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Cimetidine impairs the elimination of theophylline and antipyrine
GASTROENTEROLOGY 1981;81:19-21
Cimetidine Impairs the Elimination Theophylline and Antipyrine
of
RODERICK K. ROBERTS, JEFFREY GRICE, LAURENCE WOOD, VICTOR PETROFF, and CHRISTINE
McGUFFIE
Department of Medicine, Greenslopes Hospital, Greenslopes, Australia
In 7 healthy subjects theophylline and antipyrine elimination were determined before and during a course of oral cimetidine in a dose of 1 g/day. Plasma clearance of theophylline was reduced from 71.2 It 10.1 ml/min to 56.0 + 28.5 ml/min and the plasma clearance of antipyrine from 53.7 + 14.2 ml/ min to 48.2 f 12.7 ml/min. Elimination half-life of theophylline was prolonged from 5.1 f 1.6 to 8.1 fl.4 h. All these changes were statistically significant. Volume of distribution of theophylline (31.7 f 8.4 I, before and 39.2 + 5.6 L during cimetidine administration) and plasma binding of theophylline (44.7 + 3.8% before and 44.3 + 3.1% during cimetidine administration) were not significantly different. Similarly, volume of distribution of antipyrine (45.8 + 14.0 vs. 47.6 f 17.9) was not significantly affected by
cimetidine administration. We conclude that cimetidine impairs the elimination of theophylline and antipyrine in healthy subjects. Cimetidine, a histamine H-2 receptor antagonist is now widely used in the treatment of peptic ulcer disease (1). While cimetidine has been associated with transient rises in serum creatinine and serum transaminases, it has proved remarkably nontoxic and effective therapy. However, recent reports suggest cimetidine may potentiate the effects of several oral anticoagulants (2-4) and impair the elimination of several benzodiazepines (5-7). Recent personal experience with 1 patient suggested that cimetidine
Received November 17,1980.Accepted January 21, 1981. Address requests for reprints to: Dr. R. K. Roberts, Department of Medicine, Greenslopes Hospital, Greenslopes, 4121Australia. This work was presented in part at the annual meeting of the Gastroenterology Society of Australasia, Melbourne, May 4-5, 1980.
This work was supported by theUniversity of Queensland, The Utah Foundation, and Veterans’ Affairs Department of the Australian Government 0 1981by theAmerican Gastroenterological Association 0016-5085/81/070019-03$02.50
may potentiate the effects of theophylline. The present study investigates the effect of cimetidine on the elimination of theophylline and antipyrine in healthy subjects,
Methods Patient Selection and Experimental
Design
Seven healthy subjects, 5 male and 2 female, aged from 26 yr to 52 yr (mean 37 f 4) were studied. Each subject was normal on physical examination, and full blood examination and SMA 12 profile were normal. All were nonsmokers and stopped all drugs including alcohol and caffeine for a minimum of 2 wk before the study and during its course. All subjects gave informed consent, and the study was approval by the Institutional Review Committee. On the 1st day of the study, theophylline was administered intravenously in a dose of 3 mg/kg over 30 min. Blood was collected at 30, 45, 6O,W, and 120 min and 3, 4, 5,6,6,10,12, and 24 h after beginning the infusion. On the 2nd day of the study, antipyrine 18 mg/kg was administered intravenously over 5 min. After this, blood samples were collected at 5, 30, 60, 90, and 120 min and 5, 7, 9, 12, 24, and 48 h after the injection. Blood samples were separated, and plasma was frozen and stored immediately. On the 4th day of the study, oral cimetidine in the dosage of 200 mg t.i.d. and 400 mg at night was started. This drug was continued for a total of 10 days. On the last 3 days of cimetidine administration the theophylline and antipyrine studies were repeated as above. On both occasions antipyrine was administered 24 h after the theophylline dose. Plasma was collected before and during cimetidine administration for estimation of plasma binding of theophylline.
