Influence of arniodarone on genetically determined ...

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dextromethorphan (CYP2D6). Eight patients with arrhythmias were studied before and 76 2 16 days after amiodarone (loading dose of 1000 mglday for 10 days ...

Influence of arniodarone on genetically determined drug metabolism in humans Amiodarone has been shown to interact with the nongenetically determined hepatic elimination of several drugs, including phenytoin and digoxin. Its influence on genetically determined metabolic pathways has not been studied in humans. We examined the effects of oral amiodarone therapy on the genetically determined metabolism of isoniazid (N-acetyltransferase), mephenytoin (cytochrome P450,,,,), and dextromethorphan (CYP2D6). Eight patients with arrhythmias were studied before and 76 2 16 days after amiodarone (loading dose of 1000 mglday for 10 days followed by a maintenance dose of 200 to 400 mg/day). Genetically determined enzyme activity was assessed indirectly by calculating the metabolic and N-acetylisoniazid/isoniratio (parent drug/metabolite in 8-hour urine for CYP2D6 and P450,, azid in plasma for N-acetyltransferase) after oral administration of the parent compounds. At the time of phenotyping, plasma concentrations of amiodarone and N-desethylamiodarone were 0.66 2 0.35 pg/ml and 0.65 2 0.26 pglrnl, respectively. Amiodarone increased the log(metabolic ratio) of dextromethorphan from a median of - 2.5 (range, - 2.9 to - 2.0) to a median of - 1.9 (range, - 2.5 to - 1.5; p < 0.02) but did not alter the metabolic ratio of mephenytoin or iso~azid.The amount of dextromethorphan excreted in urine increased from a median of 0.084 pmoV8 hours (range, 0.041 to 0.161 pmoY8 hours) to a median of 0.205 pmoV8 hours (range, 0.064 to 0.288 pmoY8 hours; p < 0.02) and the amount of its metabolite (dextrorphan) tended to decrease from a median of 26 pmoY8 hours (range, 15 to 37 pmoV8 hours) to a median of 20 pmoY8 hours (range, 7 to 27 pmoY8 hours; p < 0.09). Additional in vitro studies in microsomes confirmed that amiodarone inhibits dextromethorphan 0-demethylase activity. These findings suggest that amiodarone decreases the activity of CYP2D6 and may impair the elimination of drugs whose clearance depends on this cytochrome in extensive metaboTHER 199l$O: 259-66.) lizers of dextromethorphan. (CLINPHARMACOL

Christian Funck-Brentano, MD, PhD, Evelyne Jacqz-Aigrain,MD, PhD, Antoine Leenhardt, MD, Annie Roux, PharmD, Jean-Marie Pokier, PhD, and Patrice Jaillon, MD Paris and Boulogne, France

Amiodarone is an antiarrhythmic drug that has been Despite shown to interact with several other these known drug interactions, amiodarone is often combined with other agents to gain additional antiarrhythmic efficacy.4 Also, unintentional combination From the Clinical Pharmacology Unit, Saint-Antoine University Hospital, the Clinical Pharmacology Unit, Robert Debre University Hospital, the Division of Cardiology, Lariboisi&reUniversity Hospital, Paris, and the Laboratory of Toxicology and Pharmacokinetics, Ambroise Pare University Hospital, Boulogne. Supported in part by a grant from the "Fonds d j ~ t u d e sdu Corps Mtdical des HBpitaux de Paris" (Association Claude Bernard). Presented in part at the Sixty-third Annual Meeting of the American Heart Association, Dallas, Texas, November 1990. Received for publication Jan. 23, 1991; accepted May 14, 1991. Reprint requests: Christian Funck-Brentano, MD, PhD, Unitt de Pharmacologie Clinique, HBpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France. 13/1/31038

may occur with amiodarone because its disposition kinetics are slow and it remains in the body for prolonged periods after it has been discontinued. Several mechanisms are responsible for pharmacokinetic drug interactions with amiodarone.' Amiodarone decreases the renal clearance of several drugs, including digoxin and procainamide.',5 It also decreases the hepatic metabolism of several agents, including digoxin3 and phenytoin.6,7 Animal studies have suggested that amiodarone produces a nonspecific decrease in hepatic drug m e t a b ~ l i s m . ~However, .~ studies of amiodarone effects on antipyrine kinetics in humans have yielded conflicting findings with either a decrease"' or no significant changeH in antipyrine clearance. The degree of specificity of amiodarone-induced decrease in hepatic drug metabolism remains to be determined. The hepatic metabolism of several drugs is genetically determined. Among the many different enzyme

