Effect of cimetidine on digoxin kinetics and creatinine clearance

170

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Communications

Fig.

American

2. Rhythm strip showing“R-on-T” phenomenonfollowed by torsade de pointes.

infarction is not known. Moreover, the diagnosisof this arrhythmia should not be restricted to instances where delayed repolarization or extreme bradyarrhythmias are present. The therapeutic implications of this finding are unclear. Antiarrhythmic agentswhich potentially prolong the QT interval may be relatively contraindicated in this setting and the use of bretylium or early ventricular pacing may be preferable. REFERENCES

1. Dalle XS, Meltzer E, Kravitz B: A new look at ventricular tachycardia. Acta Cardiol 22:519, 1967. 2. Smith W, Gallagher J: “Les torsades de points”: An unusual ventricular arrhythmia. Ann Intern Med 93:578, 1980. 8. Zilcher H, Glogar D, Kaindl F: Torsades de pointes: Occurrence in myocardial ischemia as a separate entity. Multiform ventricular tachycardia or not? Eur Heart J 1:63, 1980. 4. Horowitz L, Greenspan AM, Spielman SR, Josephson ME: Torsade de pointes: Electrophysiologic studies in patients without transient pharmacologic or metabolic abnormalities. Circulation 63:1120, 1981. 5. Chiche P, Haiat R, Steff P: Angina pectoris with syncope due to paroxysmal atrioventricular block: Role of ischemia. Br Heart J 36:577, 1974.

Effect of cimetidine on digoxin and creatinine clearance

kinetics

Hermann R. Ochs, M.D., Roland Gugler, M.D., Thomas Guthoff, M.D., and David J. Greenblatt, M.D. Bonn, W. Germany, and Boston, Mass.

The histamine antagonist, cimetidine, is extensively used throughout the Western world for the treatment of peptic ulcer disease.‘,’ In addition to its antisecretory effects,

From the Medizinische Pharmacology, Tufts-New

Universit$tsklinik; England Medical

and the Center.

Division

of Clinical

Supported in part by Grant Oc 10/6-X from Deutsche Forschungsgemeinschaft, Bonn-Had Godesberg:. W. Germany; and by Grant MH-3423 from the LJnited States Public Health Service. Reprint requests: Hermann nik, D-5300 Bonn-Venusberg, Presented Clinical I 983.

January, 1984 Heart Journal

R. Ochs, M.D., W. Germany.

Medizinische

Univer&itskli-

in part at the 84th Annual Meeting of the American Pharmacology and Therapeutics. San Diego, Calif.,

Society March

for II,

I. Kinetic variables for creatinine and digoxin with and without concurrent cimetidine treatment

Table

Mean

Kinetic

variables

For creatinine Serum concentration (mg/lOO ml1 Clearance (ml/mini For digoxin Volume of distribution (L/kg) Elimination half-life (hrl Total clearance (mllminikgl 7%.hour urinary excretion (pgl

Control

(i-S.E.) values: With cimetidine

Value of Student’s t

0.77 (k0.03)

0.95 ( r 0.041

6.39 (p < .OOl)

180 (t9)

139

(*8)

4.79 (p < ,001)

11.6 ( ? 1.2) 54.4 (k7.81 2.71 ( IL 0.2) 468 (t311

12.8 (i0.8) 61.9 ( + 5.9) 2.53 (kO.2) 454 (&S71

1.44 (N.S.) 0.77 (N.S.) 0.58 (N.S.) 0.31 (N.S.)

cimetidine has other important pharmacologicproperties that include impairment of hepatic microsomal drug oxidizing activity,” and reduction of hepatic blood flow.” As such, cimetidine has the potential to interact with many drugs that are biotransformed in the liver.4-nSome studies alsosuggestthat cimetidine may reduce glomerular filtration rate,9,*” making it possible that cimetidine could interact with drugs cleared primarily by renal excretion. However, investigation of such interactions is incomplete at present. This study assessed the interaction of cimetidine with digoxin, an extensively used digitalis glycoside having renal clearance as the major route of elimination.“~“’ Eleven healthy male volunteers, aged 21 to 29 years, participated after giving informed consent.They were free of any identifiable medical disease.Subjects participated in two single-dosepharmacokinetic studies of digoxin. One trial served as a control without concurrent drug administration. For the second trial, subjects ingested cimetidine (Tagamet, Smith Kline Dauelsberg GmbH, Giittingen, W. Germany), 200 mg three times daily and 400mg at bedtime, beginning 24 hours prior to the digoxin trial and continuing for the 72-hour duration of the study.

