CardiovascularDrugsandTherapy4:561-566,1990
© KluwerAcademicPublishers, Boston.Printed in U.S.A.
A Review of Encainide
Pharmacokinetics and Metabolism of Encainide Patrice Jaillon Clinical Pharmacology Unit, Saint-Antoine University Hospital Paris, France
Summary. The metabolism of encainide occurs in the liver and is polymorphically distributed according to the same genetic factor that determines the 4-hydroxylation of debrisoquine. Over 90% of patients are extensive metabolizers (EM) in whom the oral bioavailability of encainide is only 30% • because of extensive first-pass metabolism. In EMs, elimination tl/z is about 2.5 hours, with a systemic clearance of 1.8 1/ min. The plasma concentrations of the major metabolites Odesmethyl-encainide (ODE) and 3-methoxy-O-desmethylencainide (3-MODE) are higher than those of encainide and have antiarrhythmic activity. The remaining patients (< 10%) are poor metabolizers (PM), in whom the oral bioavailability is near 88% with an elimination tl/2 of 8-11 hours and a systemic clearance of 0.2 l/min. Encainide plasma concentrations are 10- to 20-fold higher than in EMs, but considerably less ODE and no 3-MODE is formed by the PMs. The conversion to the N-desmethyl-encainide (NDE) metabolite seems to be similar in both metabolizer groups, and plasma protein binding of encainide of 70-78% is also similar. During long-term treatment, the antiarrhythmic metabolites of encainide accumulate in the plasma, so that the relationships between the effect and plasma concentration on encainide, ODE, and 3-MODE are not always obvious. Minimally effective plama concentrations appear to be approximately 300 ng/ml of encainide, 35 ng/ml of ODE, and 100 ng/ml of 3-MODE. Dose adjustment is necessary in patients with decreased kidney function, but not in patients with cirrhosis, in whom the plasma levels of metabolites appear to be comparable to those in normal subjects.
Key Words. encainide, 3-methoxy-O-desmethyl-encainide, Odesmethyl-encainide, oral bioavailability, plasma protein binding, hepatic dysfunction, renal failure, dose adjustment, drug interactions
T h e main characteristic of the disposition of encainide in humans is the existence of a polymorphic distribution of its metabolism among subjects. Plasma concentrations over time measured in 11 patients with highfrequency, nonsustained ventricular arrhythmias and normal renal and hepatic function, who received a single 25-mg oral dose of encainide, revealed that one nonresponding patient had a markedly longer elimination half-life (t~) of encainide than the other patients [1]. This patient had a steady-state plasma concentration of encainide that was 20-100 times greater than that of the other ten patients and had no detectable
plasma level of the O-desmethyl metabolite of encainide. This patient was also the only one of the 11 patients who did not have a drug response. This first observation and other observations of the marked variability in encainide bioavailability suggested that the effects of the drug were mediated by the variable generation of active metabolites.