U , I N PHARMACOI. THEK SEKEMRER 1991

260 Funck-Brentano et al. Table I. Clinical characteristics of the patients Patient No.

Age (yr)

Sex

Diagnosis

Male Male Male Female Female Female Female Female

Supraventricular tachycardia, WPW Nonsustained VT Nonsustained VT Atrial fibrillation Atrial fibrillation Sustained VT Nonsustained VT Atrial fibrillation

Concomitant drug

Glibenclamide, metformine -

Fluindione Theophylline, isosorbide dinitrate -

Acenocoumarol

VT, ventricular tachycardia; WPW, Wolff-Parkinson-White syndrome;

activities that are genetically determined, three have been extensively studied recently: the N-acetyltransferase activity,I2 the polymorphic oxidation of Smephenytoin,l"'4 and the polymorphic oxidation of debrisoquin/dextromethorphan. 14-" The influence of amiodarone on these polymorphic enzyme activities has not been studied. Because the hepatic metabolism of several drugs that are likely to be combined with . genetically determined, we examiodarone4.12. 14-17 is amined the influence of amiodarone therapy on the metabolism of isoniazid (N-acetyltransferase), mephenytoin (cytochrome P450,,,,, or IIC), and dextromethorphan (CYP2D6) in humans using standard phenotyping procedures.

METHODS Patients. Eight patients (three men and five women), in whom amiodarone therapy was deemed necessary for the management of arrhythmias, gave their informed consent to participate in the study. Mean ( t S D ) age was 65 t- 19 years (range, 32 to 82 years). In all patients, amiodarone was indicated for the nonurgent treatment of various ventricular or supraventricular arrhythmias (Table I). The protocol was approved by the Ethics Committee at Saint-Antoine University (Paris, France). Study design. This was an open, nonrandomized, two-period crossover study. Patients whose arrhythmias did not require emergency treatment, who took no drugs known to interfere with phenotyping procedUres,12-14.17who had never been treated with amiodarone, and who were likely to benefit from amiodarone therapy were considered for enrollment. Of 12 such patients seen during an 18-month period, two declined to complete the second period of the study, and two declined to participate. The eight remaining patients completed the study. Each of the two periods consisted of the determination of metabolic ratios with

use of isoniazid, mephenytoin, and dextromethorphan as probes for the measurement of N-acetyltransferase, cytochrome P450,,,,, and CYP2D6 activity, respectively. During the first period, patients were hospitalized for one day in the Clinical Pharmacology Unit at Saint-Antoine University Hospital. A 12-lead electrocardiogram was recorded. A light diner was given at 6:30 PM and no food or beverage was allowed until 8:30 AM the following morning. At 9 PM, patients emptied their bladders, and 40 mg dextromethorphan (two capsules of 20 mg dextromethorphan, Laboratoire Norgan, Paris, France) was administered orally together with 100 mg racemic mephenytoin (one tablet of Mesantoin, Sandoz Pharmaceutical, Basel, Switzerland) in 100 ml tap water. Urine was collected until 5:00 AM the next morning. Immediately after the last urine collection, 300 mg isoniazid (two tablets of 150 mg Rimifon, Laboratoires Roche, Neuilly-sur-Seine, France) were administered orally in 100 ml tap water. Precisely 3 hours later (8:05 AM), one blood sample was obtained. Patients then started amiodarone treatment with a loading dose of 1000 mglday (five tablets of 200 mg Cordarone, Laboratoires Labaz, Paris, France) for 10 days, followed by a maintenance dose of 200 mg or 400 mg amiodarone each day. Patients continued to receive amiodarone for a mean of 76 -C 16 days (range, 59 to 103 days) until they were hospitalized for the second period. During this 15-hour hospitalization, the procedures described for the first period were repeated. In addition, one blood sample for the determination of amiodarone and N-desethylamiodarone plasma concentration was drawn at 9:00 AM just before amiodarone administratlon. During the study, concomitant drugs could be administered provided the dosage was not changed and they were not known to interfere with the findings of

