Br. J. clin. Pharmac. (1979), 8,33-36
EFFECTS OF SUBJECTS' SEX, AND INTAKE OF TOBACCO, ALCOHOL AND ORAL CONTRACEPTIVES ON PLASMA PHENYTOIN LEVELS E.A. De LEACY, C.D. McLEAY, M.J. EADIE & J.H. TYRER Department of Medicine, (University of Queensland), Royal Brisbane Hospital, Brisbane, Australia
I Steady state plasma phenytoin levels in 210 epileptic patients were studied by computerized analysis of covariance to determine whether the subject's sex, alcohol intake, tobacco smoking or use of oral contraceptives influenced the relation between plasma drug level and drug dose. 2 Sex, tobacco smoking and alcohol usage had no statistically significant effect. There was a trend towards higher phenytoin levels relative to drug dose in oral contraceptive users. 3 This finding prompted an additional study of plasma phenytoin levels in 40 oral contraceptive users and 135 aged matched non-users. Analysis of covariance again showed higher plasma phenytoin levels relative to drug dose in users of oral contraceptives (P = 0.061). 4 This finding raised the possibility that the relation between plasma phenytoin level and drug dose differed between males and females who did not use oral contraceptives. However, when the relation between plasma phenytoin levels and drug dose was compared in 159 females who did not use oral contraceptives and 101 males (both groups aged 15 to 70 years) no statistically significant difference was found.
Introduction There is evidence that the relationship between steady state plasma levels of the anticonvulsant phenytoin and dose of this drug is influenced by factors such as body weight and age (Eadie, Tyrer & Hooper, 1973). Whether sex of subject alters the relationship is less certain and no information is available as to whether alcohol intake, tobacco smoking and use of oral contraceptives have any effect on this relationship. It was therefore decided to study these questions in a population of treated epileptic patients aged 15 years or over. Age does not appear to influence the relation between dose and plasma level of the drug in persons aged more than 14 years (Eadie et al., 1973).
Methods The records of the Neuropharmacology Laboratory of the Department of Medicine, University of Queensland, were searched to extract all plasma phenytoin level data from patients referred by one neurologist who had made a practice of recording details of all the factors with which the present investigation was concerned, viz. age, sex, weight, alcohol and tobacco intake, and oral contraceptive use. Data on 210 consecutive patients were obtained, all investigated since 1973 (to avoid including patients studied earlier by Eadie et al., 1973). No plasma level data were included unless the patient had received a 0306-5251/79/070033-04 301.00 3
constant daily phenytoin dose for at least 1 week. This should have ensured steady-state measurement in nearly all instances. Assuming for simplicity, as a reasonable approximation, that mono-exponential rather than Michaelis-Menten kinetics can be used to describe phenytoin elimination when drug concentrations are not above the therapeutic range, as in the great majority of patients here studied, half-life of the drug averages 22 ± 9 h (Arnold & Gerber, 1970. As indicated above, only subjects aged over 14 years were included. Preliminary analysis of the data suggested that further study of the effects of oral contraceptive intake might be worthwhile. Therefore additional consecutive records were extracted to expand the series to 199 females, the number of males remaining at 101. Analysis of the data was performed by the use of a
standard computerized package (University of Pittsburgh SPSS-10). This package performs regressions and an analysis of covariance as well as computing means and standard deviations for all categories. In this study the analysis of covariance tested the variation of plasma level (as a function of dose per unit weight) with the various parameters listed above. Data entered were plasma phenytoin levels, body weight in kilograms, sex, age (in ten year groupings), and alcohol intake in four categories (i.e. nil, irregular but light intake, regular intake of less than four glasses a beer a day or the equivalent, and © Macmillan Journals Ltd 1979
34
E.A. DE LEACY, C.D. McLEAY, M.J. EADIE & J.H. TYRER
comparison was made separately using noncontraceptive taking female controls in the same group (15-49 years) to minimize any age effect. The distribution of the sample may be seen in Table 1. Ali plasma phenytoin levels were measured by a modification of the MacGee (1970) gas chromatographic assay, in which trimethylanilinium hydroxide was used as the alkylating agent.
, (S)
E .
20
0.