Materials
and Analytic
Methods
Antipyrine was extracted from alkaline plasma into an equal volume of chloroform containing phenacetin in a concentration of 8 pg/ml as internal standard. The residue from evaporation of chloroform was taken up into the HPLC eluent, and 25 ~1 was injected onto the column.
20
GASTROENTEROLOGY Vol. 81,No. 1
ROBERTS ET AL.
A Waters Associates p-Bondapak Cl8 reverse-phase partition column was used with an eluent consisting of acetonitrile/o.ol% ammonium carbonate @O/70), at a flow rate of 2 ml/min. The antipyrine was detected by UV-absorption at 254 nm. Antipyrine was 97% pure. Recovery of antipyrine in this assay was 93.2 * 3%. Plasma theophylline was measured by first treating the plasma sample with an aqueous solution containing TCA (20% wt/vol) and /3-hydroxy-ethyl theophylline as internal standard (20 pg/ml). The solution was then adjusted to pH 4 with 0.1 M sodium acetate and centrifuged. Twenty-five microliters of the supernatant were injected onto a Waters Associates pBondapak Cl8 reverse-phase partition column. The eluent was a solution of acetonitrile and 0.1 M sodium acetate (293) adjusted to pH 4 with glacial acetic acid. The flow rate was 2 ml/min and the theophylline peak was detected by UV-absorption at 254 nm. Intravenous aminophylline and oral theophylline were obtained from Riker Laboratories. Theophylline for construction of a standard curve was obtained from Riker Laboratories and was 98.3% pure. Recovery of theophylline in this assay was 94 f 2%. Plasma binding of theophylline was measured by equilibrium dialysis using plasma drawn immediately before the study. Equilibrium dialysis was at 37’C against a pH 7.4, 0.987 M phosphate buffer in an equilibrium dialysing Teflon cell system (Spectrum Medical Industries, Inc., New York, N.Y.) with a cellulose membrane. Preliminary experiments indicated that equilibrium was reached in 2 h and binding was independent of concentration over the range of 2-20 pg/ml. Plasma and buffer concentrations were measured in the above assay. All reagents were laboratory grade. The plasma concentration/time data for antipyrine and theophylline fit best a single exponential function. These data were fitted by iterative least-squares linear regression analysis to the function Cp(t) = A e-“‘, where Cp is concentration at time t, A is a constant, and (Y is the exponential disposition constant (8,9). Plasma clearance of antipyrine and theophylline was calculated as Dose/Area under curve”-“, and area under curve (AUC) was calculated by the trapezoidal rule with extrapolation to infinity. Volume of distribution was measured as Dose/a . AUC.
Statistical
Method
A two-tailed paired t-test was used to compare data before and during cimetidine administration.
Results In 6 of the 7 subjects cimetidine impaired the elimination of both antipyrine and theophylline. In 1 subject, a woman of 52 yr, antipyrine and tl+ophylline elimination was unaffected by cimetidine. Table 1 shows the pharmacokinetic parameters for antipyrine and theophylline befoie and during cimetidine administration. The plasma clearance of theophylline fell from 71.2 f 10.1 ml/min before. cimetidine to 56.0 + 16.5 ml/min during cimetidine.
Half-life increased from 5.1 f 1.6 h before to 8.1 f 1.4 h during cimetidine administration. Volume of distribution and plasma binding of theophyliine were unchanged by the administration of cimetidine. Antipyrine clearance fell from 53.7 + 14.5 ml/ min before cimetidjne to 48.1 f 11.7 ml/min during cimetidine, while there was no significant change in antipyrine half-life. The volume of distribution of antipyrine was unchanged.
