European Journal of Clinical Pharmacology
Europ. J. clin. PharmacoL 14, 191-194 (1978)
© by Springer-Verlag 1978
Comparison of Serum Phenytoin Levels in Epileptic Patients who Swallowed Their Phenytoin Tablets with or without Previous Chewing P. Bielmann and T. Levac National Institute of Scientific Research (INRS-Santr) and L H. Lafontaine Hospital, Montreal, Canada
Summary. This cross-over study was conducted to compare serum phenytoin levels after chronic ingestion of phenytoin tablets with or without previous chewing. The phenytoin therapy was administered as 50 mg chewable Infatabs® tablets in a single morning dose of 200 mg. There was no significant difference between the two modes of ingestion as regards serum phenytoin levels measured at various times after ingestion of the phenytoin tablets. Moreover, the area under the curve did not differ significantly during the 24 h interval. Minor changes between two Dilantin® formulations, however, could influence drug availability.
Key words: Phenytoin tablet, mode of ingestion, major motor epilepsy.
Recently, phenytoin bioavailability has been the subject of several publications [1, 2, 3, 4]. Some authors found bioinequivalence of capsules and tablets [1, 4], whereas others [2, 3] demonstrated different serum phenytoin concentrations obtained from various formulations of tablets. In certain cases, the differences observed in the phenytoin levels were high enough to reach the toxic range in some patients [3]. Difference in particle size has been mentioned [4, 5] as a possible factor involved in the absorbability of tablets. Recently, Smith and Kinkel [6] conducted a crossover study in which tablets and capsules of phenytoin were compared as regards their plasma levels and urinary throughputs. These authors concluded that the two preparations produced equivalent therapeutic effects providing that the tablets were thoroughly chewed before swallowing. In a previous study [7], we investigated the pos-
sible protective effects of clonazepam after gradually withdrawing phenytoin therapy in patients with major motor epilepsy. In order to keep the trial double-blind, it was necessary to reformulate the 50 mg Infatabs® tablets as 50 mg capsules so that they would be identical in appearance with the placebo. Unexpectedly, the serum phenytoin levels increased in each patient after 2 weeks on reformulated capsules so that a 52% elevation in the mean serum levels was observed. (This elevation necessitated a 6week prolongation of the standardization period). The in vitro dissolution tests performed a posteriori on the reformulated capsules 1 and on the Infatabs® tablets showed (Table 1) that a much higher dissolution rate was obtained with the capsules than with the tablets. Furthermore, a brief survey among our patients revealed that all subjects but one swallowed their Infatabs® tablets directly without previous chewing. Thus, it became important to investigate whether the way in which the tablets were swallowed influences the phenytoin blood levels obtained from chronic administration. The present crossover study was therefore undertaken in two groups of four hospitalized epileptics who swallowed their phenytoin tablets with or without previous chewing for two periods of one week each.
Patients Eight subjects were chosen from those who participated in our previous study [7]. All were well-controlled with clonazepam, phenytoin and phenobarbital during the previous study. Table 2 presents the
1 Data kindly supplied by Hoffmann-La Roche Ltd., Vaudreuil, Canada.
0031-6970/78/0014/0191/$01.00
192
P. Bielmann and T. Levac: Phenytoin Tablets in Epileptic Patients
Table 1, In vitro dissolution test * for different phenytoin formulations
Brand
Lot
Phenytoin tablet Infatabs ® 50 mg Phenytoin capsules 50 mg (reformulated from tablet FL-153) Phenytoin tablets Infatabs ® 50 mg Phenytoin tablets Infatabs ® 50 mg
Percent Phenytoin dissolved 10 min
20 min
30 min
60 min
90 min
120 min
180 min
3.5
6.0
10.0
18.0
36.5
59.5
89.0
23.3
35.0
45.0
50.5
**
**
**
G F 143
9.5
15.5
21.5
34.5
57.0
76.0
90.0
GF 239
6.0
12.0
17.0
31.0
59.5
81.0
**
FL 153
76-MEX-9
* Using USP apparatus, 2 L. Borate buffer at pH 9, 37 °C. 120 rpm. ** Not measured. Table 2. Epileptic characteristics and drug regimen
Patient No.