10
C C
Results
E0
-/,! 4 2 Dose (mg
Dr 6
8
1a
kg-Iday-1)
Figure 1 Regression for plasma phenytoin level on dose per unit weight in non-smokerm (Non-S) and smokers (S). The regression equations are, respectively: plasma level = -1.464 + 2.767 dose (i2= 0.198); and plasma level = -11.196 + 4.572 dose (r2 = 0.309). Tr = therapeutic range; Dr= dosage range corresponding to therapeutic range.
heavier intake). Tobacco smoking data were entered in three categories (nil, less than ten cigarettes a day, more than ten cigarettes per day). Whether or not oral contraceptives were used was also entered. Since data for the study included only cases seen since 1973, oral contraceptives used were virtually all the low oestrogen dose variety. The oral contraceptive Table I
Analysis of covariance of the data for 210 subjects showed no statistically significant variation in plasma levels relative to dose with age over 14 years (P=0.281), sex (P=0.999), alcohol intake (P=0.999) or tobacco use (P= 0.999). The regressions for plasma phenytoin level on drug dose in non-smokers and in heavy smokers are compared in Figure 1. There was no statistically significant difference between the two lines. Intake of oral contraceptives produced an effect on the relation between plasma phenytoin level and drug dose which was probably not due to chance (P=0.098). This finding prompted expansion .of the female sample as described above, prior to further study. A further analysis of variance was then carried out to study variation in plasma phenytoin level (as a function of dose per unit weight) with oral contraceptive status. Contraceptive usage influenced plasma phenytoin levels to an extent that was unlikely to be due to chance (P=0.061). The regressions for plasma level on dose for oral contraceptive users and
Distribution of the sample
Age
0-10 years 1 1-20 years 21-30 years 31-40 years 41-50 years 51-60 years 60+ Tobacco smoking Nil Less than 10 per day More than 10 per day Alcohol intake Nil Irregular Ught Heavy Oral contraceptives Taken Not taken
Male 101
Stage 1 Female 109
23 37 9
28 26 21
Stage 2 Total 210
Male 101
Female 199
Total 300
3
23 37 9 14 10 5 3
45 62 46 23
12 9 2
51 63 30 25 22 14 5
68 99 55 37 22 14 5
62 16 23
89 12 8
151 28 31
35
88 17 2 2
123 58 25
14 10 5
41 23 2
11
9 only (age 15-49) 20
9 only (age 15-49) 65
4
12 9 2
data not extracted for the 90 additional females.
35 41 23 2
137 58 2 2
40 135
172 99 25 4
FACTORS INFLUENCING PLASMA PHENYTOIN LEVELS
35
(M)
E 20 [TX 0~ cn
o
E
ZLe
CL
5CO Cu
Q co
n-
Dr a
2
4
6
.1 8
10
Dose (mg kg - 'day- 1)
,
EFFECTS OF SUBJECTS' SEX, AND INTAKE OF TOBACCO, ALCOHOL AND ORAL CONTRACEPTIVES ON PLASMA PHENYTOIN LEVELS E.A. De LEACY, C.D. McLEAY, M.J. EADIE & J.H. TYRER Department of Medicine, (University of Queensland), Royal Brisbane Hospital, Brisbane, Australia
I Steady state plasma phenytoin levels in 210 epileptic patients were studied by computerized analysis of covariance to determine whether the subject's sex, alcohol intake, tobacco smoking or use of oral contraceptives influenced the relation between plasma drug level and drug dose. 2 Sex, tobacco smoking and alcohol usage had no statistically significant effect. There was a trend towards higher phenytoin levels relative to drug dose in oral contraceptive users. 3 This finding prompted an additional study of plasma phenytoin levels in 40 oral contraceptive users and 135 aged matched non-users. Analysis of covariance again showed higher plasma phenytoin levels relative to drug dose in users of oral contraceptives (P = 0.061). 4 This finding raised the possibility that the relation between plasma phenytoin level and drug dose differed between males and females who did not use oral contraceptives. However, when the relation between plasma phenytoin levels and drug dose was compared in 159 females who did not use oral contraceptives and 101 males (both groups aged 15 to 70 years) no statistically significant difference was found.
Introduction There is evidence that the relationship between steady state plasma levels of the anticonvulsant phenytoin and dose of this drug is influenced by factors such as body weight and age (Eadie, Tyrer & Hooper, 1973). Whether sex of subject alters the relationship is less certain and no information is available as to whether alcohol intake, tobacco smoking and use of oral contraceptives have any effect on this relationship. It was therefore decided to study these questions in a population of treated epileptic patients aged 15 years or over. Age does not appear to influence the relation between dose and plasma level of the drug in persons aged more than 14 years (Eadie et al., 1973).
