Cardiovascular Drugs and Therapy 1991;5:733-740 9 Kiuwer Academic Publishers, Boston. Printed in U.S.A.

Pharmacokinetics of Encainide in Patients with Cirrhosis Georg W e n s i n g , 1 H e i n e r MfSnig, 1 E d g a r E. O h n h a u s , ~" a n d H a r a l d P. H o e n s c h 2 Zl. Medizinische Klinik, Christian-Albrechts-Universitiit Kiel a n d 2Medizinische Klinik, Universitdt Essen, FRG

Summary. The pharmacokinetics of encainide were investi-

gated in 10 patients with cirrhosis and 10 matched controls following single intravenous (IV, 25 mg), single oral (so, 25 rag), and multiple oral (mo, 25 mg thrice daily over 5 days) dosing. The hepatic oxidative drug-metabolizing enzyme capacity and its inducibility were assessed by antipyrine elimination and 6-[~-hydroxycortisol excretion. Eight controls and nine patients were of the extensive metabolizer phenotype (EM), as assessed by the sparteine metabolic ratio. Statistics was performed in EM only. The antipyrine half-life was significantly longer and clearance was significantly lower in patients with cirrhosis. Following IV administration, no significant differences in encainide half-life clearance, volume of distribution, or the area under the plasma concentration time curve (AUC) were observed between patients and controls. Following so and mo, there was a fourfold reduction in the oral clearance in cirrhotics. Thus, encainide bioavailability was increased in cirrhosis. Whereas the AUC of encainide was significantly higher in patients, no differences were observed in its active metabolites, O-desmethyl-encainide (ODE) and 3-methoxy-O-desmethylencainide (MODE). Plasma concentrations of encainide and its metabolites after 3 and 5 days of mo suggested steady-state conditions after 3 days of oral dosing. No change in antipyrine elimination and 6-[~-hydroxycortisol excretion following mo occurred. There was no relationship between parameters of encainide and antipyrine elimination. In conclusion, even though the elimination of encainide was reduced in patients with cirrhosis, plasma levels of the pharmacologically active metabolites, ODE and MODE, were comparable. Therefore, no dose alterations may be necessary in patients with hepatic impairment. In addition, no enzyme induction was observed following multiple oral dosing.

Cardiovasc Drugs Ther 1991;5:733-740

Key Words. Encainide, antipyrine, pharmacokinetics, cirrhosis, enzyme induction

Encainide [ 4 - m e t h o x y - 2 ' [2-(1-methyl-2-piperidyl]ethyl) b e n z a n i l i d e h y d r o c h l o r i d e ) is a compound with high a n t i a r r h y t h m i c p o t e n c y [ 1 - 3 ] t h a t has b e e n s h o w n to s u p p r e s s e c t o p i c v e n t r i c u l a r b e a t s , as well as complex ventricular arrhythmias and ventricular t a c h y c a r d i a [4,5]. B e c a u s e it d e c r e a s e s p h a s e 0 of the action p o t e n t i a l , i t h a s b e e n p l a c e d a m o n g class I anti-