Type of Epilepsy
Clonazepam (mg/day)
Phenytoin (rag/day)
Phenobarbital (mg/day)
Flurazepam (mg/day)
Without chewing first 01 Secondarily generalized 02 Secondarily generalized 03 Primarily generalized 04 Primarily generalized
8 10 4 10
200 a 200 200 200
120 120 120 120
15 15 15 15
With chewing first 05 Secondarily generalized 06 Primarily generalized 07 Secondarily generalized 08 Primarily generalized
8 8 6 8
200 200 200 200
120 60 120 120
15 15 15 15
Chlorpromazine (mg/day)
I
2O0
Phenytoin was given as 4 × 50 mg tablets in the morning
epileptic characteristics of the patients included in the trial and the anticonvulsant drugs administered. All subjects were told the purposes of the study, particular care being given to questioning about compliance to medication. Throughout the trial, the nursing staff checked each patient's daily ingestion of the phenytoin tablets. After a twelve-week standardization period during which the patients swallowed their phenytoin tablets as usual, one group of patients was told to chew the tablets thoroughly before swallowing for one week, while a second group continued to swallow their medication directly. In the second week, the mode of ingestion was reversed. Blood samples were taken on the eight day of each experimental week. The epileptic attacks were reported daily for each patient on special ward sheets. The usual emergency procedure of the hospital was followed: if a patient had two consecutive generalized seizures or absences, a 10 mg dose of diazepam was administered
intramuscularly; if the patient had persistent seizures, a dose of 130 mg phenobarbital was given. Blood samples for the determination of phenytoin and phenobarbital levels were withdrawn into heparinized tubes the eight day of each experimental week, immediately before drug administration [0] and 4, 8, 12 and 24 h after the ingestion of the 200 mg phenytoin dose. The samples were centrifuged immediately and the serum was separated and frozen until assayed.
Drugs Phenytoin, 50 mg chewable Infatabs ® tablets, ParkeDavis, Brockville, Ont. Canada, Lot FL 153. Clonazepam, Rivotril ®, 2 mg tablet, Hoffmann-La Roche, Canada, Lot 76346. Phenobarbital, 30 mg tablet, Nova Drug Ltd., Montreal, Lot 419-G. Flurazepam, Dalmane ®, 15 mg tablet, Hoffmann-La
P. Bielmann and T. Levac: Phenytoin Tablets in Epileptic Patients
193
Table 3. Serum phenytoin concentration obtained with or without previous chewing Mode of Ingestion
Crossover End of first experimental week
End of second experimental week
Subject
tO
t4
t8
t12
t24
Subject
tO
t4
t8
t12
t24
Without chewing first
01 02 03 04
3* 3 3 2
3.5 7.5 4.5 3.0
4 7 6 5
4 9 7.5 7
2.5 6 7 3
01 02 03 04
2 7.5 4 4
4 7 8 4
2.5 4.5 8 4
4 8 7 4
2.5 4.5 1 3
With chewing first
05 06 07 08
3 6.5 1.5 0
4.5 10 5 7
6 12 4 7
3.5 14 6 6
3 9.5 5 2.5
05 06 07 08
4 7.5 4.5 4
3 8 3 8
4 6 6 7
4 7 4 6
2.5 6 2.5 1.5
* All values are expressed as p.g/ml.
Roche, Canada, All drugs were obtained from the hospital pharmacy.
...o.~
Serum phenytoin levels (/~g/ml)
.--'"
N,S.
N.S.
Analysis of Phenytoin The serum samples were assayed for phenytoin by spectrophotometry following the procedure of Lee and Bass [8]. This method was reported to have a sensitivity limit of 1 ~tg/ml and a recovery of 96% for blood.
¢ 0
o ...... o With chewing 3
Statistical Analysis The parametric data were analyzed by analysis of variance which tested the within-and between-subject variations [9]. An analysis of covariance was used for adjusting the mean value obtained after 4, 8, 12 and 24 h after the 200 mg morning dose of phenytoin, the covariate being the mean value obtained at time 0. The non-parametric data, i. e. the seizure frequency and the number of administrations of emergency medication, observed with and without previous chewing were analyzed by Wilcoxon's nonparametric test [10].
