European Journal of Clinical Pharmacology © by Springer-Verlag I979
Europ. J. clin. Pharmacol. 15, 63-68 (1979)
Significance of the Acetylation Phenotype and the Therapeutic Effect of Procainamide P. Schr6der, N. A. Klitgaard, and E. Simonsen Medical Department, HaderslevHospital and the Clinical Chemical Department, Odense UniversityHospital, Denmark
Summary. In order to estimate the relative antiarrhythmic effect of procainamide and N-acetylprocainamide, 18 randomly selected, patients with arrhythmia were divided into two groups; the first was treated with Pronestyl ® in the first half of the investigation period, followed by Duretter ® in the second half, and the second group began with Duretter ® and terminated with Pronestyl ®. The concentrations of procainamide and N-acetylprocainamide were measured twice a day during the steady state part of each treatment period. The acetylation phenotype of the patients was determined with sulfadimidine, and was compared with the relative serum concentrations of procainamide and N-acetylprocainamide. N-acetylprocainamide was found to antagonize the action of procainamide.
Key words: procainamide, N-acetylprocainamide, arrhythmia; acetylator phenotype, antagonism.
Adequate regulation of procainamide (PA) treatment in arrhythmia patients by analysis of serum concentration has often been difficult to attain despite establishment of the therapeutic range of 4-8 ~tg/ml by Koch-Weser and Klein [1]. Dreyfuss et al. [2, 3] discovered that a portion of the PA in blood was acetylated to N4-acetylprocainamide ~ A P A ) . The acetylation was thought to be catalyzed by the same enzyme system that acetylates isoniazide and sulfonamides. Numerous investigations have shown that acetylation of the latter compounds takes place bimodally, so that experimental subjects can be divided into slow or rapid acetylators. Genetically, slow acetylation is determined by an autosomal recessive gene, and its phenotype is expressed in 50
percent of the population of Scandinavia [4, 6]. The purpose of the present investigation was to determine whether an important relationship exists between the serum concentration of N A P A and the acetylation phenotype and, since NAPA has been found to have an anti-arrhythmic effect (Elson, [7]; Atkinson, [8]; and Lee et al., [9]), to determine whether better control of therapeutic effect would be achieved by serum analysis of both PA and N A P A than by PA alone. Since Elson et al. [7] had found that the antiarrhythmic effects of PA and N A P A were additive, a lower dose of PA than the 3-5 g recommended by Koch-Weser and Klein [1] was employed in the present work. Either 2-2.5 g of Duretter ® or Pronestyl ® (considered by Karlsson [5] to have similar bioavailabilities) were administered, which provided P A in the normal and the sustained form, respectively. By use of two drugs with different absorption rates, a wider range of serum levels of PA and N A P A was anticipated than that resulting from use of only one preparation. This should provide a better opportunity to estimate the relative anti-arrhythmic effect of P A and NAPA.
Material and Methods Patients
Nineteen patients, aged 48 to 82 years, who had symptoms of ventricular extrasystole (VPB) that required treatment were given procainamide. Fourteen of them suffered from acute myocardial infarction, 2 from pulmonary stasis without myocardial infarction, 2 from bronchial pneumonia and atherosclerotic heart disease and one from myocardial ischemia without myocardial infarction. After two days of treatment the lastmentioned patient 0031-6970/79/0015/0063/$01.20
64
P. Schr6der et al.: Acetylation Phenotype and Procainamide 4.5 hours a f t e r the.~last
VPB, multifocal VPB and VPB which occured at or near to the T-wave in the electrocardiogram.
dose of Pronestyl~J
100 r-
Drug Dosage and the Relationship Between Times of Drug Ingestion and Blood Sampling.
e-
"0 7 5
•0
E
(~
"o tO.