a r r h y t h m i c s [6]. T h e m e t a b o l i s m of e n c a i n i d e is polym o r p h i c a l l y d i s t r i b u t e d a n d is l i n k e d to t h e 4 - h y d r o x y lation of d e b r i s o q u i n e [ 7 - 9 ] . S e v e r a l m e t a b o l i c p a t h w a y s h a v e b e e n identified. I n e x t e n s i v e m e t a b o lizers ( E M ) , t h e t w o m a j o r m e t a b o l i t e s a r e O-desmethyl-encainide (ODE) and 3-methoxy-O-desmethyle n c a i n i d e ( M O D E ) , t h e m e t a b o l i s m f r o m O D E to M O D E also b e i n g p o l y m o r p h i c a l l y d i s t r i b u t e d [10]. I n n o n e x t e n s i v e m e t a b o l i z e r s (PM), N - d e s m e t h y l e n c a i n i d e ( N D E ) is t h e m a j o r m e t a b o l i t e , w h e r e a s O D E p l a s m a l e v e l s a r e 10-fold l e s s t h a n in E M , and M O D E is a b s e n t f r o m p l a s m a [10]. T h e m e t a b o l i t e s of e n c a i n i d e h a v e b e e n s h o w n to b e p h a r m a c o l o g i c a l l y a c t i v e a n d to c o n t r i b u t e to its a n t i a r r h y t h m i c efficacy [2,11-13]. Encainide undergoes extensive first-pass metabolism in t h e liver. T h e r e f o r e it a p p e a r s likely t h a t t h e p h a r m a c o k i n e t i c s a n d m e t a b o l i s m of e n c a i n i d e m a y be a f f e c t e d in p a t i e n t s w i t h h e p a t i c i m p a i r m e n t . P r e viously, t h e p h a r m a c o k i n e t i c s of e n c a i n i d e w e r e s t u d ied in p a t i e n t s w i t h c i r r h o s i s [14]. T h e m e t a b o l i c pot e n t i a l o f t h e liver, h o w e v e r , w a s n o t m e a s u r e d and oral t h e r a p y w a s only c o n t i n u e d for 3 d a y s , a t i m e i n t e r v a l t h a t m a y b e too s h o r t to r e a c h s t e a d y - s t a t e c o n d i t i o n s for t h e m e t a b o l i t e s O D E and M O D E . T h e r e f o r e , w e i n v e s t i g a t e d t h e p h a r m a c o k i n e t i c s and m e t a b o l i s m of e n c a i n i d e in 10 p a t i e n t s w i t h h e p a t i c i m p a i r m e n t a n d 10 m a t c h e d c o n t r o l s a f t e r a single int r a v e n o u s , a single oral, a n d m u l t i p l e oral d o s i n g of 5 d a y s . A s e c o n d o b j e c t i v e w a s to d e t e r m i n e t h e capaci t y of e n c a i n i d e to i n d u c e t h e h e p a t i c m i c r o s o m a l e n z y m e s y s t e m a n d to r e v e a l a p o s s i b l e c o r r e l a t i o n b e t w e e n p a r a m e t e r s of a n t i p y r i n e and e n c a i n i d e elimination.

Address for correspondence and reprint requests: Dr. G. Wensing, Medizinische Klinik I, Friedrich-Alexander-Universit~tt, Krankenhausstr. 12, 8520 Erlangen, FRG. * Deceased. 733

734

Wensing, MSnig, Ohnhaus and Hoensch

Table 1. Group matching, phenotyping, and selective laboratory parameters in control subjects and patients with cirrhosis

Sex: Males Females Age (years) W e i g h t (kg) H e i g h t (cm) Smokers Nonsmokers Phenotype EM PM Albumin (g/dl) Bilirubin (mg/dl) P r o t h r o m b i n time (%) ~/-Glutamyltransferase (u/l) Creatinine (mg/dl)

Controls (n = 10)

Cirrhosis (n = 10)

5 5 51.8 64.4 166.1 5 5 8 2 4.2 0.5 98.8 17.7 0.8

5 5 55.6 65.7 167.1 5 5 9 1 3.5 4.6 64.1 104 0.8

• 8.9 --- 10.4 • 8.2

• • • • ---

0.3 0.3 2.8 14.7 0.05

-+ 8.8 • 15.1 -+ 10.3

• 0.5 a _+ 9.9 a - 20.2 ~ • 136.3 ~ • 0.2

ap < 0.05 (mean -+ SD).