the tests performed. 12-14," Concomitant drugs are indicated in Table I. Heparin was administered to patients 4 and 8 before amiodarone and was replaced by fluindione and acenocoumarol, respectively, during the second period. Measurements of enzyme activities. The activity of N-acetyltransferase, cytochrome P450,,,,, and CYP2D6 were measured indirectly by calculating metabolic ratios (isoniazid and dextrornethorphan) or an hydroxylation index (mephenytoin) from plasma (isoniazid) and urine (dextromethorphan and mephenytoin) samples obtained during the standard phenotyping procedures described above. N-Acetyltransferase activity. The blood sample obtained 3 hours after isoniazid administration was centrifuged within 2 hours, and the plasma was collected and stored at -80" C until further assay within 1 to 7 days. Plasma concentrations of isoniazid and N-acetylisoniazid were determined by HPLC by use of a method described previously.18 The metabolic ratio for isoniazid was calculated as follows: plasma concentration of N-acetylisoniazidlplasma concentration of isoniazid. With this method, rapid acetylators of isoniazid have metabolic ratios >0.7, whereas slow acetylators have metabolic ratios 50.7.'' 4'-Hydroxylation of S-rnephenytoin. The volume of the 8-hour urine collection was measured, and two 25 ml aliquots were taken and frozen at -30" C until further assay within 2 months. In one aliquot, urine was analyzed for 4'-hydroxymephenytoin by use of an HPLC assay as described previously. '"ecause only trace or undetectable amounts of mephenytoin are eliminated unchanged in 8-hour urine samples, the activity of cytochrome P450,,,, was expressed as the hydroxylation index, that is, the amount of S-mephenytoin administered (50% of the racemic dose) divided by the molar amount of 4'-hydroxymephenytoin eliminated over 8 hours." By use of this method in a population of young healthy volunteers, extensive and poor metabolizers of mephenytoin have a log(hydroxy1ation index) < l and 2 1, respectively. I' Dextrornethorphan 0-dernethylation. The second urine aliquot was assayed for dextromethorphan and its 0-demethylated metabolite, dextrorphan, by use of an HPLC assay as previously described. 'y320 he metabolic ratio for dextromethorphan was calculated as the ratio of dextrornethorphan to dextrorphan elimination over 8 hours. This method gives values of log(metabo1ic ratio) of 0 or less for extensive metabolizers and of more than 0 for poor metabolizers of dextromethorphan.

''

Amiodarone and N-desethylamiodarone plasma concentration. Amiodarone and N-desethylamiodarone plasma concentrations were determined during the second period of the study by use of a previously described HPLC assay ." Data analysis. Because of the small number of patients studied, results before and during amiodarone administration were compared by the signed-ranks test using PC!INFO computer software (Retriever Data System, Seattle, Wash.). A difference was considered statistically significant if the probability of erroneously rejecting the null hypothesis of no difference was less than 5%. Results are reported as median and range. In vitro studies. Livers were obtained from macaca fascicularis monkeys, a nonhuman primate model of human debrisoquin/dextromethorphan polymorphism.'2 Microsomes were prepared as described previously .23 Protein concentration was determined according to the method of Lowry et a ~ . Microsomal '~ protein (250 pg) was preincubated at 37" C for 10 minutes in a final volume of 1 ml with 100 pI of a NADPH regenerating system (NADP, 10 mmollL; isocitrate, 50 mmol/L; isocitrate deshydrogenase, 10 unitslml; MgCI', 50 mmol/L) in 0.1 mol1L sodium phosphate buffer (pH 7.4). In control experiments, the reaction was started by adjunction of dextrornethorphan (5 to 500 pmolIL). In inhibitory experiments, the inhibitor was added as a 100 p1 solution of 10 times the desired concentration. Dextromethorphan 0-demethylase activity was measured at dextromethorphan concentrations of 5 pmollL, 50 pmol/L, and 500 pmol/L alone (control) and in the presence of amiodarone, debrisoquin, quinidine, or mephenytoin (100 pmol/L). In addition, dextromethorphan 0-demethylase activity was determined over the range of 5 to 250 pmol/L dextrornethorphan in the presence of 5 , 2 5 , and 50 pmol/L amiodarone. The reaction was stopped after 30 minutes by addition of citric acid buffer (pH 3). Denaturated protein was precipitated by centrifugation. The production of dextrorphan was determined by HPLC with fluorescence dete~tion.~' Dextromethorphan hydrobromide and dextrorphan tartrate were provided by Hoffman-La Roche Company (Basel, Switzerland) and amiodarone by Sanofi Recherche (Paris, France). All other chemicals and solvents were analytic grade. All data points were assayed at least in duplicate. The velocity of dextrornethorphan metabolism was expressed in nanomoles (dextrorphan) per milligram proteinlhour, and the effect of the inhibitors tested was expressed in percentage of control activity (in the absence of inhibitor). The estimated kinetic parameters