Results Figure 1 and Table 3 show the serum phenytoin concentrations obtained with or without previous chewing. Although the mean concentrations were higher after chewing at times 4, 8 and 12 h, no statistically significant difference was found. It is important to note that no difference were found between the groups and between the weeks (periods) at these
O0
N.S.
•
• Without
or,0 Hours
4 after
drug
chewing
8
12
24
administration
Fig. 1. Mean serum phenytoin concentrations observed with o r
without previous chewing after chronic administration of Infatabs® tablets
time intervals. Only at time 0 was there a significant difference (p = 0.029) between the two weeks, the second week demonstrating higher mean serum levels. On performing a separate analysis for each week, no statistical difference was found between serum levels obtained from ingestion with or without previous chewing. The area under the curve did not differ significantly for the two modes of ingestion. Even after separate analysis for each week, no statistically significant difference was observed, though the area was slightly greater for ingestion with chewing. As expected, the serum phenobarbital levels were almost identical in both groups. No significant variation between the periods or the groups was observed. The number of seizures experienced by the subjects who swallowed their tablets directly did not dif-
194
P. Bielmann and T. Levac: PhenytoinTablets in Epileptic Patients
fer from that observed in the patients who previously chewed them. No difference was also reported as regards the n u m b e r of injections of emergency medication (diazepam and phenobarbital). N o difference in sideeffects or state of well-being was noted in either group.
Acknowledgements. The authors wish to thank Mrs. G. Farahat and the pharmaceutical staff of the L. H. Lafontaine Hospital for clinical help, and HoffmannLa R o c h e (Canada) for technical assistance in performing the in vitro tests.
References Discussion and Conclusion The results of this randomized cross-over study demonstrate that in the steady-state situation, the mode of ingestion of the phenytoin tablets does not influence the serum phenytoin levels in patients maintained chronically on a multiple drug regimen. Although the concentrations obtained after chewing were slighly superior at times 4, 8 and 12 h, the area under the curve did not markedly differ in either mode of ingestion. The differences are probably too small to be of biological significance. The differences between tablets and capsules observed by Manson et al. [1] were reported to be possibly due to the fact that the tablets were ingested without previous chewing [6]. O u r results suggest that this was not the case and that another factor could be responsible. Furthermore, the conclusion reported here cannot explain the striking differences observed in the serum phenytoin levels when Infatabs ® tablets were reformulated into capsules of equal phenytoin content. It is well known, however, that differences in the manufacturing process or in the excipient m a y alter drug availability [11, 12, 13]. The tablets used in our previous study [7] were crushed in a "Fitz mill", then mixed with lactose and talc before filling into capsules. It is thus probable that such a process was responsible for the differences observed in the serum concentrations. It is interesting to note that in our case the in vitro tests performed on the tablets and the reformulated capsules [14] predicted the bioinequivalence of the two preparations. This is in accordance with the findings of others [2] who demonstrated a positive correlation between A U C and the in vitro dissolution rate of phenytoin preparations. In conclusion, it can be stated that the m o d e of ingestion of the phenytoin tablets does not alter their absorption in epileptics receiving chronically a combined anticonvulsant therapy; caution must be taken, however, when differences, even minor, are suspected between phenytoin formulations.