00
50
®o% ~
® 25
o~
o
oo
o¢~b
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2'0 S - N - A c e t yl procai namidet
S-Procainamide
9.5 hours a f t e r th,~last E
~
dose of Duretter nLFJ
100
.E
(5,36)'-,
E
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(5.8S)-,
"10
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ew
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o
o
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I
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The 18 randomly-selected patients were distributed into two groups, so tfiat 10 began the first half of the treatment period with Pronestyl ® and ended with Duretter ®, and the remaining 8 patients began with Duretter ® and ended with Pronestyl ®. The dose of Pronestyl ® was 500mg, 5 times per day (04.00, 09.00, 13.00, 18.00 and 23.00 h), and of Duretter ~ it was 500 mg, 4 times per day (09.00, 13.00, 18.00 and 23.00 h). The reason for use of the cross-over method was to cancel out any effect that the natural course of the illness might have on the VPB measurements. After the patients had been treated for more than one day with either Pronestyl ® or Duretter ®, blood samples were taken on the second and third day of treatment (08.30 and 15.30 h), after which medication was changed to the other preparation. During the course of procainamide treatment, the patients were monitored constantly, and VPB was measured each hour by a 70 second recording of the electrocardiogranl. At the beginning of the treatment period, 15 of the 18 patients required treatment with lidocaine i. v. The dose of lidocaine was reduced to half after the second dose of procainamide, and it was terminated after the third procainamide treatment. Apart from this, no other anti-arrhythmic preparation than procainamide was employed during the study. Two patients were given digoxin during treatment.
S-N-Acety| procainamidet S-Procainamide
l~g. 1. Relationship between percentage acetylated sulfadimidine (6 h after a single oral dose of 10 mg/kg body weight) and the ratio N A P A / P A in serum 4.5 h after the last dose of Pronestyl ® (upper part) and 9.5 h after the last dose of Duretter ® (lower part), respectively. • = rapid and © = slow acetylators classified by the sulfadimidine test
developed diarrhea, which required cessation of treatment and omission of the patient from the investigation. No side effects were observed in the remaining 18 patients. Patients with third degree A-V block, severe cardiac insuffiency, known hypersensitivity to PA, renal insufficiency and patients whose symptoms were caused by drug intoxication or electrolyte disorders were excluded from the material. The symptoms judged to require procainamide treatment were: VPB greater than 10%, trains of
Phenotype Determination At the conclusion of the experimental treatment and blood sampling period, attempts were made to discontinue procainamide treatment, and then to perform phenotype determinations no earlier than two days after cessation of procainamide medication. If VPB continued that required treatment, procainamide administration was resumed. After it had been terminated, with the patient either in hospital or ambulant, the phenotype was determined. The reason for the two day delay between cessation of procainamide medication and phenotype determination was because of interference by the drug with sulfadimidine analysis. Phenotype determinations were performed by the method described by Ewans [10]. The fasting patient was given a close of sulfadimidine based on body weight, and after 6 h
P. Schr6der et al.: Acetylation Phenotype and Procainamide
blood was sampled for analysis of sulfadimidine and acetylsulfadimidine concentration in plasma.
65 SLOW ACETYLATORS O~ o ~
Determination of PA and N A P A in Serum The sera from blood samples were maintained at --21 ° C until analysed for PA and NAPA. The concentrations of PA and NAPA were deterrnined by the method of Klitgaard [11], which required extraction of both PA and NAPA with d!chloromethane, acidification of the solutions and colourometric analysis of PA by the Bratton-Marshall method, before and after acid hydrolysis of NAPA.
o
.c
o
CL
U3
!
i
i
i
83°(day2) 15~ 8~day 3) 15~° Time of sampling
T T
Results
Relationship Between the Rate of Acetylation and the Relative Concentrations of PA and N/! PA in Serum Phenotypic analysis of the 18 patients indicated that 6 were fast and 12 were slow acetylators. By comparison of acetylsulfadimidine, as a percentage of total sulfadimidine concentration in serum, with the relationship between the serum concentrations of NAPA and PA, it can be seen (Fig. 1) that determination of PA and its metabolite clearly provided an adequate basis for distinguishing the two phenotypes. It is also apparent in Figure 1 that determination of the NAPA/PA ratio 9.5 h after the last dose of Duretter ® gave better separation of the two phenotypes than did determinations 4.5 h after the final dose of Pronestyl®. Some overlap of the two phenotypes was found when the NAPA/PA ratio was analysed 2.5 h after the final dose of drug.