Patients and Methods F o u r t e e n patients with proven cirrhosis (histology or history of liver disease and classical signs of decompensated cirrhosis as ascites a n d / o r esophageal varices) and 10 controls were enrolled in the study. Four patients were discontinued at an early stage for reasons unrelated to the study. In the remaining 10, cirrhosis was due to alcohol abuse (n = 7), chronic active hepatitis (n = 1), autoimmune hepatitis (n = 1), and hemochromatosis (n = 1). Five patients were classified as Child A, t h r e e as Child B, and two as Child C. They were matched for sex, age, body weight, height, and smoking with 10 healthy volunteers (Table 1). No patient showed signs of significant renal dysfunction or severe cardiovascular disease. Drugs with a known effect on the hepatic monooxygenases, such as cimetidine, barbiturates, antiepileptics, and rifampicin, as well as antiarrhythmic drugs, were discontinued at least 2 weeks prior to the study. Patients received spironolactone (n = 5), furosemide (n = 4), chlorthalidone (n = 2), ranitidine (n = 2), folic acid (n = 2), metoclopramide (n = 1), A1-Mg-hydroxid (n = 1), and lactulose (n = 1) for the t r e a t m e n t of complications of liver disease and digoxin (n = 5) for the treatment of mild cardiac failure. All subjects gave their informed written consent to participate in the study. The study protocol was approved by the local hospital ethics committee. Before entering the study, the following investigations were performed: medical history, physical examination, liver bio~psy or ultrasound examination (not in controls), 12-lead electrocardiogram (ECG), and labo-

ratory tests. E x c e p t for liver biopsy or ultrasound examination, all investigations were repeated at the end of the study. The individual phenotypes of all patients and all but two volunteers were characterized by the sparteine metabolic ratio after oral administration of 100 mg of sparteine sulfate [7]. The sparteine metabolic ratio is defined as the total amount of sparteine excreted in a 12-hour urine sample divided into the total amount of its 2- and 5-dehydrometabolites excreted. In two volunteers the individual phenotype was determined by the ability to form the encainide m e t a b o l i t e s - ODE, MODE, and N D E - - a s assessed by the cumulative 48-hour urinary excretion following single oral dosing. Two days before administration of the first encainide dose and following multiple oral dosing of encainide, antipyrine 1200 mg was given orally. Blood samples for the estimation of antipyrine plasma concentrations were taken at 0, 3, 6, 9, 12, 24, 36, and 48 hours. Urine was collected up to 48 hours for the determination of 6-~-hydroxycortisol and 17-hydroxycorticosteroids. On day 1, 25 mg encainide were infused over 15 minutes. Blood samples were taken immediately before and at 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours following encainide infusion. On day 3, 25 mg encainide were given orally. Blood samples were taken immediately before and at 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours following encainide administration. Multiple oral dosing was started on day 5. Encainide 25 mg was administered thrice daily. Blood samples were collected 1 and 8 hours after the seventh dose on day 7. The last dose was taken as a morning dose on day 9 (a total of 13 doses). Thereafter, blood was taken in timed intervals, as described for single oral dosing. ECGs were performed before entering the study, at the end of the intravenous infusion, 1 hour after single oral dosing, 1 hour after the first as well as the last dose of multiple oral dosing, and at the end of the study. The drugs were administered after an overnight fast and breakfast, and concomitant medication was allowed as early as 2 hours later, except for doses 2 - 1 2 during multiple oral dosing. Intravenous infusion of encainide was done by a cannula in a forearm vein. All blood samples for encainide and antipyrine plasma concentrations were taken by puncture of the vena cubitalis or a remaining cannula in a forearm vein, in case of intravenous infusion of encainide on the contralateral arm. Blood for the determination of encainide and its metabolites was collected into prechilled glass tubes, centrifuged immediately at 4~ and stored at -20~ until analyzed. Blood for antipyrine plasma concentrations was centrifuged at room t e m p e r a t u r e and also stored at