1. Manson, J.I., Beal, S.M., Margarey, A., Pollard, A.C., O'Reilly, W.J., Sansom, L.N.: Bioavailability of phenytoin from various pharmaceutical preparations in children. Med. J. Aust. 2, 590-592 (1975) 2. Pentikainen, P.J., Neuvonen, P. J., Elfving, S.M.: Bioavailability of four brands of phenytoin tablets. Europ. J. Clin. Pharmacoi. 9, 213-218 (1975) 3. Rambeck, B., Boenigk, H.E., Stenzel, E.: Bioavailability of three phenytoin preparations in healthy subjects and in epileptics. Europ. J. Ciin. Pharmacoi. 12, 285-290 (1977) 4. Lund, L: Clinical significance of generic inequivalenee of three different pharmaceutical preparations of phenytoin. Europ. J. Clin. Pharmacol. 7, 119-124 (1974) 5. Johansen, H.E., Wiese, C.F.: The influence of particle size and other technological factors on the absorption and in vitro dissolution rate of phenytoin from tablets. Arch. Pharmacol. Chem. 127, 243-250 (1970) 6. Smith, Th. C., Kinkel, A.: Absorption and metabolism of phenytoin from tablets and capsules. Clin. Pharm. Ther. 20, 738-742 (1976) 7. Bielmann, P., Levac, T.: Can phenytoin be gradually withdrawn in patients with major motor epilepsy maintained on clonazepam and phenobarbital? Current Ther. Res. 23, 253-259 (1978) 8. Lee, S.I., Bass, N.H.: Microassay of diphenylhydantoin. Blood and regional brain concentration in rats during acute intoxication. Neurology 20, 115-124 (1970) 9. Lindquist, E.F.: Design and Analysis of Experiments in Psychology and Education, p. 273-281. Boston: Houghton Mifflin 1956 10. Siegel, S.: Non parametric Statistics for the Behavioural Sciences, p. 75-83. New-York: McGraw-Hill 1956 11. Glazko, A.J., Chang, T.: Diphenylhydantoin, Absorption, Distribution and Excretion. In: Antiepileptic Drugs. Woodbury, D.M., Penry, J.K. and Schmidt, R, P. (eds.), p. 127-148. New York: Raven Press 1972 12. Eadie, M. J., Sutherland, J. M., Tyrer, J. H.: "Dilantin" overdosage. Med. J. Aust. 2, 515 (1968) 13. Rail, L.: "Dilantin" overdosage. Med. J. Aust. 2, 329 (1968) 14. Dissolution: in: U. S. Pharmacopea XIX, p. 934 Received." April 28, 1978, accepted: June 20, 1978
Dr. P. Bielmann, National Institute of Scientific Research (INRS-Sant6) L.-H. Lafontaine Hospital 7401 Hochelaga St., Montreal, Quebec H1N 3M5, Canada
Europ. J. clin. PharmacoL 14, 191-194 (1978)
© by Springer-Verlag 1978
Comparison of Serum Phenytoin Levels in Epileptic Patients who Swallowed Their Phenytoin Tablets with or without Previous Chewing P. Bielmann and T. Levac National Institute of Scientific Research (INRS-Santr) and L H. Lafontaine Hospital, Montreal, Canada
Summary. This cross-over study was conducted to compare serum phenytoin levels after chronic ingestion of phenytoin tablets with or without previous chewing. The phenytoin therapy was administered as 50 mg chewable Infatabs® tablets in a single morning dose of 200 mg. There was no significant difference between the two modes of ingestion as regards serum phenytoin levels measured at various times after ingestion of the phenytoin tablets. Moreover, the area under the curve did not differ significantly during the 24 h interval. Minor changes between two Dilantin® formulations, however, could influence drug availability.
Key words: Phenytoin tablet, mode of ingestion, major motor epilepsy.
Recently, phenytoin bioavailability has been the subject of several publications [1, 2, 3, 4]. Some authors found bioinequivalence of capsules and tablets [1, 4], whereas others [2, 3] demonstrated different serum phenytoin concentrations obtained from various formulations of tablets. In certain cases, the differences observed in the phenytoin levels were high enough to reach the toxic range in some patients [3]. Difference in particle size has been mentioned [4, 5] as a possible factor involved in the absorbability of tablets. Recently, Smith and Kinkel [6] conducted a crossover study in which tablets and capsules of phenytoin were compared as regards their plasma levels and urinary throughputs. These authors concluded that the two preparations produced equivalent therapeutic effects providing that the tablets were thoroughly chewed before swallowing. In a previous study [7], we investigated the pos-
sible protective effects of clonazepam after gradually withdrawing phenytoin therapy in patients with major motor epilepsy. In order to keep the trial double-blind, it was necessary to reformulate the 50 mg Infatabs® tablets as 50 mg capsules so that they would be identical in appearance with the placebo. Unexpectedly, the serum phenytoin levels increased in each patient after 2 weeks on reformulated capsules so that a 52% elevation in the mean serum levels was observed. (This elevation necessitated a 6week prolongation of the standardization period). The in vitro dissolution tests performed a posteriori on the reformulated capsules 1 and on the Infatabs® tablets showed (Table 1) that a much higher dissolution rate was obtained with the capsules than with the tablets. Furthermore, a brief survey among our patients revealed that all subjects but one swallowed their Infatabs® tablets directly without previous chewing. Thus, it became important to investigate whether the way in which the tablets were swallowed influences the phenytoin blood levels obtained from chronic administration. The present crossover study was therefore undertaken in two groups of four hospitalized epileptics who swallowed their phenytoin tablets with or without previous chewing for two periods of one week each.