PA and N/1PA Concentrations in Sera /}om &low and Fast Acetylators The mean concentrations of PA and NAPA in fast acetytators and slow acetylators, determined from blood samples taken 2 and 3 days after initiation of each t}qge of drug treatment are shown in Figures 2 and 3. There was only a slight difference in the concentration of PA in the two phenotypes, whereas the concentration of NAPA in fast acetylators was more than twice that in slow acetylators (Table 1). The total concentration of PA + NAPA was considerably higher in the fast acetylators who were treated with Pronestyl® (Table 1).
Effect on the Rate of Ventricular Extrasystoles The average values of VPB per minute per patient, calculated from measurements made over a period of
T T
T
T T
T T
T T
T
T T
Time of administration
T T
Ou,ette, Pro.estyI
Fig. 2. Mean concentrations (+_ SEM) of PA and NAPA in slow acetylators determined in blood samples taken 2 and 3 days after initiation of each type of drug treatment. Duretter®-NAPA (O .... O), Duretter®-PA ( © - - O ) , Pronestyl®-NAPA (D .... if]) and Pronestyl®-PA ( [ ~ - - E t )
FAST ACETYLATORS
11
tO
C9 E
= o
8 s
,3_4 2e~ 2
e. 1 8x~,day2) 15~° 83°(day 3) 1530 Time of sampling
T 1'
I" T T
1
T
T
T
T
T
T T T T t" Time of administration
Duretter
Pronestyl
Fig. 3. Mean concentrations (+ SEM) of PA and NAPA in fast acetylators determined in blood samples taken 2 and 3 days after initiation of each type of drug treatment. Duretter®-NAPA (O .... O), Duretter®-PA ( O - - O ) , Pronestyl®-NAPA (E3.... [2]) and Pronestyl®-PA (E3--E3)
66
P. Schr6der et al.: Acetylation Phenotype and Procainamide
Table 1. Mean serum concentrations (p,g m1-1) of PA and NAPA in fast and slow acetylators respectively, as determined in blood samples
taken 2 and 3 days after initiation of each type of drug treatment. [PA]m~xrepresent the concentration of procainamide 2.5 h after dosage and [PA]min is the procainamide concentration just before the morning dose. [P-A] and [NAPA] represent the mean of procainamide and Nacetylprocainamide concentrations, respectively, found in all blood samples withdrawn on Days 2 and 3 [PAlm~x
[PAI,u.
A[PA]
[P--A]
[NAPA]
[PA---] + [NAPA]
Fast acetylators
Pronestyl* Duretter ®
5.51 3.66
3.83 2.19
1.68 1.47
4.67 2.92
9.84 6.46
14.51 9.38
Slow acetylators
Pronestyl ® Duretter ®
5.79 4.36
4.22 2.65
1.57 1.71
5.00 3.50
3.60 3.16
8.60 6.66
Time of 18 administration
23 ~, ~
4 ~
9
13 1, ~
18 ~ J~
23 ~ Jr
4
18 23
4
9
13
18
23
4
13 ~, PronestyL ~, Duretter
2.0
1.5
1,0 ¢¢b
O. t-
o.s en
a.
Ig 0.I 9
13
18 Time
Fig. 4. Average ventricular premature beats per minute per patient, calculated from measurements made over a period of 4-5 hours, plotted with respect to time during the second and third day of administration of each type of drug to slow and fast acetylators, respectively. Slow acetylators given Pronestyl ® ( © - - © ) , slow acetylators given Duretter ® (O------Q), fast aeetylators given Pronestyl ® (D--r-q) and fast acetylators given Duretter ® ( m - - m ) .