Pharmacokinetics of Encainide in
Healthy Subjects Further studies have confirmed this hypothesis and Figure 1 shows the metabolic pathways of encainide. As shown, the major pathway leads to the formation of O-desmethylencainide (ODE) and to 3-methoxy-Odesmethylencainide (MODE). The second metabolic pathway leads to N-desmethylencainide (NDE). The ability to metabolize encainide to the ODE and MODE metabolites is a genetic trait that is distributed according to the same genetic factor that determines the 4-hydroxylation of debrisoquine and that is related to the P 450 hydroxylase system in the hepatocytes. In the more than 90% of the population who have the ability to metabolize encainide to ODE and MODE, the elimination half-life of encainide is short, and its absolute bioavailability is low because of a significant hepatic first-pass effect. In the remaining 79% of the population, plasma concentrations of encainide are higher, with a higher and more stable bioavailability and a much higher elimination half-life. It has been shown [2] that there is a linear relationship (r = 0.72; p < 0.001) between the fractional excretions of ODE and 4-hydroxy debrisoquin in a group of 22 normal subjects. The pharmacokinetic differences between extensive metabolizers (EM) in whom ODE and MODE are formed and the poor metabolizers (PM) in whom MODE is not formed has been demonstrated in a study in healthy volunteers [3]. An intravenous radiolabeled tracer dose of encainide was adminis-
Address for correspondenceand reprint requests: ProfessorPatrice Jaillon, Unit6 de PharmacologyClinique, H6pitalSaint-Antoine, 184 Rue du Fg Saint-Antoine, 75012Paris, France. 56/
~62
Jaillon
OCH3 Encainide
H
v
"OCH3
N-desmethylencainide
(NDE)
,
H
v
-OH
O-desmethylencainide
(ODE)
l
3-Methoxy-O-desmethylencainide (MODE) Fig. 1. Metabolicpathways of encainide
tered simultaneously with an oral dose, and kinetic studies were done after one dose (acute) and after six doses over 2 days (chronic). After a single dose of encainide, the EM volunteers have a rapid elimination of encainide and higher concentrations of the ODE and MODE metabolites than the PM volunteers, who had much higher plasma levels of encainide and some ODE and NDE but no MODE metabolites. The pharmacokinetic parameters derived from the 24-hour urinary excretion of encainide and its metabolites in this study are given in Table 1. The encainide tl/2 is shorter (2.7 hours) and its systemic clearance much higher (1.8 1/min) in the EMs than are these same parameters (8.1 hours and .21 1/min, respectively) in the PMs after acute dosing. Because of an important first-pass effect, the oral bioavailability of encainide is only 26% in the EM group, compared with 88% in the PM group. Protein binding was similar in both groups, and the results after 2 days of dosing were not significantly different from those after a single dose. In the EM group, ODE is the major metabolite in the urine, accompanied by somewhat less MODE and a minor amount of encainide. In the PM group the major portion of encainide is excreted un-
changed in the urine, accompanied by relatively little NDE metabolite, a minor amount of ODE, and no MODE. After 2 days of treatment, encainide disposition was not altered, but encainide was accumulating in the PM group, while the two metabolites ODE and MODE were accumulating in the EM group, as shown in Figure 2.
Effect o f R e n a l or H e p a t i c Disease on the P h a r m a c o k i n e t i c s o f E n c a i n i d e The slow elimination rate of the metabolites ODE and MODE results in accumulation with increasing plasma levels in EMs. It has been reported [4] that after longterm oral encainide administration the ratio of steadystate plasma concentrations of ODE and MODE to encainide varied from 0.67 to 9.37 (mean 5.02 -- 2.61) for ODE, and from 0.06 to 12.9 (mean 5.15 -+ 4.13) for MODE. This was due to the long tl/2, which was found to be more than 11 hours for ODE. The tl/2 for MODE was so long that it was not possible to calculate or estimate it after 24 hours of plasma sampling. The mean plasma concentration of MODE, 24 hours after discontinuation of treatment was still 59.8 -+ 39.9% of
Pharmacokinetics and Metabolism of Encainide
563
Table 1. Pharmacokinetics of encainide Extensive Metabolizer Acute Half-life (hr) Systemic clearance (l/min) % bioavailable Plasma protein binding
Poor Metabolizer
Chronic
2.7 _+ 0.3
2.3 - 0.3
8.1 + 1.1
1.8 + 0.2 26.3 ± 6.7
1.9 +- 0.2 30.0 -+ 6.8
0.21 _+ 0.02 88.4 +_ 4.3
70.5 _+ 2.2
% dose in 24-hour urine Encainide ODE MODE NDE
Chronic
Acute
11.3 _+ 0.3
0.18 +_ 0.002 83.2 +_ 9.4
78.1 -+ 0.6 4.9 -+ 2.3 10.6 _+ 3.0 3.6 - 2.8 Not detected
39.3 _~ 5.6 3.0 -+ 0.15 Not detected 1.8 -!--0.6
NDE = N-desmethyl encainide; ODE = O-desmethyl encainide; 3-MODE = 3-methoxy O-desmethyl encainide. Reproduced with permission of Wang et al. [3] and American Society for Pharmacology Experimental Therapeutics.