Encainide in Cirrhosis

-20~ until analyzed. Urine volume was measured at the end of the collection period and an aliquot of 40 ml frozen at - 2 0 ~ Antipyrine plasma concentrations and plasma and urine samples for encainide and its metabolites were measured by high-pressure liquid chromatography [15,16]. 6-~-hydroxycortisol and 17hydroxycorticosteroids were measured in 24-hour urine samples by a specific radioimmunoassay [17] and a colorimetric method [18]. The pharmacokinetic parameters of antipyrine were calculated as described previously [19]. The maximum plasma concentration of encainide (C~a~) and the time to reach maximum plasma concentration (tmax) were taken directly from the plasma concentration time curve. The area under the plasma concentration versus time curve (AUC) and the area under the first moment plasma concentration versus time curve (AUMC) w e r e calculated by means of the trapezoidal rule. The half-life (tl/2) was calculated as ln2 divided by the elimination rate constant (ke) determined by least-square regression analysis. The systemic (Cliv) and oral (C1o) clearance were calculated as dose divided by AUC. The volume of distribution at steady state (Vs~) was determined as C1 • AUMC/AUC. The bioavailability was estimated (F) by Cliv/C1o. In the above calculations, AUC is AUC to infinity for encainide after single oral and single intravenous dosing. The extrapolated area was less than 8%. AUC was calculated over the dosing interval for multiple oral dosing. The results between single groups were compared by the Student's t test or, in case of a lack of normality distribution, by the Wilcoxon test for paired and unpaired observations. P < 0.05 was chosen as the minimum level of significance. Data are expressed as mean -- standard deviation (SD).

Results The data for group matching, phenotyping, and selective laboratory parameters are presented in Table 1. No severe adverse effects were observed in patients and controls following encainide administration. Two subjects complained about a mild headache and fatigue, which resolved spontaneously. Based on the sparteine metabolic ratio and, in the two volunteers who did not undergo sparteine phenotyping, the ability to form the encainide metabolites ODE, MODE, and N D E , two control subjects and one patient with cirrhosis were classified as poor metabolizers (PM). PM E x c r e t e d no MODE and only low amounts of ODE, while NDE excretion was up to 11.2% of the dose. In EM, cumulative 48-hour urinary excretion of ODE and MODE accounted for 8.3 -- 4.5

735

versus 13.5 - 8.6% and 2.0 -- 0.6 versus 2.4 _+ 1.4% of the dose in patients and controls, respectively (difference not significant). The pharmacokinetic parameters of PM are presented separately. The pharmacokinetic parameters of encainide after single intravenous, single oral, and multiple oral dosing are presented in Tables 2 and 3. Plasma concentrations of some samples in individual subjects were below the level of detection, so that the number of samples was too low to calculate the pharmacokinetic parameters reliably. Therefore, the number of subjects included in the statistics varies between the different routes of administration. Following a single intravenous dose, t h e r e were no significant differences in encainide tl/2, AUC, Cliv and Vdss between patients and controls (Table 2). Following single and multiple oral dosing, patients showed a significant increase in AUC and a significant decrease in C1o (Table 3). Encainide tl/2 tended to be lower in controls, although the difference was only slight after multiple oral dosing. No significant differences were observed in Cmax and tma~, however, Cmax tended to be higher in patients. Whereas in controls the encainide C1 was substantially lower and AUC substantially higher following intravenous compared to oral administration, the pharmacokinetic p a r a m e t e r s in patients following oral dosing were not significantly different from those observed following intravenous dosing. Thus, cirrhosis led to a twofold increase in encainide bioavailability. While the disposition parameters of encainide were substantially altered following oral dosing in cirrhosis, the plasma concentrations of the metabolites ODE and MODE were comparable in both groups (Figure 1). Although ODE and MODE accumulated significantly following multiple oral dosing, no significant differences in AUC were observed between patients with cirrhosis and control subjects. The AUC for ODE was even lower in patients than in controls. Steady-state conditions for encainide and its metabolites ODE and MODE appear to have been achieved after the seventh dose of oral dosing since the eight hour plasma concentrations after the seventh and the last dose did not differ significantly (controls: encainide 3 -+ 7 vs. 0 -- 0, ODE 51 _+ 38 vs. 46 -- 40, and MODE 73 +-- 25 vs. 67 -4- 18 ng/ml; patients: encainide 13 __ 15 vs. 14 -+ 13, ODE 43 +_ 24 vs. 43 +24, and MODE 66 -+ 48 vs. 72 -- 46 ng/ml). No significant differences were observed in the change of E C G intervals between control subjects and patients after either of the doses. Following multiple oral dosing, QRS was increased by 5.2 -+ 3.7% and 8.1 -+ 5.8%, PR by 6.8 -+ 5.1 and 4.8 -+ 4.1%, and QT by 3.0 - 1.9 and 3.6 -- 4.6% in controls and patients, respectively.