Patients Eight subjects were chosen from those who participated in our previous study [7]. All were well-controlled with clonazepam, phenytoin and phenobarbital during the previous study. Table 2 presents the
1 Data kindly supplied by Hoffmann-La Roche Ltd., Vaudreuil, Canada.
0031-6970/78/0014/0191/$01.00
192
P. Bielmann and T. Levac: Phenytoin Tablets in Epileptic Patients
Table 1, In vitro dissolution test * for different phenytoin formulations
Brand
Lot
Phenytoin tablet Infatabs ® 50 mg Phenytoin capsules 50 mg (reformulated from tablet FL-153) Phenytoin tablets Infatabs ® 50 mg Phenytoin tablets Infatabs ® 50 mg
Percent Phenytoin dissolved 10 min
20 min
30 min
60 min
90 min
120 min
180 min
3.5
6.0
10.0
18.0
36.5
59.5
89.0
23.3
35.0
45.0
50.5
**
**
**
G F 143
9.5
15.5
21.5
34.5
57.0
76.0
90.0
GF 239
6.0
12.0
17.0
31.0
59.5
81.0
**
FL 153
76-MEX-9
* Using USP apparatus, 2 L. Borate buffer at pH 9, 37 °C. 120 rpm. ** Not measured. Table 2. Epileptic characteristics and drug regimen
Patient No.
Type of Epilepsy
Clonazepam (mg/day)
Phenytoin (rag/day)
Phenobarbital (mg/day)
Flurazepam (mg/day)
Without chewing first 01 Secondarily generalized 02 Secondarily generalized 03 Primarily generalized 04 Primarily generalized
8 10 4 10
200 a 200 200 200
120 120 120 120
15 15 15 15
With chewing first 05 Secondarily generalized 06 Primarily generalized 07 Secondarily generalized 08 Primarily generalized
8 8 6 8
200 200 200 200
120 60 120 120
15 15 15 15
Chlorpromazine (mg/day)
I
2O0
Phenytoin was given as 4 × 50 mg tablets in the morning
epileptic characteristics of the patients included in the trial and the anticonvulsant drugs administered. All subjects were told the purposes of the study, particular care being given to questioning about compliance to medication. Throughout the trial, the nursing staff checked each patient's daily ingestion of the phenytoin tablets. After a twelve-week standardization period during which the patients swallowed their phenytoin tablets as usual, one group of patients was told to chew the tablets thoroughly before swallowing for one week, while a second group continued to swallow their medication directly. In the second week, the mode of ingestion was reversed. Blood samples were taken on the eight day of each experimental week. The epileptic attacks were reported daily for each patient on special ward sheets. The usual emergency procedure of the hospital was followed: if a patient had two consecutive generalized seizures or absences, a 10 mg dose of diazepam was administered
intramuscularly; if the patient had persistent seizures, a dose of 130 mg phenobarbital was given. Blood samples for the determination of phenytoin and phenobarbital levels were withdrawn into heparinized tubes the eight day of each experimental week, immediately before drug administration [0] and 4, 8, 12 and 24 h after the ingestion of the 200 mg phenytoin dose. The samples were centrifuged immediately and the serum was separated and frozen until assayed.