Discussion Cimetidine has previously been shown to impair the elimination of warfarin and antipyrine (4). In single-dose kinetic studies the clearance of bra1 doses of warfarin and of oral antipyrine fell after 2 wk of cimetidine administration in a dose of 1.6 g/ day (4). In a further study the clearance of intravenously administered diazepam was reduced 50% by pretreatment with cimetidine for 1 day in five divided doses of 200 mg (5), suggesting that the effect developed rapidly. Two subsequent -studies indicate cimetidine may have a differential effect on elimination pathways. The clearance of chlordiazepoxide, which undergoes microsomal oxidation, was reduced by 50% after 1 wk of cimetidine, while the clearance of lorazepam and oxazepam, which are glucuronidated, was unaffected by cimetidine (7). The present study indicbtes that cimetidine significantly impairs the elimination of theophylline and confirms the earlier data on antipyrine, reduction in clearance being greater for theophylline than for antipyrine. While both drugs are eliminated by microsdmal inixed function oxidases, antipyrine metabolism is cytochrome P,,,-dependent and theophylline metabolism cytochrome Pm-dependent. An effect of cimetidine on a Pam-dependent substrate has previously been dem,onstrated in vivo in animal studies but not in humans (10). In this study citietidine impaired the [‘“Clcaffeine breath test but had no apparent effect on [‘4C]phenacetin metabolism. In vitro studies using rat liver homogenates also suggest an effect of cimetidine on both cytochrome P,, and P,, (11). C imetidine inhibited aininopyrine Ndemethylation and benzo (A)-pyrene hydrdxylation in control rats’ as well as rats pretreated with phenobarbital or 3-methylcholanthrene. The evidence to date then indicates cimetidine administration leads to a general inhibition of hepatic microsomal mixed function oxidases and may impair the elimination of drugs undergoing metabolism by these enzymes. The effect of cimetidine on theophylline clearance has considerable clinical importance. A reduction in theophylline clearance of almost 30% would lead to a similar percentage increase in theophylline levels during multiple dosing. As theophylline has a nar-
CIMETIDINE, THEOPHYLLINE
July 1981
Table
1.
Effect of Cimetidine
on Pharmacokinetic
Parameters
(Mean
+ SD) of Theophylline
and
INTERACTION
21
Antipyrine After
Intravenous Administration Antipyrine
Theophyiline Before cimetidine Plasma clearance h/z(h) vd tarea)
(mJ/min)
&)
AUC (h+g/ml-‘) AOLgh0 Cy(h-‘) Binding (%)
71.2 f 10.1 5.lf 1.6 31.7zt8.4 41.4+ 8.8 5.49f 1.25 0.148f0.043 44.7 f 3.6
During cimetidine 56.0 f 18.5" 8.1+ 1.4" 39.2f 5.6 58.2+-18.1b 5.37f 1.27 0.088f 0.016" 44.3 f 3.1
Before cimetidine 53.7214.5 10.0f 2.0 45.8k 14.0 380.5 f 87.5 27.3f 5.5 0.075k 0.014 -
During cimetidine 48.1f 11.7b 11.5f3.7 47.6f 17.9 417.7+ 65.1 27.8f 3.9 0.072f 0.030 -
a p < 0.01. b p < 0.05.
row therapeutic window, even this relatively small increase in clearance could increase blood levels to the toxic range. Theophylline elimination is sensitive to a variety of other influences (12). These include age (9, liver disease (la), smoking (IS), and cardiac and pulmonary disease (16,17). While it is difficult to predict the overall effect of these various influences on theophylline metabolism in an individual patient, the potential for an interaction of cimetidine and theophylline in a clinical setting clearly exists. This should be taken into account when these drugs are used in combination.