CLIN PHAKMACOI. THER SE.PTEMRER 1991

262 Funck-Brentano et al.

n

n

n

Ctrl Arnio

Ctrl Arnio

Ctrl Amio

Fig. 1. Metabolic ratio for dextromethorphan (left panel), rnephenytoin (middle panel), and isoniazid (right panel) before (Ctrl) and during (Amio) amiodarone administration. Extensive metabolizers are shown by closed circles; poor metabolizers are shown by open circles. NS, Not signif-

icant. were the maximum velocity (V,,,) and the apparent affinity constant (K,, in micromoles per liter). For amiodarone, the apparent dissociation constant (K,, in micromoles per liter) of the enzyme-inhibitor complex was determined from Dixon plots of the data. RESULTS Amiodarone was well tolerated in all patients. The mean maintenance dose of amiodarone was 286 t 107 mglday (median, 200 mglday; range, 200 to 400 mglday). Trough plasma concentrations of amio0.35 darone and N-desethylamiodarone were 0.66 kglml and 0.65 -C 0.26 kglrnl, respectively. Heart rate corrected QT interval duration increased from 437 t 35 msec to 487 ? 45 msec during amiodarone administration @ < 0.05). All plasma samples could be analyzed for the determination of isoniazid metabolic ratio, whereas urine collection was incomplete in patient 8. Therefore the hydroxylation index for mephenytoin and the metabolic ratio for dextromethorphan were calculated in seven patients. N-Acetyltransferase activity. Individual results before and during amiodarone are shown in Fig. 1 (right panel). Six of eight patients (patients 1 through 4, 7,

*

and 8) were slow acetylators of isoniazid before amiodarone administration. In this subset, amiodarone did not alter the metabolic ratio (median, 0.31; range, 0.25 to 0.54 versus median, 0.31; range, 0.21 to 0.46; p = NS). Amiodarone did not change the phenotype (rapid or slow) in any of the eight patients. 4'-Hydroxylation of S-mephenytoin. Individual results before and during amiodarone are shown in Fig. 1 (middle panel). Five of seven patients (patient 2, 3, and 5 through 7) were extensive metabolizers of mephenytoin before amiodarone administration. In this subset, amiodarone did not alter the log(hydroxylation index) (median, 0.73; range, 0.27 to 0.99 versus median, 0.82; range, 0.59 to 0.84; p = NS). Amiodarone did not change the phenotype (extensive or poor) in any of the seven patients. Dextromethorphan 0-demethylation. Individual results before and during amiodarone are shown in Fig. 1 (left panel). Before amiodarone, the median log(metabolic ratio) was -2.54 (range, -2.94 to -2.02). Amiodarone therapy significantly increased this value to a median of -1.88 (range, -2.49 to - 1SO; p < 0.02). The log(metabo1ic ratio) increased in each of the seven patients by a mean of 22% +-

VOLUME SO NVMBER 3

Amiodarone effects on drug metabolism 263

Control Arniodarone

Control Arniodarone

Fig. 2. Amount of dextromethorphan (DEM; left panel) and dextrorphan (DOR; right panel) ex-

creted in 8-hour urine before and during amiodarone therapy.