736

Wensing, MOnig, Ohnhaus and Hoensch

Table 2. Pharmacokinetic parameters of encainide in controls and patients with cirrhosis after single intravenous administration of encainide (mean • SD) EM

Half-life (hr) Clearance (l/min) AUC (ng • hr/ml)

PM

Controls n=8

Cirrhosis n=8

3.3 • 2.5 0 . 9 3 • 0.5 747 -+ 723 b

3.3 • 2.7 0.85 • 0.5 641 • 337 b

Volume of distribution

137 •

66

139 •

Controls n=2

Cirrhosis n=l

11.0 -- 4 . 9 0 . 2 3 -+ 0.1 1783 • 763 b

59

201 •

21.4 0.09 4265 b

5.6

165

a t s t e a d y s t a t e (1) EM = extensive metabolizer; PM = poor metabolizer. ap < 0.05 b e t w e e n control a n d cirrhosis; b A U C to infinity.

Table 3. Pharmacokinetic parameters of encainide in control subjects and patients with cirrhosis after single oral and multiple oral (3 • 25 mg over 5 days) dosing (mean +- SD) EM

PM

Single oral Controls n=5 Half-life (hr) Clearance (l/min) A U C (ng • hr/ml) Bioavailability Maximum plasma concentration (ng/ml) Time to m a x i m u m plasma contraction (hr)

1.2 4.2 1241 0.29 60.8

• -+ • • -•

Multiple oral

Cirrhosis n=6 0.2 1.7 76 0.147 33.4

1.1 • 0.4

2.6 1.5 335 0.48 100.7

• • • • •

Controls n=6 1.0~ 0.9 ~ 164 ~'b 0.18 ~ 50.0

0.9 -+ 1.1

2.8 5.0 147~ 0.35 75.2

• +• • -+

3.1 3.9 119 0.29 60.3

0.9 • 0.2

Single oral

Cirrhosis n=9 3.1 1.2 4162 0.66 151

• 1.5 • 0.9 a • 245 a • 0.34 ~ -+ 105.5

1.3 • 1.0

Controls n=2 8.8 0.27 1786 0.95 149

• • -+ • -+

6.0 0.18 1211 b 0.3 29.7

1.6 • 0

Multiple oral

Cirrhosis n=l

Controls n=2

7.7 0.10 4473 b 1.05 452

9.4 0.20 2360 r 1.3 435

4

• • -+ • -+

Cirrhosis n=l 6.1 0.12 1435 0.3 234

1.4 • 0.5

9.0 0.18 2211 r 0.52 328 3

ap < 0.05 b e t w e e n cirrhosis a n d controls; b A U C to infinity; c A U C 0-8. EM = extensive metabolizer; PM = poor metabolizer.

Pharmacokinetic parameters from the three PM are presented in Tables 2 and 3. Due to the small number of subjects, the results in general and the comparison between normal subjects and patients should be taken with caution. The data, however, indicate that the pharmacokinetic parameters of encainide are determined to a substantially higher degree by the PM phenotype than by hepatic impairment. Evaluation of parameters of antipyrine elimination and 6-~-hydroxycortisol and 17-hydroxycorticosteroid excretion before and after multiple oral dosing of encainide revealed no change in either of the parameters in patients or controls (Table 4). No significant correlation was observed between parameters of antipyrine elimination and encainide half-life, clearance, AUC, tmax, and Cm~ or ODE and MODE AUC.