Volume Number

107 1

Brief

Communications

17 1

. . .

. l

Contr

--z--4*.**

.

I

I

PRE

24 HOURS

AFTER

48 DIGOXIN

72

Cimstidine

Cimstidine

Control

Fig. 2. Serum creatinine concentration (left) and creatinine clearance (right) during control and cimetidine trials. Individual and mean ( 2 SE) values are shown. See Table I for statistical analysis.

DOSE

Fig. 1. Individual serum cimetidine concentrations measured during the digoxin-cimetidine interaction study. Horizontal bars indicate mean values at that point in time.

At least 6 weeks elapsed between the two trials, the sequence of which was randomized. For each digoxin study, subjects received a single 1.25 mg dose of digoxin (Lanoxin, Deutsche Wellcome GmbH, Burgwedel, W. Germany) by rapid intravenous injection, Whole blood samples were drawn into additive-free tubes at multiple points in time over the next 72 hours. All urine was collected in 24-hour segments for 72 hours after each digoxin dose. Serum samples and aliquots of urine were frozen until the time of assay. Digoxin concentrations in all samples were determined by radioimmunoassay.’ Compliance with the prescribed cimetidine regimen was verified by measurement of serum cimetidine concentrations’” once daily in each subject concurrent with the morning sampling for the digoxin study. Concentrations of creatinine in each morning blood sample and in an aliquot of each 24-hour urine collection were determined by autoanalyzer. Serum digoxin concentrations were analyzed by iterative nonlinear least-squares regression techniques described previously. I6 Data points were fitted to a linear sum of exponential terms. Coefficients and exponents from the fitted function were used to determine the following kinetic variables for digoxin: volume of distribution using the area method, elimination half-life, and total clearance. For each subject the values of serum creatinine and creatinine clearance during control and cimetidine trials (n = 3 for each) were averaged. Differences between trials in kinetic variables for digoxin and creatinine were analyzed statistically using Student’s paired t test. Serum cimetidine concentration determinations indicated good compliance with the prescribed regimen. Mean serum levels drawn just before digoxin dosage and at 24,

.

-0 ------------A

= CONTROL = WITH CIMETIDINE

I

0

12

24 HOURS

4s AFTER

72

DOSE

Fig. 3. Serum digoxin concentrations following a single intravenous dose of digoxin to a healthy volunteer in the control state and again during cimetidine coadministration. Lines represent pharmacokinetic functions determined by nonlinear least-squares regression analysis.

48, and 72 hours thereafter were: 0.27, 0.64, 1.05, and 0.31 pg/ml (Fig. 1). These are consistent with cimetidine concentrations achieved during treatment with usual therconcentrations were apeutic doses. I7 Serum creatinine significantly higher, and creatinine clearance was significantly lower, during the cimetidine trial compared to the control period (Table I, Fig. 2). In all subjects disappearance of digoxin from plasma was well described by a linear sum of two or three exponential terms (Fig. 3). Pharmacokinetic variables for digoxin between control and cimetidine-treatment trials were very similar, and differences did not approach significance (Table I); 72-hour urinary

172

Brief

Communications

American

on microsomal cot

L $ r 300.0 g 25 z 200.0 s ii

WITH

0.0 i

4 0 COLLECTION

CIMETIDINE

, 24 ENDPOINT

48 (hours

72 after

dose)

Fig. 4. Cumulative urinary excretion of digoxin during the control and cimetidine treatment trials. Each point is the mean (k SE) for all 11 subjects at the corresponding time. None of the differences approached significance.

excretion of digoxin averaged 468 and 454 bg, respectively, for the two trials (Table I, Fig. 4). The difference did not approach significance. The ability of cimetidine to impair clearance of hepatitally metabolized drugs is well established,4-8 but its effect on renal clearance of drugs excreted primarily by the kidney is incompletely evaluated. Such potential interactions are of considerable clinical importance, since many important drugs with narrow therapeutic indexes are cleared in part or primarily by renal excretion of the intact drug. Digoxin is among the most important of such agents, since renal clearance accounts for more than 50% of total clearance, and its therapeutic index is narrow. In the present study and in previous reports: I” cimetidine significantly reduced glomerular filtration rate as measured by creatinine clearance. However, this effect did not lead to impairment of digoxin clearance in healthy individuals. Total clearance of digoxin as well as its total urinary excretion were unchanged by concurrent cimetidine treatment. This suggests that renal clearance of digoxin and creatinine may occur by different mechanisms that are differentially influenced by cimetidine. In any case, a clinically important interaction between digoxin and cimetidine appears unlikely to occur in persons with normal renal function. REFERENCES