References 1. Burland
WL, Simkins MA. Cimetidine: Proceedings of the Second International Symposium on Histamine Hz-Receptor Antagonists. Amsterdam-Oxford: Excerpta Medica 1977. 2. Flind AC. Cimetidine and oral anticoagulants. Br Med J 1978;11:1367. 3. Silver BA, Bell WR. Cimetidine potentiation of the hypoprothrombinaemic effect of warfarin. Ann Intern Med 1979; 90:348-g. 4. Serlin MJ, Sibeon RG, Mossman S, et al. Cimetidine: interaction with oral anticoagulants. Lancet X979$1:317-19. 5. Klotz U, Reimann I. Delayed clearance of diazepam due to cimetidine. N Engl J Med 1980;301:1012-14. 6. Desmond PV, Patwardhan R, Schenker S, et al. Cimetidine
impairs elimination of chlordiazepoxide (Librium) in man. Ann Intern Med 1980;93:266-8. 7. Patwardhan RV, Yarborough GW, Desmond PV, et al. Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology 1980;79:912-17. 8. Brown D, Manno JE. ESTRIP a BASIC computer program for obtaining initial polyexponential parameter estimates. J Pharm Sci 1978;67:1687-91. 9. Knott GD, Reece DK. MLAB: a civilised curve fitting system. In: Proceedings of the Online 72 International Conference. 1972;1:497-526, Brunei University, England. 10.Desmond PV, Patwardhan R, Parker R, et al. Effect of cimetidine and other antihistaminics on the elimination of aminopyrine, phenacetin and caffeine. Life Sci 1980;20:1261-8. 11.Puurunen J, Pelkonen 0. Cimetidine inhibits microsomal drug metabolism in the rat. Eur J Pharmacol 1979;55:335-6. 12.Ogilvie RI. Clinical pharmacokinetics of theophylline. Clin Pharmacokinet 1978;3:267-93. 13.Loughnan PM, Sitar DS, Ogilvie RJ, et al. Pharmacokinetic analysis of the disposition of theophylline in young children. J Pediatr 1976;88:874-9. 14.Piafsky KM, Sitar DS, Rangno RE, et al. Theophylline disposition in patients with hepatic cirrhosis. N Engl J Med 1977;196:1495-7. 15.Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther 1976$9:548-X. 16.Piafsky KM, Sitar DS, Rangno RE, et al. Theophylline kinetics in acute pulmonary oedema. Clin Pharmacol Ther 1977;21: 310-16. 17.Vicuna N, McNay JL, Ludden TM, et al. Impaired theophylline clearance in patients with car pulmonale. Br J Clin Pharmacol 1979;7:33-7.
Cimetidine Impairs the Elimination Theophylline and Antipyrine
of
RODERICK K. ROBERTS, JEFFREY GRICE, LAURENCE WOOD, VICTOR PETROFF, and CHRISTINE
McGUFFIE
Department of Medicine, Greenslopes Hospital, Greenslopes, Australia
In 7 healthy subjects theophylline and antipyrine elimination were determined before and during a course of oral cimetidine in a dose of 1 g/day. Plasma clearance of theophylline was reduced from 71.2 It 10.1 ml/min to 56.0 + 28.5 ml/min and the plasma clearance of antipyrine from 53.7 + 14.2 ml/ min to 48.2 f 12.7 ml/min. Elimination half-life of theophylline was prolonged from 5.1 f 1.6 to 8.1 fl.4 h. All these changes were statistically significant. Volume of distribution of theophylline (31.7 f 8.4 I, before and 39.2 + 5.6 L during cimetidine administration) and plasma binding of theophylline (44.7 + 3.8% before and 44.3 + 3.1% during cimetidine administration) were not significantly different. Similarly, volume of distribution of antipyrine (45.8 + 14.0 vs. 47.6 f 17.9) was not significantly affected by
cimetidine administration. We conclude that cimetidine impairs the elimination of theophylline and antipyrine in healthy subjects. Cimetidine, a histamine H-2 receptor antagonist is now widely used in the treatment of peptic ulcer disease (1). While cimetidine has been associated with transient rises in serum creatinine and serum transaminases, it has proved remarkably nontoxic and effective therapy. However, recent reports suggest cimetidine may potentiate the effects of several oral anticoagulants (2-4) and impair the elimination of several benzodiazepines (5-7). Recent personal experience with 1 patient suggested that cimetidine
Received November 17,1980.Accepted January 21, 1981. Address requests for reprints to: Dr. R. K. Roberts, Department of Medicine, Greenslopes Hospital, Greenslopes, 4121Australia. This work was presented in part at the annual meeting of the Gastroenterology Society of Australasia, Melbourne, May 4-5, 1980.