Methods The records of the Neuropharmacology Laboratory of the Department of Medicine, University of Queensland, were searched to extract all plasma phenytoin level data from patients referred by one neurologist who had made a practice of recording details of all the factors with which the present investigation was concerned, viz. age, sex, weight, alcohol and tobacco intake, and oral contraceptive use. Data on 210 consecutive patients were obtained, all investigated since 1973 (to avoid including patients studied earlier by Eadie et al., 1973). No plasma level data were included unless the patient had received a 0306-5251/79/070033-04 301.00 3
constant daily phenytoin dose for at least 1 week. This should have ensured steady-state measurement in nearly all instances. Assuming for simplicity, as a reasonable approximation, that mono-exponential rather than Michaelis-Menten kinetics can be used to describe phenytoin elimination when drug concentrations are not above the therapeutic range, as in the great majority of patients here studied, half-life of the drug averages 22 ± 9 h (Arnold & Gerber, 1970. As indicated above, only subjects aged over 14 years were included. Preliminary analysis of the data suggested that further study of the effects of oral contraceptive intake might be worthwhile. Therefore additional consecutive records were extracted to expand the series to 199 females, the number of males remaining at 101. Analysis of the data was performed by the use of a
standard computerized package (University of Pittsburgh SPSS-10). This package performs regressions and an analysis of covariance as well as computing means and standard deviations for all categories. In this study the analysis of covariance tested the variation of plasma level (as a function of dose per unit weight) with the various parameters listed above. Data entered were plasma phenytoin levels, body weight in kilograms, sex, age (in ten year groupings), and alcohol intake in four categories (i.e. nil, irregular but light intake, regular intake of less than four glasses a beer a day or the equivalent, and © Macmillan Journals Ltd 1979
34
E.A. DE LEACY, C.D. McLEAY, M.J. EADIE & J.H. TYRER
comparison was made separately using noncontraceptive taking female controls in the same group (15-49 years) to minimize any age effect. The distribution of the sample may be seen in Table 1. Ali plasma phenytoin levels were measured by a modification of the MacGee (1970) gas chromatographic assay, in which trimethylanilinium hydroxide was used as the alkylating agent.
, (S)
E .
20
0.
10
C C
Results
E0
-/,! 4 2 Dose (mg
Dr 6
8
1a
kg-Iday-1)
Figure 1 Regression for plasma phenytoin level on dose per unit weight in non-smokerm (Non-S) and smokers (S). The regression equations are, respectively: plasma level = -1.464 + 2.767 dose (i2= 0.198); and plasma level = -11.196 + 4.572 dose (r2 = 0.309). Tr = therapeutic range; Dr= dosage range corresponding to therapeutic range.
heavier intake). Tobacco smoking data were entered in three categories (nil, less than ten cigarettes a day, more than ten cigarettes per day). Whether or not oral contraceptives were used was also entered. Since data for the study included only cases seen since 1973, oral contraceptives used were virtually all the low oestrogen dose variety. The oral contraceptive Table I
Analysis of covariance of the data for 210 subjects showed no statistically significant variation in plasma levels relative to dose with age over 14 years (P=0.281), sex (P=0.999), alcohol intake (P=0.999) or tobacco use (P= 0.999). The regressions for plasma phenytoin level on drug dose in non-smokers and in heavy smokers are compared in Figure 1. There was no statistically significant difference between the two lines. Intake of oral contraceptives produced an effect on the relation between plasma phenytoin level and drug dose which was probably not due to chance (P=0.098). This finding prompted expansion .of the female sample as described above, prior to further study. A further analysis of variance was then carried out to study variation in plasma phenytoin level (as a function of dose per unit weight) with oral contraceptive status. Contraceptive usage influenced plasma phenytoin levels to an extent that was unlikely to be due to chance (P=0.061). The regressions for plasma level on dose for oral contraceptive users and
Distribution of the sample
Age
0-10 years 1 1-20 years 21-30 years 31-40 years 41-50 years 51-60 years 60+ Tobacco smoking Nil Less than 10 per day More than 10 per day Alcohol intake Nil Irregular Ught Heavy Oral contraceptives Taken Not taken
Male 101
Stage 1 Female 109
23 37 9
28 26 21
Stage 2 Total 210
Male 101
Female 199
Total 300
3
23 37 9 14 10 5 3
45 62 46 23
12 9 2
51 63 30 25 22 14 5
68 99 55 37 22 14 5
62 16 23
89 12 8
151 28 31
35
88 17 2 2
123 58 25
14 10 5
41 23 2
11
9 only (age 15-49) 20
9 only (age 15-49) 65
4
12 9 2
data not extracted for the 90 additional females.
35 41 23 2
137 58 2 2
40 135
172 99 25 4
FACTORS INFLUENCING PLASMA PHENYTOIN LEVELS
35
(M)
E 20 [TX 0~ cn
o
E
ZLe
CL
5CO Cu
Q co
n-
Dr a
2
4
6
.1 8
10
Dose (mg kg - 'day- 1)
,