Discussion A large number of investigations have provided evidence that hepatic oxidative drug metabolism is re-

duced in patients with hepatic dysfunction [20,21]. This holds especially true for drugs with extensive first-pass metabolism. The diagnosis of cirrhosis, however, does not implicate a reduction in the activity of the drug-metabolizing enzymes in all instances [22]. Estimation of antipyrine elimination has been suggested to provide a useful parameter of the activity of hepatic drug-metabolizing enzymes in humans [23]. Based on the parameters of antipyrine elimination, the hepatic drug-metabolizing enzyme activity was reduced by approximately 50% in patients with cirrhosis in the present study. The metabolism of encainide has been shown to be polymorphically determined, and the production of the pharmacologically active metabolite ODE has been found to be linked to the 4-hydroxylation of debrisoquine [9]. Because there is a comparative pharmacogenetics between sparteine and debrisoquine [7,8], the subjects in the present study could be phenotyped as EM and PM by their sparteine metabolic ratio, as well as their ability to form ODE and NDE. The results for the disposition parameters of en-

E n c a i n i d e in Cirrhosis

x

2000"

1000

0 (J -1

i

slngle

.....

single

IV

9 []

oral

rnultlple

oral

control cirrhosis

2000

E

J:: 1000 -I

0

I

single

, i/

iv

single oral mulllplrs

oral

Fig. 1. Area u n d e r the p l a s m a concentration time curve (AUC) of O-desmethyl-encainide (ODE) and 3-methoxy-Odesmethylencainide ( M O D E ) f r o m 0 to 48 hours in control subjects and patients with cirrhosis following single intravenous (iv), single oral, and multiple oral (3 x 25 mg over 5 days) dosing o f encainide. *p < 0.05 compared to single oral and intravenous dosing; x = p < 0.05 compared to single intravenous dosing. ( m e a n +- S E M ) .

cainide are, in general, in agreement with those reported previously [14,24]. Bergstrand and coworkers found a significant 40% decrease in the systemic clearance of encainide in patients with cirrhosis when compared to younger healthy volunteers [14]. The reduction in systemic clearance in patients with cirrhosis in the present study was only slight, and the difference between patients and controls did not reach statistical significance. Substantial interindividual differences in the disposition of encainide, however, were observed

737

in the present and the previous study, and such differences m a y influence the results in small sample sizes. Smaller changes observed in the present study might also be due to differences in the stage of liver disease; however, no data about the severity of disease are available from the study of B e r g s t r a n d et al. In control subjects, the oral clearance of encainide was three- to fivefold higher than the systemic clearance. These results are in agreement with previous findings [24] and reflect the high first-pass metabolism of orally administered encainide. Changes in intrinsic clearance affect plasma concentrations of a drug with a high first-pass metabolism to a greater extent following oral than intravenous administration. The smaller difference between oral and intravenous clearance in the hepatic impairment group is consistent with a reduction of encainide metabolism in cirrhosis, resulting in increased bioavailability of the drug. Encainide clearance and half-life were altered to a substantially higher degree in PM than in patients with hepatic impairment. As infered from the above observations, it would be expected that the antiarrhythmic efficacy of a similar dose of encainide might differ substantially in EM and PM. Interestingly, similar doses of the drug are required to suppress arrhythmias in both groups of patients [25]. Accumulation of ODE and MODE in EM and of encainide in PM appears to result in a comparable antiarrhythmic efficacy in both patient populations [25,26]. While the pharmacokinetics of encainide were altered substantially in cirrhosis, plasma concentrations of the active metabolites ODE and MODE appeared to be unaffected. Although accumulation of the metabolites occurred during multiple oral dosing, no differences between control subjects and patients with hepatic impairment were observed. In addition, ECG changes were comparable in both groups. Since the antiarrhythmic potency of encainide in EM has been

Table 4. Parameters o f antipyrine elimination and 6-~-hydroxycortisol and 17-hydroxycorticosteroid excretion in controls and patients with cirrhosis before study began and after multiple oral dosing o f encainide (3 x 25 mg over 5 days).

Controls (n = 10)

Volume of distribution (I) Half-life (Hr) Clearance (ml/min) 6-~-Hydroxycortisol (~g/day) 17-Hydroxycorticosteroids (mg/day)

Cirrhosis (n = 0)

Before

After

32.8 - 6.1 10.6 -+ 5.2 41.4 -+ 15 432.9 -+ 317.8

34.4 9.2 48.3 368.1

7.6 -+ 4.6

- 7.7 -+ 3.4~ -+ 20.5a -+ 145.1

6.8 -+ 2.0

Before

After

36.1 +- 16.1 17.8 - 9.4 26.1 -+ 8.4 430.7 -+ 168.9

36.8 -+ 10.8 18.2 -+ 10.1 29.2 -+ 15.8 383.8 -+ 195.6

4.7 -+ 3.0

4.7 +- 2.0

ap < 0.05 control vs. cirrhosis; parameters were not significantlydifferent before and after encainide administration (mean -+ SEM).