This work was supported by theUniversity of Queensland, The Utah Foundation, and Veterans’ Affairs Department of the Australian Government 0 1981by theAmerican Gastroenterological Association 0016-5085/81/070019-03$02.50
may potentiate the effects of theophylline. The present study investigates the effect of cimetidine on the elimination of theophylline and antipyrine in healthy subjects,
Methods Patient Selection and Experimental
Design
Seven healthy subjects, 5 male and 2 female, aged from 26 yr to 52 yr (mean 37 f 4) were studied. Each subject was normal on physical examination, and full blood examination and SMA 12 profile were normal. All were nonsmokers and stopped all drugs including alcohol and caffeine for a minimum of 2 wk before the study and during its course. All subjects gave informed consent, and the study was approval by the Institutional Review Committee. On the 1st day of the study, theophylline was administered intravenously in a dose of 3 mg/kg over 30 min. Blood was collected at 30, 45, 6O,W, and 120 min and 3, 4, 5,6,6,10,12, and 24 h after beginning the infusion. On the 2nd day of the study, antipyrine 18 mg/kg was administered intravenously over 5 min. After this, blood samples were collected at 5, 30, 60, 90, and 120 min and 5, 7, 9, 12, 24, and 48 h after the injection. Blood samples were separated, and plasma was frozen and stored immediately. On the 4th day of the study, oral cimetidine in the dosage of 200 mg t.i.d. and 400 mg at night was started. This drug was continued for a total of 10 days. On the last 3 days of cimetidine administration the theophylline and antipyrine studies were repeated as above. On both occasions antipyrine was administered 24 h after the theophylline dose. Plasma was collected before and during cimetidine administration for estimation of plasma binding of theophylline.
Materials
and Analytic
Methods
Antipyrine was extracted from alkaline plasma into an equal volume of chloroform containing phenacetin in a concentration of 8 pg/ml as internal standard. The residue from evaporation of chloroform was taken up into the HPLC eluent, and 25 ~1 was injected onto the column.
20
GASTROENTEROLOGY Vol. 81,No. 1
ROBERTS ET AL.
A Waters Associates p-Bondapak Cl8 reverse-phase partition column was used with an eluent consisting of acetonitrile/o.ol% ammonium carbonate @O/70), at a flow rate of 2 ml/min. The antipyrine was detected by UV-absorption at 254 nm. Antipyrine was 97% pure. Recovery of antipyrine in this assay was 93.2 * 3%. Plasma theophylline was measured by first treating the plasma sample with an aqueous solution containing TCA (20% wt/vol) and /3-hydroxy-ethyl theophylline as internal standard (20 pg/ml). The solution was then adjusted to pH 4 with 0.1 M sodium acetate and centrifuged. Twenty-five microliters of the supernatant were injected onto a Waters Associates pBondapak Cl8 reverse-phase partition column. The eluent was a solution of acetonitrile and 0.1 M sodium acetate (293) adjusted to pH 4 with glacial acetic acid. The flow rate was 2 ml/min and the theophylline peak was detected by UV-absorption at 254 nm. Intravenous aminophylline and oral theophylline were obtained from Riker Laboratories. Theophylline for construction of a standard curve was obtained from Riker Laboratories and was 98.3% pure. Recovery of theophylline in this assay was 94 f 2%. Plasma binding of theophylline was measured by equilibrium dialysis using plasma drawn immediately before the study. Equilibrium dialysis was at 37’C against a pH 7.4, 0.987 M phosphate buffer in an equilibrium dialysing Teflon cell system (Spectrum Medical Industries, Inc., New York, N.Y.) with a cellulose membrane. Preliminary experiments indicated that equilibrium was reached in 2 h and binding was independent of concentration over the range of 2-20 pg/ml. Plasma and buffer concentrations were measured in the above assay. All reagents were laboratory grade. The plasma concentration/time data for antipyrine and theophylline fit best a single exponential function. These data were fitted by iterative least-squares linear regression analysis to the function Cp(t) = A e-“‘, where Cp is concentration at time t, A is a constant, and (Y is the exponential disposition constant (8,9). Plasma clearance of antipyrine and theophylline was calculated as Dose/Area under curve”-“, and area under curve (AUC) was calculated by the trapezoidal rule with extrapolation to infinity. Volume of distribution was measured as Dose/a . AUC.