O-desmethyl encainide
Encainide
4000 p
© KluwerAcademicPublishers, Boston.Printed in U.S.A.
A Review of Encainide
Pharmacokinetics and Metabolism of Encainide Patrice Jaillon Clinical Pharmacology Unit, Saint-Antoine University Hospital Paris, France
Summary. The metabolism of encainide occurs in the liver and is polymorphically distributed according to the same genetic factor that determines the 4-hydroxylation of debrisoquine. Over 90% of patients are extensive metabolizers (EM) in whom the oral bioavailability of encainide is only 30% • because of extensive first-pass metabolism. In EMs, elimination tl/z is about 2.5 hours, with a systemic clearance of 1.8 1/ min. The plasma concentrations of the major metabolites Odesmethyl-encainide (ODE) and 3-methoxy-O-desmethylencainide (3-MODE) are higher than those of encainide and have antiarrhythmic activity. The remaining patients (< 10%) are poor metabolizers (PM), in whom the oral bioavailability is near 88% with an elimination tl/2 of 8-11 hours and a systemic clearance of 0.2 l/min. Encainide plasma concentrations are 10- to 20-fold higher than in EMs, but considerably less ODE and no 3-MODE is formed by the PMs. The conversion to the N-desmethyl-encainide (NDE) metabolite seems to be similar in both metabolizer groups, and plasma protein binding of encainide of 70-78% is also similar. During long-term treatment, the antiarrhythmic metabolites of encainide accumulate in the plasma, so that the relationships between the effect and plasma concentration on encainide, ODE, and 3-MODE are not always obvious. Minimally effective plama concentrations appear to be approximately 300 ng/ml of encainide, 35 ng/ml of ODE, and 100 ng/ml of 3-MODE. Dose adjustment is necessary in patients with decreased kidney function, but not in patients with cirrhosis, in whom the plasma levels of metabolites appear to be comparable to those in normal subjects.
Key Words. encainide, 3-methoxy-O-desmethyl-encainide, Odesmethyl-encainide, oral bioavailability, plasma protein binding, hepatic dysfunction, renal failure, dose adjustment, drug interactions
T h e main characteristic of the disposition of encainide in humans is the existence of a polymorphic distribution of its metabolism among subjects. Plasma concentrations over time measured in 11 patients with highfrequency, nonsustained ventricular arrhythmias and normal renal and hepatic function, who received a single 25-mg oral dose of encainide, revealed that one nonresponding patient had a markedly longer elimination half-life (t~) of encainide than the other patients [1]. This patient had a steady-state plasma concentration of encainide that was 20-100 times greater than that of the other ten patients and had no detectable
plasma level of the O-desmethyl metabolite of encainide. This patient was also the only one of the 11 patients who did not have a drug response. This first observation and other observations of the marked variability in encainide bioavailability suggested that the effects of the drug were mediated by the variable generation of active metabolites.