Drugs Phenytoin, 50 mg chewable Infatabs ® tablets, ParkeDavis, Brockville, Ont. Canada, Lot FL 153. Clonazepam, Rivotril ®, 2 mg tablet, Hoffmann-La Roche, Canada, Lot 76346. Phenobarbital, 30 mg tablet, Nova Drug Ltd., Montreal, Lot 419-G. Flurazepam, Dalmane ®, 15 mg tablet, Hoffmann-La
P. Bielmann and T. Levac: Phenytoin Tablets in Epileptic Patients
193
Table 3. Serum phenytoin concentration obtained with or without previous chewing Mode of Ingestion
Crossover End of first experimental week
End of second experimental week
Subject
tO
t4
t8
t12
t24
Subject
tO
t4
t8
t12
t24
Without chewing first
01 02 03 04
3* 3 3 2
3.5 7.5 4.5 3.0
4 7 6 5
4 9 7.5 7
2.5 6 7 3
01 02 03 04
2 7.5 4 4
4 7 8 4
2.5 4.5 8 4
4 8 7 4
2.5 4.5 1 3
With chewing first
05 06 07 08
3 6.5 1.5 0
4.5 10 5 7
6 12 4 7
3.5 14 6 6
3 9.5 5 2.5
05 06 07 08
4 7.5 4.5 4
3 8 3 8
4 6 6 7
4 7 4 6
2.5 6 2.5 1.5
* All values are expressed as p.g/ml.
Roche, Canada, All drugs were obtained from the hospital pharmacy.
...o.~
Serum phenytoin levels (/~g/ml)
.--'"
N,S.
N.S.
Analysis of Phenytoin The serum samples were assayed for phenytoin by spectrophotometry following the procedure of Lee and Bass [8]. This method was reported to have a sensitivity limit of 1 ~tg/ml and a recovery of 96% for blood.
¢ 0
o ...... o With chewing 3
Statistical Analysis The parametric data were analyzed by analysis of variance which tested the within-and between-subject variations [9]. An analysis of covariance was used for adjusting the mean value obtained after 4, 8, 12 and 24 h after the 200 mg morning dose of phenytoin, the covariate being the mean value obtained at time 0. The non-parametric data, i. e. the seizure frequency and the number of administrations of emergency medication, observed with and without previous chewing were analyzed by Wilcoxon's nonparametric test [10].
Results Figure 1 and Table 3 show the serum phenytoin concentrations obtained with or without previous chewing. Although the mean concentrations were higher after chewing at times 4, 8 and 12 h, no statistically significant difference was found. It is important to note that no difference were found between the groups and between the weeks (periods) at these
O0
N.S.
•
• Without
or,0 Hours
4 after
drug
chewing
8
12
24
administration
Fig. 1. Mean serum phenytoin concentrations observed with o r
without previous chewing after chronic administration of Infatabs® tablets
time intervals. Only at time 0 was there a significant difference (p = 0.029) between the two weeks, the second week demonstrating higher mean serum levels. On performing a separate analysis for each week, no statistical difference was found between serum levels obtained from ingestion with or without previous chewing. The area under the curve did not differ significantly for the two modes of ingestion. Even after separate analysis for each week, no statistically significant difference was observed, though the area was slightly greater for ingestion with chewing. As expected, the serum phenobarbital levels were almost identical in both groups. No significant variation between the periods or the groups was observed. The number of seizures experienced by the subjects who swallowed their tablets directly did not dif-
194
P. Bielmann and T. Levac: PhenytoinTablets in Epileptic Patients
fer from that observed in the patients who previously chewed them. No difference was also reported as regards the n u m b e r of injections of emergency medication (diazepam and phenobarbital). N o difference in sideeffects or state of well-being was noted in either group.
Acknowledgements. The authors wish to thank Mrs. G. Farahat and the pharmaceutical staff of the L. H. Lafontaine Hospital for clinical help, and HoffmannLa R o c h e (Canada) for technical assistance in performing the in vitro tests.