Statistical
Method
A two-tailed paired t-test was used to compare data before and during cimetidine administration.
Results In 6 of the 7 subjects cimetidine impaired the elimination of both antipyrine and theophylline. In 1 subject, a woman of 52 yr, antipyrine and tl+ophylline elimination was unaffected by cimetidine. Table 1 shows the pharmacokinetic parameters for antipyrine and theophylline befoie and during cimetidine administration. The plasma clearance of theophylline fell from 71.2 f 10.1 ml/min before. cimetidine to 56.0 + 16.5 ml/min during cimetidine.
Half-life increased from 5.1 f 1.6 h before to 8.1 f 1.4 h during cimetidine administration. Volume of distribution and plasma binding of theophyliine were unchanged by the administration of cimetidine. Antipyrine clearance fell from 53.7 + 14.5 ml/ min before cimetidjne to 48.1 f 11.7 ml/min during cimetidine, while there was no significant change in antipyrine half-life. The volume of distribution of antipyrine was unchanged.
Discussion Cimetidine has previously been shown to impair the elimination of warfarin and antipyrine (4). In single-dose kinetic studies the clearance of bra1 doses of warfarin and of oral antipyrine fell after 2 wk of cimetidine administration in a dose of 1.6 g/ day (4). In a further study the clearance of intravenously administered diazepam was reduced 50% by pretreatment with cimetidine for 1 day in five divided doses of 200 mg (5), suggesting that the effect developed rapidly. Two subsequent -studies indicate cimetidine may have a differential effect on elimination pathways. The clearance of chlordiazepoxide, which undergoes microsomal oxidation, was reduced by 50% after 1 wk of cimetidine, while the clearance of lorazepam and oxazepam, which are glucuronidated, was unaffected by cimetidine (7). The present study indicbtes that cimetidine significantly impairs the elimination of theophylline and confirms the earlier data on antipyrine, reduction in clearance being greater for theophylline than for antipyrine. While both drugs are eliminated by microsdmal inixed function oxidases, antipyrine metabolism is cytochrome P,,,-dependent and theophylline metabolism cytochrome Pm-dependent. An effect of cimetidine on a Pam-dependent substrate has previously been dem,onstrated in vivo in animal studies but not in humans (10). In this study citietidine impaired the [‘“Clcaffeine breath test but had no apparent effect on [‘4C]phenacetin metabolism. In vitro studies using rat liver homogenates also suggest an effect of cimetidine on both cytochrome P,, and P,, (11). C imetidine inhibited aininopyrine Ndemethylation and benzo (A)-pyrene hydrdxylation in control rats’ as well as rats pretreated with phenobarbital or 3-methylcholanthrene. The evidence to date then indicates cimetidine administration leads to a general inhibition of hepatic microsomal mixed function oxidases and may impair the elimination of drugs undergoing metabolism by these enzymes. The effect of cimetidine on theophylline clearance has considerable clinical importance. A reduction in theophylline clearance of almost 30% would lead to a similar percentage increase in theophylline levels during multiple dosing. As theophylline has a nar-
CIMETIDINE, THEOPHYLLINE
July 1981
Table
1.