12%. All patients were extensive metabolizers of dextromethorphan before amiodarone administration, and the phenotype was not changed to a pseudo poor metabolizer phenotype during amiodarone therapy. The amount of dextrorphan excreted in 8-hour urine tended to decrease from a median of 26.0 pmol (range, 15.0 to 36.7 pmol) before amiodarone to a median of 19.9 pmol (range, 7.0 to 27.9 pmol) during amiodarone (Fig. 2; p < 0.09). The difference was statistically significant (n = 6; p = 0.03) after exclusion of one patient in whom the amount of dextrorphan excreted increased during amiodarone therapy. The amount of dextromethorphan excreted in 8-hour urine increased from a median of 0.084 pmol (range, 0.041 to 0.161 pmol) before amiodarone to a median of 0.205 pmol (range, 0.064 to 0.288 pmol) during amiodarone (Fig. 2; p < 0.02). The percent change in log(metabolic ratio) did not correlate with the baseline log(metabolic ratio) value, and it did not correlate with the percent increase in heart rate corrected QT interval duration or with plasma concentration of amiodarone and N-desethylamiodarone. Dextromethorphan 0-demethylase activity in vitro. Dextromethorphan 0-demethylation kinetics in primate liver microsomes was the same as that described

23 nmollmg propreviously (K,, 4 pmollL; V,,,, teinlhour). Amiodarone, debrisoquin, and quinidine inhibited dextrorphan formation, whereas mephenytoin had no effect (Fig. 3). The apparent K, for amiodarone was 30 pmolIL.

DISCUSSION Our findings suggest that amiodarone therapy selectively decreases the genetically determined activity of CYP2D6 without significantly altering N-acetyltransferase or cytochrome P450,,,, activity. N-Acetyltransferase activity. N-Acetyltransferase activity did not decrease during amiodarone in our eight patients. Six of these eight patients were slow acetylators of isoniazid at baseline. Inasmuch as enzyme activity was initially low in six of our eight patients, it is unlikely that a decrease in N-acetyltransferase activity could have been detected in these six patients. However, the metabolic ratio of isoniazid in the two rapid acetylators did not even show a trend toward a decrease during amiodarone (Fig. 1, right panel). Moreover, previous studies of the interaction between amiodarone and procainamide did not show a decrease in its N-acetylation to ~ - a c e t ~ l ~ r o c a i n a m i d e . ~ ~ Animal studies have shown that amiodarone does not

CLIN PHARMACOL THER SEPTEMBER 1991

264 Funck-Brentano et al. DEM 5 pM DEM 5 0 p M 0DEM 5 0 0 p M

DEM 0-demethylase activity (% from control)

100

-

90

-

80

-

70

-

50 -

60

40

-

30 20 10 0

Ctrl

Amio

Debri Quini

Meph

Fig. 3. Inhibition of dextromethorphan (DEM) 0-demethylation in monkey liver microsomes. Inhibitory experiments were performed in duplicate in the presence of 100 p,mol/L amiodarone

(Amio), debrisoquin (Debri), quinidine (Quini), and mephenytoin (Meph). Results are expressed as percentage of control (Ctrl) values. decrease the partial metabolic clearance of procainamide to ~ - a c e t ~ l ~ r o c a i n a m i Therefore d e . ~ ~ our findings are consistent with the fact that amiodarone does not impair genetically determined N-acetylation. Preliminary findings obtained in rats also suggest that amiodarone does not alter drug sulfation, another conjugation reaction.27 4'-Hydroxylation of S-mephenytoin. Amiodarone did not irripair the activity of cytochrome P45OMEP, as assessed by the hydroxylafion index. Because the number of patients studied was small, it is possible that our study lacked power to detect a decrease in cytochrome P45OMEPHactivity with amiodarone. There has been no report of interactions between amiodarone and drugs known to be metabolized by cytochrome ~450,,,,.'~ However, such interactions have not been specifically studied. Our findings suggest that amiodarone would not impair the disposition kinetics of drugs metabolized by cytochrome P45OMEPH. Dextromethorphan 0-demethylation. Amiodarone invariably increased the metabolic ratio of dextromethorphan in the seven patients in whom urine data were available. Such an increase in metabolic ratio suggests that amiodarone decreased CYP2D6 activity.

