature without further research. Dr. Kelly cites studies (his reference 1) to support a lack of drug
IDIOPATHIC HYPERAMMONEMIA AFTER HIGH-DOSE CHEMOTHERAPY
LACK OF EVIDENCE FOR REDUCTION OF THEOPHYLLINE CLEARANCE BY RANITIDINE
To the Editor: A syndrome of idiopathic hyperammonemia in patients with hematologic malignancy has recently been described by Mitchell et al (Am J Med 1988; 85: 662-667). Central to their description of the syndrome is the appearance of elevated plasma ammonia levels following cytoreductive chemotherapy. We report a patient with idiopathic hyperammonemia in the setting of untreated multiple myeloma. A 67-year-old white man was admitted with a two-week history of increasing lethargy, hallucinations, and back pain. Results of initial neurologic examination were nonfocal, but the patient had alternating periods of lucidity and delirium. Findings on laboratory studies were as follows: blood urea nitrogen 46 mg/dL; creatinine 8.5 mg/ dL; serum calcium 16.8 mg/dL; ammonia 67 mg/dL; normal bilirubin, alkaline phosphatase, and hepatic transaminases. Multiple myeloma (IgG-kappa) was diagnosed based on urine and serum immunoelectrophoretic studies and bone marrow aspiration. The patient’s level of consciousness varied widely, and ammonia levels remained persistently elevated despite lactulose therapy. On two occasions, the patient developed acute hypoventilation, requiring intubation. Despite initiation of aggressive chemotherapy, the patient died on the 27th hospital day. We believe that this patient demonstrated the syndrome of idiopathic hyperammonemia in the setting of hematologic malignancy, and suggest that the syndrome be considered in patients with the appropriate clinical presentation, even in the absence of cytoreductive chemotherapy. PAUL FINE, M.D. KENNETH ADLER, M.D. DAVID GERSTENFELD,M.D. Morristown Memorial Hospital Morristown, New Jersey
To the Editor: Roy et al (Am J Med 1988; 85: 525527) recently reported three patients who had elevated theophylline levels and symptoms of theophylline toxicity associated with ranitidine administration. The authors concluded from their findings that the increase in serum theophylline levels in their patients was a result of inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism, producing a decreased theophylline clearance. The authors make this claim without sufficient documentation in their patients and despite the fact that eight controlled clinical studies in more than 70 subjects have shown no effect of ranitidine on theophylline clearance [l]. However, the authors do raise a series of interesting questions in defense of their assumption. These include: (1) Do singledose intravenous studies reflect what is seen with oral administration at steady state in patients? (2) Do elderly patients or patients with chronic obstructive pulmonary disease (COPD) respond differently from healthy volunteers in studies?, and (3) Studies, even with large numbers, may not detect interindividual sensitivity to the drug effect. An extensive review of the existing literature on cimetidine, a proven inhibitor of the cytochrome P-450 enzymes, reveals the answers to these questions. Utilizing a single intravenous dose of aminophylline, Powell et al [2] showed that cimetidine at 300 mg four times daily produced a 36% (range, 22% to 49%) decrease in theophylline clearance in 12 healthy adult volunteers. Hsu et al [3] found the same degree of inhibition of theophylline clearance in 19 elderly COPD patients at steady state using rapid-release theophylline (37.80/o, 26.2% to 46.7%) or sustained-release theophylline (33.4%, 22.2% to 45%). Furthermore, using stable isotope methodology, Vestal et al [4] confirmed that elderly
Submitted January 20, 1989, and accepted January 27, 1989
May 1989
COPD patients receiving steadystate oral sustained-release theophylline do not respond differently (33% decrease) from healthy volunteers. In a comparative study designed specifically to determine the influence of age, Adebayo and Coker [5] found no difference between the effect of cimetidine on theophylline disposition in the elderly versus young adults. In regard to ranitidine, Roy et al did not note in their discussion that single intravenous aminophylline studies in elderly COPD patients [6] and multiple-dose oral sustained-release theophylline studies at steady state in asthmatic patients [7] and elderly COPD patients [B] have also failed to demonstrate an effect of ranitidine on theophylline clearance. As pointed out by the authors, the possibility of interindividual sensitivity to an effect is difficult to assess by studies designed to determine the predominant response in the population However, when that logic is used, 21 of 41 subjects from studies in which individual data are available had apparent decreases in theophylline clearance during ranitidine