738

Wensing, MOnig, Ohnhaus and Hoensch

shown to be best correlated to ODE plasma levels [13], dose adjustments probably may not be necessary in patients with cirrhosis. As in the previous study [14], however, interindividual differences in the metabolism of encainide were substantial, and high plasma concentrations were observed in individual patients. Therefore, caution should be taken when higher doses of encainide are administered. As unidentified p a t h w a y s of encainide metabolism account for approximately 50% of the biotransformation of the drug, these pathways appear to be preferentially reduced in hepatic disease [14]. Comparison of plasma concentrations of encainide, ODE, and MODE after 3 and 5 days of multiple oral dosing revealed no differences in plasma levels of either of the compounds 8 hours after drug administration, both in control subjects and patients. These results indicate that steady-state conditions may have been achieved after 3 days of oral dosing and that necessary dose adjustments should be made after 3-5 days of chronic dosing. Antipyrine elimination and 6-~-hydroxycortisol and 17-hydroxycorticosteroid excretion were unaltered after multiple oral dosing of encainide when compared to prestudy values. Although the observed period of 5 days was short, these data indicate that encainide, in the administered dose, did not induce the metabolism of these substances. However, considering the diversity of the hepatic cytochrome P-450 system, care should be taken when generalizing these results to the hepatic d r u g metabolizing enzymes in general. The Cardiac A r r h y t h m i a Suppression Trial (CAST) is investigating the effect of antiarrhythmic therapy in patients with asymptomatic or mildly symptomatic ventricular a r r y h t h m i a after myocardial infarction. The preliminary report of the study recently revealed a higher death rate in patients treated with antiarryhthmics, including encainide, than in patients on placebo [27]. It was concluded that encainide should not be used in the t r e a t m e n t of asymptomatic or mildly symptomatic ventricular arrhthmia after myocardial infarction. Although it is not clear whether these results apply to other groups of patients, caution should be taken in using the drug, especially since marked intraindividual differences in plasma concentrations are observed. In conclusion, although the metabolism of encainide was impaired in cirrhosis, dose adjustments may probably not be necessary, as the production of the more active metabolites ODE and MODE was not affected. Steady-state conditions for encainide and its metabolites were achieved after 3 days of oral dosing, suggesting that doses should be increased for 3-5 days. Since high plasma concentrations were observed

in individual subjects, doses should be increased with caution.

Acknowledgments

The authors wish to thank Bristol Myers International Corporation for the determination of encainide plasma concentrations and Prof. Dr. M. Eichelbaum, Margarete Fischer-Bosch Institut far Klinische Pharmakologie, Stuttgart, for the determination of sparteine in urine.