However, any mechanism that would lead to an increase in dextromethorphan and/or a decrease in dextrorphan urinary excretion could theoretically explain an increase in dextromethorphan metabolic ratio. Amiodarone decreases the urinary excretion of digoxin and procainamide3,5 and could thus decrease the urinary excretion of dextrorphan. However, if this were the case, such a decrease in dextrorphan urinary excretion, which occurred in six of our seven patients, would have no reason to be associated with an increase in the urinary excretion of dextromethorphan as observed in our study (Fig. 2). Thus the increase in dextromethorphan urinary excretion, the decrease in dextrorphan urinary excretion we found during amiodarone administration in the present study, and our in vitro data (see below) strongly suggest that the resulting increase in the metabolic ratio indeed reflects a reduction in CYP2D6 activity. As pointed out by Schellens et al.," clearance studies give more reliable information about changes in enzyme activities than studies based on metabolic ratio calculations and would therefore be useful to confirm our findings. We used monkey liver microsomes to assess amiodarone-induced inhibition of dextromethorphan

VOLUME 50 NUMBER 3

0-demethylation in vitro. This monkey species has been shown to exhibit interindividual variations of debrisoquin m e t a b o l i ~ m . Recent ~~ in vitro studies demonstrated catalytic and immunologic similarities, as well as identical substrate specificity of CYP2D6 between human and nonhuman primate, indicating that this monkey model may be useful for studies of CYP2D subfamily polymorphism. 29 Amiodarone was a competitive inhibitor of dextromethorphan 0-demethylation in vitro. Debrisoquin, a substrate of CYP2D6, and quinidine, a potent inhibitor of C Y P ~ D ~ , also ~ " inhibited dextromethorphan 0-demethylation in this monkey model, whereas mephenytoin had no effect. The increase in the metabolic ratio of dextromethorphan we have observed in our patients is consistent with these in vitro results. It has been suggested that amiodarone was a nonspecific inhibitor of cytochrome P450-dependent hepatic drug metaboli~m.~,~."ne possible explanation for this absence of specificity is the ability of a yetunidentified metabolite of amiodarone to form an inactive complex with cytochrome ~ 4 5 0 . ' However, in some of the animal experiments of Larrey et a ~ . ami, ~ odarone decreased several monooxygenase activities even in the absence of cytochrome P450-metabolite complex formation. Our study, together with the studies in animal^^,^^.^' and in human^^."^^^ discussed above, suggests that amiodarone-induced inhibition of hepatic drug metabolism has a certain degree of specificity. Competitive inhibition of CYP2D6 activity has been reported with several compounds. Most, but not all, of these compounds were substrates of this cytochrome."'." In fact, quinidine, a drug that is not metabolized by C Y P ~ D is~ one , ~ of ~ the most potent inhibitors of its a ~ t i v i t (Fig. ~ ~ ~3).~ Therefore ~ ~ - ~ ~ our findings do not necessarily indicate that amiodarone is a substrate of CYP2D6. Preliminary findings obtained in an animal model of CYP2D6 deficiency have shown that amiodarone and N-desethylamiodarone accumulation in plasma and liver increased in genetically deficient animals.36 This suggests that the biotransformation of amiodarone and N-desethylamiodarone into one or more other metabolites may in part cosegregate with the genetically determined metabolism of debrisoquinldextromethorphan. Clinical implications. The findings of our study indicate that amiodarone may modify the results of phenotyping when dextromethorphan is used as a probe to determine CYP2D6 activity. This is likely to be true only in subjects with the extensive metabolizer phenotype because no inhibition is expected in subjects in

Amiodarone effects on drug metabolism 265 whom enzyme activity is initially None of our patients' phenotypes changed from extensive to poor during amiodarone. However, initial values of metabolic ratios were very low in all subjects. It is very likely that amiodarone administration would lead to incorrect phenotype classification in extensive metabolizers with comparatively high metabolic ratios at baseline (although still within the range of extensive metabolizers distribution). Finally, one possible clinical implication of our findings may be that the interaction of amiodarone with drugs whose elimination depends on CYP2D6 is genetically determined. In fact, previous studies with quinidine have shown that extensive metabolizers, but not poor metabolizers, of debrisoquinidextromethorphan were exposed to pharmacokinetic or pharmacodynamic interactions with this d r ~ ~ . " ~ ~Further ~." studies are required to prospectively test the existence and clinical relevance of interactions between amiodarone and drugs whose elimination depends on CYP2D6. We thank Alain Hagege, MD, and Ariel Cohen. MD, for referring patients to us for this study and Marc Thiollet. MD, and Pascal Angebaud for technical assistance. We thank the CIRMF (Medical Research Center) of Franceville. Gabon, for providing us with the monkey livers.

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