administration when compared with control subjects [2,7,9,10]. In contrast, 20 of 41 subjects had an increase or no change in theophylline clearance, which provides as much evidence for induction of metabolism as inhibition. However, this probably represents the well-documented intraindividual variation of theophylline clearance over time, which can fluctuate as much as 30% [ 111. Case reports are important to alert clinicians and researchers to the possibility of adverse effects of drugs and deleterious drug interactions; however, when they are in direct contradiction with established findings of well-controlled studies, it is essential that they be well documented. It is my opinion that Roy et al provided insufficient data and documentation to warrant their conclusions. It is probably no coincidence that the authors’ three patients and the previous two other patients reported in the literature
The American
Journal
of Medicine
Volume
86
629
CORRESPONDENCE
H. WILLIAMKELLY,
TABLE I Theophylline
Clearance
Values in Patient 1 of Roy et a/
were taking sustained-release oral theophylline preparations, and the changes in apparent theophylline clearance were based on single theophylline level determinations. Sustained-release theophylline preparations have well-documented inconsistent absorption characteristics that can be affected by food, gastric pH changes, and diurnal variation, as well as being randomly inconsistent [12]. Data from two patients in an excellent study by Rogers et al [13] illustrate this problem: In Patient 1, two 6 A.M. theophylline levels obtained within 48 hours of each other were 10 pg/ mL and 13.5 pg/mL, a 35% difference, and a 6 P.M. level was 16 pg/ mL (60%), producing a 37.5% alteration in apparent clearance if calculated in the manner of Roy et al; Patient 2 would have a 68% change in apparent theophylline clearance if the minimum and maximum theophylline levels recorded over the 48-hour interval were used to calculate the clearance. Although the authors stated the theophylline levels were all obtained 12 hours following the last dose of theophylline, they did not state whether they were drawn at the same time of day. In addition, using the data supplied by the authors and their method of calculations, I came up with totally different clearance values (Table I). There are other unanswered questions as well. When were the first levels obtained that were used to calculate the initial clearance values? How long before ranitidine administration was started? Was it at the time the patients initially presented with gastrointestinal complaints of gastric pain or hematemesis, or both, which are documented toxicities of theophylline [14]? At that time, the patients may have had increasing theophylline levels producing theophylline toxicity before initiation of ranitidine. The readers, however, are unable to determine that. In addition, an estimate of the apparent half630
May 1989
The American
Journal
lives for the patients’ clearance rates (Patient 1, 35.4 hours and 39.5 hours; Patient 2, 36.2 hours; Patient 3, three to 17 hours) during ranitidine administration would indicate that only Patient 3 had truly reached steady state (five half-lives) and that the authors’ estimated change is an underestimate if there was a change in clearance. The question of compliance should also be raised if the levels obtained while ranitidine was discontinued were during outpatient visits and the levels drawn when ranitidine was being administered were during hospitalization, when compliance could be assured. One reason for noncompliance are side effects from the drug (e.g., gastric pain). The authors have already stated that Patient 3 was not at steady state for the first determination, and the difference in theophylline levels seen is consistent with the variability in absorption or the intrapatient variability in clearance, or both. Finally, Patient 2 was taking a sustained-release preparation that has a documented increased rate of dissolution and absorption with antacids and elevated gastric pH [15]. That leaves only Patient 1 with an unexplained increase in serum theophylline concentrations and an apparently phenomenal decrease in theophylline clearance (68% or greater) compared to even the known potent inhibitor cimetidine, which produces a 5% to 50% inhibition. Could this be an individual sensitivity of this patient to competitive inhibition of P-450 isozymes responsible for theophylline metabolism by ranitidine, as suggested? It is unlikely, in that ranitidine does not impair the metabolism of antipyrine, a compound that shares metabolic isozymes with theophylline [1,9]. Also, despite the authors’ last statement in the discussion, there is no evidence that ranitidine and theophylline share the same isozymes for their respective metabolic conversion.
of Medicine
Volume
86
Pharm.~.