An attempt to evaluate the anti-arrhythmic effect of NAPA is shown in Table 2. Based on change in the rate of VPB in slow acetylators treated with Duretter ® who were then shifted to treatment with Pronestyl®, an expression of the pharmacodynarnic effect of PA was obtained, since the concentration of NAPA changed only insignificantly under those conditions (Fig. 3). The data allowed calculation of an effect factor, namely the change in rate of VPB in relation to the change in serum procainamide concentration (Table 2). By utilization of the effect factor to examine the remaining three types of drugphenotype combination, it can be seen (Table 2) that the decline in rate of VPB on changing from Duretter ® (fast) to Pronestyl® (fast) was less than expected, whereas the decline in VPB rate was larger than expected for the transition from Duretter ® (fast) to Duretter ® (slow), and from Pronestyl® (fast) to Pronestyl® (slow). These surprising results can only be explained by assuming that NAPA antagonize PA. Even a small increase in serum PA concentration brought about a sharp decrease in the VPB rate, but only if there was a simultaneous decline in serum NAPA.
Discussion
4-5 h, are plotted against time in Figure 4. Other forms of ventricular arrhythmia were not recorded during monitoring. By comparison of the results in Table 1 with Figure 4 it can be seen that, by and large the rates of VPB, were inversely proportional to serum PA concentration, so that the least therapeutic effect on extrasystoles resulted when Duretter ® had been administered to a fast acetylator, since that combination of phenotype and drug type produced the lowest serum PA (2.9 ~tg/ml). The best effect was obtained with Pronestyl® given to a slow acetylator, when the serum PA concentration was maximal (5.0 ~tg/ml).
The question of the extent to which acetylation of PA influences its therapeutic effect was studied in the present investigation. Serum NAPA attained a higher level in fast acetylators, whereas no clear difference in the serum level of PA was found between the two phenotypes, which was in agreement with the observations of Karlsson and Molin [4]. The ratio of the concentrations of NAPA and PA provided an adequate distinction between the two phenotypes after treatment both with Pronestyl® and Duretter ® (Fig. 1), as long as determinations were performed on blood samples obtained no earlier than 4.5 h after the last dose of drug. Consequently, it is unnecessary to interrupt pro-
P. Schr6der et al.: Acetylation P h e n o t y p e and Procainamide
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Europ. J. clin. Pharmacol. 15, 63-68 (1979)
Significance of the Acetylation Phenotype and the Therapeutic Effect of Procainamide P. Schr6der, N. A. Klitgaard, and E. Simonsen Medical Department, HaderslevHospital and the Clinical Chemical Department, Odense UniversityHospital, Denmark
Summary. In order to estimate the relative antiarrhythmic effect of procainamide and N-acetylprocainamide, 18 randomly selected, patients with arrhythmia were divided into two groups; the first was treated with Pronestyl ® in the first half of the investigation period, followed by Duretter ® in the second half, and the second group began with Duretter ® and terminated with Pronestyl ®. The concentrations of procainamide and N-acetylprocainamide were measured twice a day during the steady state part of each treatment period. The acetylation phenotype of the patients was determined with sulfadimidine, and was compared with the relative serum concentrations of procainamide and N-acetylprocainamide. N-acetylprocainamide was found to antagonize the action of procainamide.
Key words: procainamide, N-acetylprocainamide, arrhythmia; acetylator phenotype, antagonism.
Adequate regulation of procainamide (PA) treatment in arrhythmia patients by analysis of serum concentration has often been difficult to attain despite establishment of the therapeutic range of 4-8 ~tg/ml by Koch-Weser and Klein [1]. Dreyfuss et al. [2, 3] discovered that a portion of the PA in blood was acetylated to N4-acetylprocainamide ~ A P A ) . The acetylation was thought to be catalyzed by the same enzyme system that acetylates isoniazide and sulfonamides. Numerous investigations have shown that acetylation of the latter compounds takes place bimodally, so that experimental subjects can be divided into slow or rapid acetylators. Genetically, slow acetylation is determined by an autosomal recessive gene, and its phenotype is expressed in 50
percent of the population of Scandinavia [4, 6]. The purpose of the present investigation was to determine whether an important relationship exists between the serum concentration of N A P A and the acetylation phenotype and, since NAPA has been found to have an anti-arrhythmic effect (Elson, [7]; Atkinson, [8]; and Lee et al., [9]), to determine whether better control of therapeutic effect would be achieved by serum analysis of both PA and N A P A than by PA alone. Since Elson et al. [7] had found that the antiarrhythmic effects of PA and N A P A were additive, a lower dose of PA than the 3-5 g recommended by Koch-Weser and Klein [1] was employed in the present work. Either 2-2.5 g of Duretter ® or Pronestyl ® (considered by Karlsson [5] to have similar bioavailabilities) were administered, which provided P A in the normal and the sustained form, respectively. By use of two drugs with different absorption rates, a wider range of serum levels of PA and N A P A was anticipated than that resulting from use of only one preparation. This should provide a better opportunity to estimate the relative anti-arrhythmic effect of P A and NAPA.