Effect of Cimetidine
on Pharmacokinetic
Parameters
(Mean
+ SD) of Theophylline
and
INTERACTION
21
Antipyrine After
Intravenous Administration Antipyrine
Theophyiline Before cimetidine Plasma clearance h/z(h) vd tarea)
(mJ/min)
&)
AUC (h+g/ml-‘) AOLgh0 Cy(h-‘) Binding (%)
71.2 f 10.1 5.lf 1.6 31.7zt8.4 41.4+ 8.8 5.49f 1.25 0.148f0.043 44.7 f 3.6
During cimetidine 56.0 f 18.5" 8.1+ 1.4" 39.2f 5.6 58.2+-18.1b 5.37f 1.27 0.088f 0.016" 44.3 f 3.1
Before cimetidine 53.7214.5 10.0f 2.0 45.8k 14.0 380.5 f 87.5 27.3f 5.5 0.075k 0.014 -
During cimetidine 48.1f 11.7b 11.5f3.7 47.6f 17.9 417.7+ 65.1 27.8f 3.9 0.072f 0.030 -
a p < 0.01. b p < 0.05.
row therapeutic window, even this relatively small increase in clearance could increase blood levels to the toxic range. Theophylline elimination is sensitive to a variety of other influences (12). These include age (9, liver disease (la), smoking (IS), and cardiac and pulmonary disease (16,17). While it is difficult to predict the overall effect of these various influences on theophylline metabolism in an individual patient, the potential for an interaction of cimetidine and theophylline in a clinical setting clearly exists. This should be taken into account when these drugs are used in combination.
References 1. Burland
WL, Simkins MA. Cimetidine: Proceedings of the Second International Symposium on Histamine Hz-Receptor Antagonists. Amsterdam-Oxford: Excerpta Medica 1977. 2. Flind AC. Cimetidine and oral anticoagulants. Br Med J 1978;11:1367. 3. Silver BA, Bell WR. Cimetidine potentiation of the hypoprothrombinaemic effect of warfarin. Ann Intern Med 1979; 90:348-g. 4. Serlin MJ, Sibeon RG, Mossman S, et al. Cimetidine: interaction with oral anticoagulants. Lancet X979$1:317-19. 5. Klotz U, Reimann I. Delayed clearance of diazepam due to cimetidine. N Engl J Med 1980;301:1012-14. 6. Desmond PV, Patwardhan R, Schenker S, et al. Cimetidine
impairs elimination of chlordiazepoxide (Librium) in man. Ann Intern Med 1980;93:266-8. 7. Patwardhan RV, Yarborough GW, Desmond PV, et al. Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology 1980;79:912-17. 8. Brown D, Manno JE. ESTRIP a BASIC computer program for obtaining initial polyexponential parameter estimates. J Pharm Sci 1978;67:1687-91. 9. Knott GD, Reece DK. MLAB: a civilised curve fitting system. In: Proceedings of the Online 72 International Conference. 1972;1:497-526, Brunei University, England. 10.Desmond PV, Patwardhan R, Parker R, et al. Effect of cimetidine and other antihistaminics on the elimination of aminopyrine, phenacetin and caffeine. Life Sci 1980;20:1261-8. 11.Puurunen J, Pelkonen 0. Cimetidine inhibits microsomal drug metabolism in the rat. Eur J Pharmacol 1979;55:335-6. 12.Ogilvie RI. Clinical pharmacokinetics of theophylline. Clin Pharmacokinet 1978;3:267-93. 13.Loughnan PM, Sitar DS, Ogilvie RJ, et al. Pharmacokinetic analysis of the disposition of theophylline in young children. J Pediatr 1976;88:874-9. 14.Piafsky KM, Sitar DS, Rangno RE, et al. Theophylline disposition in patients with hepatic cirrhosis. N Engl J Med 1977;196:1495-7. 15.Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther 1976$9:548-X. 16.Piafsky KM, Sitar DS, Rangno RE, et al. Theophylline kinetics in acute pulmonary oedema. Clin Pharmacol Ther 1977;21: 310-16. 17.Vicuna N, McNay JL, Ludden TM, et al. Impaired theophylline clearance in patients with car pulmonale. Br J Clin Pharmacol 1979;7:33-7.