Pharmacokinetics of Encainide in
Healthy Subjects Further studies have confirmed this hypothesis and Figure 1 shows the metabolic pathways of encainide. As shown, the major pathway leads to the formation of O-desmethylencainide (ODE) and to 3-methoxy-Odesmethylencainide (MODE). The second metabolic pathway leads to N-desmethylencainide (NDE). The ability to metabolize encainide to the ODE and MODE metabolites is a genetic trait that is distributed according to the same genetic factor that determines the 4-hydroxylation of debrisoquine and that is related to the P 450 hydroxylase system in the hepatocytes. In the more than 90% of the population who have the ability to metabolize encainide to ODE and MODE, the elimination half-life of encainide is short, and its absolute bioavailability is low because of a significant hepatic first-pass effect. In the remaining 79% of the population, plasma concentrations of encainide are higher, with a higher and more stable bioavailability and a much higher elimination half-life. It has been shown [2] that there is a linear relationship (r = 0.72; p < 0.001) between the fractional excretions of ODE and 4-hydroxy debrisoquin in a group of 22 normal subjects. The pharmacokinetic differences between extensive metabolizers (EM) in whom ODE and MODE are formed and the poor metabolizers (PM) in whom MODE is not formed has been demonstrated in a study in healthy volunteers [3]. An intravenous radiolabeled tracer dose of encainide was adminis-
Address for correspondenceand reprint requests: ProfessorPatrice Jaillon, Unit6 de PharmacologyClinique, H6pitalSaint-Antoine, 184 Rue du Fg Saint-Antoine, 75012Paris, France. 56/
~62
Jaillon
OCH3 Encainide
H
v
"OCH3
N-desmethylencainide
(NDE)
,
H
v
-OH
O-desmethylencainide
(ODE)
l
3-Methoxy-O-desmethylencainide (MODE) Fig. 1. Metabolicpathways of encainide
tered simultaneously with an oral dose, and kinetic studies were done after one dose (acute) and after six doses over 2 days (chronic). After a single dose of encainide, the EM volunteers have a rapid elimination of encainide and higher concentrations of the ODE and MODE metabolites than the PM volunteers, who had much higher plasma levels of encainide and some ODE and NDE but no MODE metabolites. The pharmacokinetic parameters derived from the 24-hour urinary excretion of encainide and its metabolites in this study are given in Table 1. The encainide tl/2 is shorter (2.7 hours) and its systemic clearance much higher (1.8 1/min) in the EMs than are these same parameters (8.1 hours and .21 1/min, respectively) in the PMs after acute dosing. Because of an important first-pass effect, the oral bioavailability of encainide is only 26% in the EM group, compared with 88% in the PM group. Protein binding was similar in both groups, and the results after 2 days of dosing were not significantly different from those after a single dose. In the EM group, ODE is the major metabolite in the urine, accompanied by somewhat less MODE and a minor amount of encainide. In the PM group the major portion of encainide is excreted un-
changed in the urine, accompanied by relatively little NDE metabolite, a minor amount of ODE, and no MODE. After 2 days of treatment, encainide disposition was not altered, but encainide was accumulating in the PM group, while the two metabolites ODE and MODE were accumulating in the EM group, as shown in Figure 2.
Effect o f R e n a l or H e p a t i c Disease on the P h a r m a c o k i n e t i c s o f E n c a i n i d e The slow elimination rate of the metabolites ODE and MODE results in accumulation with increasing plasma levels in EMs. It has been reported [4] that after longterm oral encainide administration the ratio of steadystate plasma concentrations of ODE and MODE to encainide varied from 0.67 to 9.37 (mean 5.02 -- 2.61) for ODE, and from 0.06 to 12.9 (mean 5.15 -+ 4.13) for MODE. This was due to the long tl/2, which was found to be more than 11 hours for ODE. The tl/2 for MODE was so long that it was not possible to calculate or estimate it after 24 hours of plasma sampling. The mean plasma concentration of MODE, 24 hours after discontinuation of treatment was still 59.8 -+ 39.9% of
Pharmacokinetics and Metabolism of Encainide
563
Table 1. Pharmacokinetics of encainide Extensive Metabolizer Acute Half-life (hr) Systemic clearance (l/min) % bioavailable Plasma protein binding
Poor Metabolizer
Chronic
2.7 _+ 0.3
2.3 - 0.3
8.1 + 1.1
1.8 + 0.2 26.3 ± 6.7
1.9 +- 0.2 30.0 -+ 6.8
0.21 _+ 0.02 88.4 +_ 4.3
70.5 _+ 2.2
% dose in 24-hour urine Encainide ODE MODE NDE
Chronic
Acute
11.3 _+ 0.3
0.18 +_ 0.002 83.2 +_ 9.4
78.1 -+ 0.6 4.9 -+ 2.3 10.6 _+ 3.0 3.6 - 2.8 Not detected
39.3 _~ 5.6 3.0 -+ 0.15 Not detected 1.8 -!--0.6
NDE = N-desmethyl encainide; ODE = O-desmethyl encainide; 3-MODE = 3-methoxy O-desmethyl encainide. Reproduced with permission of Wang et al. [3] and American Society for Pharmacology Experimental Therapeutics.
O-desmethyl encainide
Encainide
4000 p