Brogden RN, Heel RC, Speight TM, Avery GS: Cimetidine: A review of its pharmacological properties and therapeutic efficacy in peptic ulcer disease. Drugs 15:93, 1978. 2. Finkelstein W, Isselbacher KJ: Drug therapy: Cimetidine. N Engl J Med 299:992, 1978. .?. Puurunen J, Sotaniemi E, Pelkonen 0: Effect of cimetidine

18:185,

drug

metabolism

in man.

January, 1984 Heart Journal

Eur J Clin

Pharma-

1980.

4. Feeley J, Wilkinson GR, Wood AJJ: Reduction of liver blood flow and propranolol metabolism by cimetidine. N Engl J Med 304:692, 1987. 5. Abernethy DR. Greenblatt Dd, Divoll M. Ameer B, Shader RI: Differential effect of cimetidine on drug oxidation (antipyrine and diazepaml versus conjugation (acetaminophen and lorazepam): Prevention of acetaminophen toxicity by cimetidine. .J Pharmacol Exp Ther 224:508, 1983. 6. Jackson JE, Powell JR, Wandell M, Bentley J, Dorr R: Cimetidine decreases theophylline clearance. Ann Rev Resp Dis 123:615, 1981. 7. Desmond PV, Patwardhan RV, Schenker S, Speeg KV: Cimetidine impairs elimination of chlordiazepoxide (Librium) in man. Ann Intern Med 93:266, 1980. 8. Serlin MJ, Sibeon RG, Mossman S, Breckenridge AM: Cimetidine interaction with oral anticoagulants in man. Lancet 2:317, 1979. 9. Dubb dW, Stote RM, Familiar RG, Lee K, Alexander F: Etfect of cimetidine on renal function in normal man. Clin Pharmacol Ther 24:76, 1978. 10. Dutt MK, Moody P, Northfield TC: Effect of cimetidine on renal function inman. Br J Clin Pharmacol 12:47, 1981. 11. Ochs HR, Greenblatt DJ, Bodem G, Harmatz JS: Doseindependent pharmacokinetics of digoxin in humans. AM HEART J 97:507, 1978. 12. Ochs HR, Greenblatt DJ, Bodem G: Single- and multipledose kinetics of intravenous digoxin. Clin Pharmacol Ther 28:340, 1980. 13. ‘Dchs HR. Bodem G, Greenblatt DJ: Effect of dose on bioavailability of oral digoxin. Eur J Clin Pharmacol 19:53, 1981. 14. Smith TW, Butler VP, Haber E: Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay. N Engl J Med 281:1212, 1969. 15. Randolph WC, Osborne VL, Walkenstein SS, Intocicca AP: High pressure liquid chromatographic analysis of cimetidine, a histamine H,-receptor antagonist, in blood and urine. J Pharm Sci 66:1148, 1977. 16. Ochs HR, Bodem G, Bales G, Greenblatt DJ, Smith TW: Increased clearance of digoxin in rabbits during repeated administration. J Pharmacol Exp Ther 205:516, 1978. 17. Bodemar G, Norlander B, Walan A: Pharmacokinetics of cimetidine after single doses and during continuous treatment. Clin Pharmacokinet 6:306, 1981.

Echocardiographic mitral prosthesis finding

diagnosis dehiscence.

of porcine A new

Gianni Slavich, M.D., Bruno Pinamonti, Bruno De Piccoli, M.D. Trieste and Mirano (Venezia), Italy

M.D., and

M-mode echocardiography (ME) has been useful to detect some malfunctions in porcine valves.‘” Below we describe another unreported ME feature detected in two patients with dehiscent porcine valves in the mitral position. Case 1. R.A., a 38-year-old man with rheumatic mitral

1.

From the Divisione and the Divisione Reprint My.

requests:

di Cardiologia, di Cardiologia, Gianni

Slavich,

Ente Ospedaliero Ospedale M.D.,

Civile via

Regionale

di Trieste;

di Mirano.

Timeus

14, 34100

Tribe,