Uniuersitv of New Mexico Albuquerque, Ngw’Merico 87131 1. Mitchard M, Harris A, Mullinger BM: Ranitidine drug interactions-a literature review. Pharmacol Ther 1987; 32: 293-325. 2. Powell JR, Rogers JF. Wargin WA, eta/: Inhibition of theophylline clearance by cimetidine but not ranitidine. Arch Intern Med 1984; 144: 484-486. 3. Hsu K, Garton A, Spoule BJ. et a/:The influence of orally administered cimetidine and theophylline on the elimination of each drug in patients with chronic airways obstruction. Am Rev Respir Dis 1984; 130: 740-743. 4.Vestal RE, Thummel KE. Musser B, Mercer GD: Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonarv disease: a studv using stable isotope methodology during multiple oral dose administration. Br J Clin Pharmacol 1983; 15: 411-418. 5. Adebayo GI, Coker HAB: Cimetidine inhibition of theophylline elimination: the influence of adult age and the time course. Biopharm Drug Dispos 1987; 8: 149-158. 6. Dal Negro R. Pomari C, Zoccatelli 0, et a6 Pharmacokinetics of theophylline and the He-antagonist drugs cimetidine and ranitidine. Int J Clin Pharmacol Ther Toxicol 1984; 22: 221-226. 7. Seggev JS, Barzilay M, Schey G: No evidence for interaction between ranitidine and theophylline. Arch Intern Med 1987; 147: 179-180. 8. Dal Nearo R. Turco P. Zoccatelli 0. eta/: HP-antaeonist derangement of the kinetics of sustained-release oral theophylline. Int J Clin Pharmacol Ther Toxicol 1985; 23: 329-332. 9. Breen KJ, Bury R. Desmond PV, et al: Effects of cimetidine and ranitidine on heoatic drue metabolism. Clin Pharmacol Ther 1982: 31: 2971300. 10. Kelly HW, Powell RJ, Donohue JF: Ranitidine at very large doses does not inhibit theophylline elimination. Clin Pharmacol Ther 1986; 39: 577-581. 11. Uoton RA. Thiercelin J-F. Guentert TW. et al: Intraindividual variability in theophylline pharmacokinetics: statistical verification in 39 of 60 healthy young adults. J Pharmacokinet Biopharm 1982; 10: 123-133. 12. Szefler SJ: Theoohvlline and its fickle unoredictability of absorption.‘Ann Allergy 1985; 55: 5iO-583. 13. Rogers RJ, Kalisker A, Wiener MB, et al: Inconsistent absorption from a sustained-release theophylline preparation during continuous therapy in asthmatic children. J Pediatr 1985; 106: 496-501. 14. Kelly HW: Theophylline toxicity. In: Jenne JW, Murphy S, eds. Drug therapy for asthma. New York: Marcel Dekker. 1987: 925-951. 15. Myhre KI, Walstad RA: The influence of antacid on the absorotion of two different sustained-release formulationsof theophylline. Br J Clin Pharmacol 1983; 15: 683-687. I
-
L
Submitted January 23, 1989, and accepted February 21. 1989
The Reply:
Dr. Kelly asks some “unanswered” questions relating to our patients, which I am pleased to answer since the data further document ranitidine-theophylline interactions. Some of the questions he raises have been answered earlier in a letter to the editor in the previous issue of this journal (Am J Med 1989; 86: 513). Dr. Kelly also speculates on issues that cannot be answered definitively from the available literature without further research. Dr. Kelly cites studies (his reference 1) to support a lack of drug