Material and Methods Patients
Nineteen patients, aged 48 to 82 years, who had symptoms of ventricular extrasystole (VPB) that required treatment were given procainamide. Fourteen of them suffered from acute myocardial infarction, 2 from pulmonary stasis without myocardial infarction, 2 from bronchial pneumonia and atherosclerotic heart disease and one from myocardial ischemia without myocardial infarction. After two days of treatment the lastmentioned patient 0031-6970/79/0015/0063/$01.20
64
P. Schr6der et al.: Acetylation Phenotype and Procainamide 4.5 hours a f t e r the.~last
VPB, multifocal VPB and VPB which occured at or near to the T-wave in the electrocardiogram.
dose of Pronestyl~J
100 r-
Drug Dosage and the Relationship Between Times of Drug Ingestion and Blood Sampling.
e-
"0 7 5
•0
E
(~
"o tO.
00
50
®o% ~
® 25
o~
o
oo
o¢~b
r-
CO
31o
2'0 S - N - A c e t yl procai namidet
S-Procainamide
9.5 hours a f t e r th,~last E
~
dose of Duretter nLFJ
100
.E
(5,36)'-,
E
tO
(5.8S)-,
"10
"~
7S
•
•
•
•
(s.0~3-.
ew
50 ill >, o
¢d
® 25 ot f6 E
IX.
o
o
o -~°°u o
oo CO
oo
o
O0 O0
I
1.0
210.....
310
The 18 randomly-selected patients were distributed into two groups, so tfiat 10 began the first half of the treatment period with Pronestyl ® and ended with Duretter ®, and the remaining 8 patients began with Duretter ® and ended with Pronestyl ®. The dose of Pronestyl ® was 500mg, 5 times per day (04.00, 09.00, 13.00, 18.00 and 23.00 h), and of Duretter ~ it was 500 mg, 4 times per day (09.00, 13.00, 18.00 and 23.00 h). The reason for use of the cross-over method was to cancel out any effect that the natural course of the illness might have on the VPB measurements. After the patients had been treated for more than one day with either Pronestyl ® or Duretter ®, blood samples were taken on the second and third day of treatment (08.30 and 15.30 h), after which medication was changed to the other preparation. During the course of procainamide treatment, the patients were monitored constantly, and VPB was measured each hour by a 70 second recording of the electrocardiogranl. At the beginning of the treatment period, 15 of the 18 patients required treatment with lidocaine i. v. The dose of lidocaine was reduced to half after the second dose of procainamide, and it was terminated after the third procainamide treatment. Apart from this, no other anti-arrhythmic preparation than procainamide was employed during the study. Two patients were given digoxin during treatment.