References

1. Harrison DC, Winkle RA, Sami M, Mason JW. Eneainide: A new and potent antiarrhythmic agent. A m Heart J 1980;100:1046-1054. 2. Roden DM, Reehe SB, Higgins SB, et al. Total suppression of ventricular arrhythmias by encainide. N E~gl J Med 1980;302:878-882. 3. Winkle RA, Peters F, Kates RE, et al. Clinical pharmacology and antiarrhythmic effacacy of encainide in patients with chronic ventricular arrhythmias. Circulation 1981;64: 290-296. 4. DiBiancoR, Fletcher RB, Cohen AJ. Treatment of frequent ventricular arrhythmias with encainide: Assessment of using serial ambulatory electro-cardiograms, intracardiac eleetrophysiologie studies, treadmill exercise tests and radionucleide cineangiographic studies. Circulation 1982;65: 1134-1147. 5. MasonJW, Peters FA. Antiarrhythmic efficacyof encainide in patients with refractory recurrent ventricular tachycardia. Circulation 1981;63:670-675. 6. Gibson JK, Somani P, Bassett AL. Electrophysiologic effects of encainide on canine Purkinje fibers. Eur J Pharmacol 1978;52:161. 7. Eichelbaum M, Bertilsson L, S~iweJ, Zekorn C. Polymorphic oxidation of sparteine and debrisoquine: Related pharmacogenetic entities. Clin Pharmacol Ther 1982;31:184186. 8. Inaba T, Vinks A, Otton V, Kalow W. Comparative pharmacogenetics of sparteine and debrisoquine. Clin Pharmacol Ther 1983;33:394-399. 9. Woosley RL, Roden DM, Dai G, et al. Coinheritance of the polymorphic metabolism of encalnide and debrisoquine. Clin Pharmacol Ther 1986;39:282-287. 10. Wang T, Roden DM, Wolfenden HT, et al. Influence of genetic polymorphism on the metabolism and disposition of encainide. J Pharmacol Exp Ther 1984;228:605-611. 11. Ellharrar V, Zipes DP. Effects of encainide (MI 14030 and MJ 944) on canine Purkinje and ventricular fibers. J Pharmacol Exp Ther 1982;220:440-447. 12. Kerr MJ, Allken JD, Harron DWG, Sharks RG. Effects of encainide and its major metabelites O-des-methylencainide and 3-methoxy-O-des-methylencainide on experimental cardiac arrhythmias in dogs. J Cardiovasc Pharmacol 1985;7: 539-547. 13. Carey EM, Duff HJ, Roden DM, et al. Encainide and its metabolites: Comparative effects in man on ventriculararrhythmic and electro-cardiographic intervals. J Clin Invest 1984;73:539-547. 14. Bergstrand RH, Wang T, Roden DM, et al. Encainide dispo-

Encainide in Cirrhosis

15.

16.

17. 18.

19.

sition in patients with cirrhosis. Clin Pharmacol Ther 1986; 40:148-154. Eichelbaum M, Somogy A. Rapid and sensitive method for the determination of antipyrine in biological fluids by high pressure liquid chromatography. J Chromatogr 1977;140: 288-292. Mayol RS, Gammans RE, LaBudde IA. Analysis of encalnide and its metabolites in man using a high pressure liquid chromatographic method. Clin Pharmacol Ther 1981; 29:265-270. Park BK. A direct radioimmunoassay for 6-~-hydroxycortisol in human urine. J Steroid Biochem 1978;9:963-966. Sanghvi A, Wight C, Parikh B, Desai H. Urinary 17hydroxycorticosteroid determination with p-hydrazinobenzene-sulfonic-acid-phosphoric acid. A m J Clin Pathol 1973;60:684-690. Ohnhaus EE, Martin J, Kinser J, Colombo JP. Enzyme induction and renal function in man. B r J Clin Pharmacot 1977;4:33-37.

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20. Wilkinson GA, Schenker S. Drug disposition in liver disease. Drug Metab R e v 1975;4:139-175. 21. Williams RL. Drug administration in hepatic disease. N E n g l J M e d 1983;309:1616-1622. 22. Ohnhauss EE, Mtinch U, Meir J. Elimination of pindolol in liver disease. E u r J Clin Pharmacol 1982;22:247-251. 23. Branch RA. Drugs as indicators of hepatic function Hepatology 1982;2:97-105. 24. Turgeon J, Roden DM. Pharmacokinetic profile ofencainide. Clin Pharmacol Ther 1989;45:692-694. 25. Roden DM. Encainide and related antiarrhythmic drugs. In: I S I atlas o f science: Pharmacology 1989;374-379. 26. Antonaccio MJ, Verjee S. Dosing recommendations for encainide. A m J Cardiol 1986;58:114C-116C. 27. Cardiac Arrhythmia Suppression Trial. Preliminary report: Effect of encainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N E n g l J M e d 1989;321:406-412.

Pharmacokinetics of encainide in patients with cirrhosis.

The pharmacokinetics of encainide were investigated in 10 patients with cirrhosis and 10 matched controls following single intravenous (IV, 25 mg), si...
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