References Discussion and Conclusion The results of this randomized cross-over study demonstrate that in the steady-state situation, the mode of ingestion of the phenytoin tablets does not influence the serum phenytoin levels in patients maintained chronically on a multiple drug regimen. Although the concentrations obtained after chewing were slighly superior at times 4, 8 and 12 h, the area under the curve did not markedly differ in either mode of ingestion. The differences are probably too small to be of biological significance. The differences between tablets and capsules observed by Manson et al. [1] were reported to be possibly due to the fact that the tablets were ingested without previous chewing [6]. O u r results suggest that this was not the case and that another factor could be responsible. Furthermore, the conclusion reported here cannot explain the striking differences observed in the serum phenytoin levels when Infatabs ® tablets were reformulated into capsules of equal phenytoin content. It is well known, however, that differences in the manufacturing process or in the excipient m a y alter drug availability [11, 12, 13]. The tablets used in our previous study [7] were crushed in a "Fitz mill", then mixed with lactose and talc before filling into capsules. It is thus probable that such a process was responsible for the differences observed in the serum concentrations. It is interesting to note that in our case the in vitro tests performed on the tablets and the reformulated capsules [14] predicted the bioinequivalence of the two preparations. This is in accordance with the findings of others [2] who demonstrated a positive correlation between A U C and the in vitro dissolution rate of phenytoin preparations. In conclusion, it can be stated that the m o d e of ingestion of the phenytoin tablets does not alter their absorption in epileptics receiving chronically a combined anticonvulsant therapy; caution must be taken, however, when differences, even minor, are suspected between phenytoin formulations.
1. Manson, J.I., Beal, S.M., Margarey, A., Pollard, A.C., O'Reilly, W.J., Sansom, L.N.: Bioavailability of phenytoin from various pharmaceutical preparations in children. Med. J. Aust. 2, 590-592 (1975) 2. Pentikainen, P.J., Neuvonen, P. J., Elfving, S.M.: Bioavailability of four brands of phenytoin tablets. Europ. J. Clin. Pharmacoi. 9, 213-218 (1975) 3. Rambeck, B., Boenigk, H.E., Stenzel, E.: Bioavailability of three phenytoin preparations in healthy subjects and in epileptics. Europ. J. Ciin. Pharmacoi. 12, 285-290 (1977) 4. Lund, L: Clinical significance of generic inequivalenee of three different pharmaceutical preparations of phenytoin. Europ. J. Clin. Pharmacol. 7, 119-124 (1974) 5. Johansen, H.E., Wiese, C.F.: The influence of particle size and other technological factors on the absorption and in vitro dissolution rate of phenytoin from tablets. Arch. Pharmacol. Chem. 127, 243-250 (1970) 6. Smith, Th. C., Kinkel, A.: Absorption and metabolism of phenytoin from tablets and capsules. Clin. Pharm. Ther. 20, 738-742 (1976) 7. Bielmann, P., Levac, T.: Can phenytoin be gradually withdrawn in patients with major motor epilepsy maintained on clonazepam and phenobarbital? Current Ther. Res. 23, 253-259 (1978) 8. Lee, S.I., Bass, N.H.: Microassay of diphenylhydantoin. Blood and regional brain concentration in rats during acute intoxication. Neurology 20, 115-124 (1970) 9. Lindquist, E.F.: Design and Analysis of Experiments in Psychology and Education, p. 273-281. Boston: Houghton Mifflin 1956 10. Siegel, S.: Non parametric Statistics for the Behavioural Sciences, p. 75-83. New-York: McGraw-Hill 1956 11. Glazko, A.J., Chang, T.: Diphenylhydantoin, Absorption, Distribution and Excretion. In: Antiepileptic Drugs. Woodbury, D.M., Penry, J.K. and Schmidt, R, P. (eds.), p. 127-148. New York: Raven Press 1972 12. Eadie, M. J., Sutherland, J. M., Tyrer, J. H.: "Dilantin" overdosage. Med. J. Aust. 2, 515 (1968) 13. Rail, L.: "Dilantin" overdosage. Med. J. Aust. 2, 329 (1968) 14. Dissolution: in: U. S. Pharmacopea XIX, p. 934 Received." April 28, 1978, accepted: June 20, 1978
Dr. P. Bielmann, National Institute of Scientific Research (INRS-Sant6) L.-H. Lafontaine Hospital 7401 Hochelaga St., Montreal, Quebec H1N 3M5, Canada