S-N-Acety| procainamidet S-Procainamide
l~g. 1. Relationship between percentage acetylated sulfadimidine (6 h after a single oral dose of 10 mg/kg body weight) and the ratio N A P A / P A in serum 4.5 h after the last dose of Pronestyl ® (upper part) and 9.5 h after the last dose of Duretter ® (lower part), respectively. • = rapid and © = slow acetylators classified by the sulfadimidine test
developed diarrhea, which required cessation of treatment and omission of the patient from the investigation. No side effects were observed in the remaining 18 patients. Patients with third degree A-V block, severe cardiac insuffiency, known hypersensitivity to PA, renal insufficiency and patients whose symptoms were caused by drug intoxication or electrolyte disorders were excluded from the material. The symptoms judged to require procainamide treatment were: VPB greater than 10%, trains of
Phenotype Determination At the conclusion of the experimental treatment and blood sampling period, attempts were made to discontinue procainamide treatment, and then to perform phenotype determinations no earlier than two days after cessation of procainamide medication. If VPB continued that required treatment, procainamide administration was resumed. After it had been terminated, with the patient either in hospital or ambulant, the phenotype was determined. The reason for the two day delay between cessation of procainamide medication and phenotype determination was because of interference by the drug with sulfadimidine analysis. Phenotype determinations were performed by the method described by Ewans [10]. The fasting patient was given a close of sulfadimidine based on body weight, and after 6 h
P. Schr6der et al.: Acetylation Phenotype and Procainamide
blood was sampled for analysis of sulfadimidine and acetylsulfadimidine concentration in plasma.
65 SLOW ACETYLATORS O~ o ~
Determination of PA and N A P A in Serum The sera from blood samples were maintained at --21 ° C until analysed for PA and NAPA. The concentrations of PA and NAPA were deterrnined by the method of Klitgaard [11], which required extraction of both PA and NAPA with d!chloromethane, acidification of the solutions and colourometric analysis of PA by the Bratton-Marshall method, before and after acid hydrolysis of NAPA.
o
.c
o
CL
U3
!
i
i
i
83°(day2) 15~ 8~day 3) 15~° Time of sampling
T T
Results
Relationship Between the Rate of Acetylation and the Relative Concentrations of PA and N/! PA in Serum Phenotypic analysis of the 18 patients indicated that 6 were fast and 12 were slow acetylators. By comparison of acetylsulfadimidine, as a percentage of total sulfadimidine concentration in serum, with the relationship between the serum concentrations of NAPA and PA, it can be seen (Fig. 1) that determination of PA and its metabolite clearly provided an adequate basis for distinguishing the two phenotypes. It is also apparent in Figure 1 that determination of the NAPA/PA ratio 9.5 h after the last dose of Duretter ® gave better separation of the two phenotypes than did determinations 4.5 h after the final dose of Pronestyl®. Some overlap of the two phenotypes was found when the NAPA/PA ratio was analysed 2.5 h after the final dose of drug.
PA and N/1PA Concentrations in Sera /}om &low and Fast Acetylators The mean concentrations of PA and NAPA in fast acetytators and slow acetylators, determined from blood samples taken 2 and 3 days after initiation of each t}qge of drug treatment are shown in Figures 2 and 3. There was only a slight difference in the concentration of PA in the two phenotypes, whereas the concentration of NAPA in fast acetylators was more than twice that in slow acetylators (Table 1). The total concentration of PA + NAPA was considerably higher in the fast acetylators who were treated with Pronestyl® (Table 1).
Effect on the Rate of Ventricular Extrasystoles The average values of VPB per minute per patient, calculated from measurements made over a period of
T T
T
T T
T T
T T
T
T T
Time of administration
T T
Ou,ette, Pro.estyI
Fig. 2. Mean concentrations (+_ SEM) of PA and NAPA in slow acetylators determined in blood samples taken 2 and 3 days after initiation of each type of drug treatment. Duretter®-NAPA (O .... O), Duretter®-PA ( © - - O ) , Pronestyl®-NAPA (D .... if]) and Pronestyl®-PA ( [ ~ - - E t )
FAST ACETYLATORS
11
tO
C9 E
= o
8 s
,3_4 2e~ 2
e. 1 8x~,day2) 15~° 83°(day 3) 1530 Time of sampling
T 1'
I" T T
1
T
T
T
T
T
T T T T t" Time of administration
Duretter
Pronestyl
Fig. 3. Mean concentrations (+ SEM) of PA and NAPA in fast acetylators determined in blood samples taken 2 and 3 days after initiation of each type of drug treatment. Duretter®-NAPA (O .... O), Duretter®-PA ( O - - O ) , Pronestyl®-NAPA (E3.... [2]) and Pronestyl®-PA (E3--E3)
66
P. Schr6der et al.: Acetylation Phenotype and Procainamide
Table 1. Mean serum concentrations (p,g m1-1) of PA and NAPA in fast and slow acetylators respectively, as determined in blood samples
taken 2 and 3 days after initiation of each type of drug treatment. [PA]m~xrepresent the concentration of procainamide 2.5 h after dosage and [PA]min is the procainamide concentration just before the morning dose. [P-A] and [NAPA] represent the mean of procainamide and Nacetylprocainamide concentrations, respectively, found in all blood samples withdrawn on Days 2 and 3 [PAlm~x
[PAI,u.
A[PA]
[P--A]
[NAPA]
[PA---] + [NAPA]
Fast acetylators
Pronestyl* Duretter ®
5.51 3.66
3.83 2.19
1.68 1.47
4.67 2.92
9.84 6.46
14.51 9.38
Slow acetylators
Pronestyl ® Duretter ®
5.79 4.36
4.22 2.65
1.57 1.71
5.00 3.50
3.60 3.16
8.60 6.66
Time of 18 administration
23 ~, ~
4 ~
9
13 1, ~
18 ~ J~
23 ~ Jr
4
18 23
4
9
13
18
23
4
13 ~, PronestyL ~, Duretter
2.0
1.5
1,0 ¢¢b
O. t-
o.s en
a.
Ig 0.I 9
13
18 Time
Fig. 4. Average ventricular premature beats per minute per patient, calculated from measurements made over a period of 4-5 hours, plotted with respect to time during the second and third day of administration of each type of drug to slow and fast acetylators, respectively. Slow acetylators given Pronestyl ® ( © - - © ) , slow acetylators given Duretter ® (O------Q), fast aeetylators given Pronestyl ® (D--r-q) and fast acetylators given Duretter ® ( m - - m ) .
An attempt to evaluate the anti-arrhythmic effect of NAPA is shown in Table 2. Based on change in the rate of VPB in slow acetylators treated with Duretter ® who were then shifted to treatment with Pronestyl®, an expression of the pharmacodynarnic effect of PA was obtained, since the concentration of NAPA changed only insignificantly under those conditions (Fig. 3). The data allowed calculation of an effect factor, namely the change in rate of VPB in relation to the change in serum procainamide concentration (Table 2). By utilization of the effect factor to examine the remaining three types of drugphenotype combination, it can be seen (Table 2) that the decline in rate of VPB on changing from Duretter ® (fast) to Pronestyl® (fast) was less than expected, whereas the decline in VPB rate was larger than expected for the transition from Duretter ® (fast) to Duretter ® (slow), and from Pronestyl® (fast) to Pronestyl® (slow). These surprising results can only be explained by assuming that NAPA antagonize PA. Even a small increase in serum PA concentration brought about a sharp decrease in the VPB rate, but only if there was a simultaneous decline in serum NAPA.
Discussion
4-5 h, are plotted against time in Figure 4. Other forms of ventricular arrhythmia were not recorded during monitoring. By comparison of the results in Table 1 with Figure 4 it can be seen that, by and large the rates of VPB, were inversely proportional to serum PA concentration, so that the least therapeutic effect on extrasystoles resulted when Duretter ® had been administered to a fast acetylator, since that combination of phenotype and drug type produced the lowest serum PA (2.9 ~tg/ml). The best effect was obtained with Pronestyl® given to a slow acetylator, when the serum PA concentration was maximal (5.0 ~tg/ml).
The question of the extent to which acetylation of PA influences its therapeutic effect was studied in the present investigation. Serum NAPA attained a higher level in fast acetylators, whereas no clear difference in the serum level of PA was found between the two phenotypes, which was in agreement with the observations of Karlsson and Molin [4]. The ratio of the concentrations of NAPA and PA provided an adequate distinction between the two phenotypes after treatment both with Pronestyl® and Duretter ® (Fig. 1), as long as determinations were performed on blood samples obtained no earlier than 4.5 h after the last dose of drug. Consequently, it is unnecessary to interrupt pro-
P. Schr6der et al.: Acetylation P h e n o t y p e and Procainamide
IIII
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