Glutethimide and 4-0H glutethimide: Pharmacokinetics and effect on performance in man The relationship between the plasma concentration of glutethimide (G) and the change from baseline of the standard error of the mean (IlSDE) of a tracking test was determined in 7 volunteers. There was excellent positive correlation (r = 0.9/) between log G and log IlSDE and good correlation between log G and IlSDE (r = 0.77). The metabolite, 4 hydroxyglutethimide, did not contribute significantly to the effect of G administered in therapeutic doses. No trend in performance versus level was found with 5 other tests (finger tapping, card sorting, digit substitution, subtraction, and subjective perception of drowsiness). Although the numbers were small, when the volunteers were divided into smokers (3) and nonsmokers (4) G decreased tracking ability to a greater extent in smokers than in nonsmokers.
James W. Crow, Ph.D., Pedro Lain, M.D., Felix Bochner, M.D., * Don W. Shoeman, Ph.D., and Daniel L. Azarnoff, M.D. Kansas City, Kan. Clinical Pharmacology-Toxicology Center, Departments of Medicine and Pharmacology, University of Kansas Medical Center, College of Health Sciences and Hospital
The hypnotic, glutethimide (2-ethyl-2phenylglutarmide, Doriden), is extensively metabolized to several more polar compounds. Glucuronidated metabolites excreted in the urine account for 92% to 94% of the administered drug. The two enantiomers of glutethimide (G) are metabolized differently; the dextro form produces a 4-hydroxyglutaramide ring substitution, whereas the levo forms a I-hydroxy substitution on the ethyl side chain. 12 When large amounts of the racemate are administered to selected animals and man, significant Supported by Grant GM 15956 from the United States Public Health Service. Received for publication Nov. 16, 1977. Accepted for publication June 6, 1977. Reprint requests to: Daniel L. Azarnoff, M.D., Clinical Pharmacology Center, University of Kansas Medical Center, Rainbow Blvd. at 39th, Kansas City, Kan. 66103. 'National Health and Medical Research Council of Australia Fellow in Clinical Pharmacology.
458
quantities of both 4-hydroxy-2-ethyl-2-phenylglutaramide (4-HG) and 2-(/-hydroxyethyl)2-phenylglutaramide can be identified in the urine. After long-term administration of smaller amounts of the racemic mixture to a 75-yr-old man, larger amounts of the 4-HG metabolite than of the I-hydroxy metabolite have been observed. 17 G has a half-life (tV2) of approximately 6 hr in man and produces sleep within 20 min of administration which lasts for 6 to 8 hr. Central nervous system depressed eye movements are detectable for only 2.5 hr after dosing, which suggests that this effect may not necessarily parallel venous drug concentrations. 6 With the use of the rotarod test, 4-HG administration to mice produced a sedative effect equal to or greater than that of the parent compound. The presence of this active metabolite has been used to explain the long duration and erratic recur-
Volume 22 Number 4
rence of coma observed in G overdosage in man.I,8 Our study was designed to investigate the pharmacokinetics of multiple therapeutic doses of G and the relationship between the level of G and 4-HG in plasma on selected performance tests in normal volunteers. Materials and methods
Subjects. Twelve healthy volunteers were selected and trained daily (except on weekends) on a computer-generated tracking test l6 for 12 days until a steady-state level of performance was reached. During the course of the study 3 volunteers dropped out during the training period, I had substances in plasma that interfered with the assay of G, and I did not reach steady-state performance. Thus, the data from 7 subjects (4 male and 3 female) were available for the analysis of performance and those from 8 (5 male and 3 female) for pharmacokinetic modeling. The subjects varied in age from 24 to 29 (mean, 25) yr and in weight from 57 to 90 (mean, 60) kg. The training period for the other performance tests included only the last two predrug days. Alcohol intake was not allowed after the ninth day of the training period and caffeinecontaining beverages (coffee, tea, cocoa, and colas) after the eleventh day. Compliance was monitored only by verbal questioning. On day 12, 500 mg of G was administered orally every 8 hr. The subjects fasted from 8 P.M. on day 12 until noon on day 13, at which time they received a standard lunch. On the morning of day 13, the fourth and final dose of 500 mg of G was administered. Blood samples were taken just prior to administration of the last dose, every 2 hr for 4 hr, and every hour for 6 hr more. Performance was evaluated just before the last dose and every 2 hr for 10 hr at times corresponding with the blood sampling. On days 14 and 15 blood samples were drawn and performance was measured once in the morning and once in the evening. On day 16, these were repeated only once. Psychomotor tests Based on reports that they were affected by various central nervous system depressants, the
Glutethimide and 4-0H glutethimide
459
following tests were selected to evaluate each subject's psychomotor performance: Tracking test. A Digital Equipment Corporation PDP- 12 computer was implemented to generate an apparently moving set of parallel lines whose direction was randomly determined by sampling a white noise generator. 16 Each subject was instructed to position a cross-hair cursor under joy stick control in the middle of the parallel (tracking) lines. The subjects were allowed a 0.25 in preview of the track which had an apparent speed of 33 in/min with 0.75 in between the lines. Each trial consisted of two 7-min tests separated by a 20-sec rest period. Two thousand sample points were collected during each I4-min sampling period. The standard deviation of the error (SDE) was calculated according to Equation I for each of the two 7-min trials and the average of these two values used to define the volunteer's performance at each test period: SDEi= [
Ieln
)2]y.
(I e j -n-
(1)
where e j is the jth sample distance, n = 1000, and i = the number of any sample period, I, 2 ... ,7. Each individual's performance was tested 5 to 7 different times after receiving the last dose of G (Fig. I). Preliminary evaluation made it obvious that it would be necessary to provide motivation to achieve and maintain steady-state performance. Accordingly, the subjects lost a portion of the compensation they would receive for participating in the study as a function of their performance, i.e., the better their performance during their training and experimental periods, the greater their monetary reward. Card sorting. A board was placed on the table in front of the volunteer with slots containing the ace, 2, 3, 4, 5, 6, 7, and 8 from a deck of cards. The same cards in all suits were separated from another deck of cards and shuffled 3 times. The deck of 32 cards was handed face down to the subjects and they were instructed to turn each card in sequence as rapidly as possible with the preferred hand and place it in the slot matching its face value. Three trials were done at each test period. The number of errors and
460
Crow et al.
Clinical Pharmacology and Therapeutics
8.0'
7.0
•
6.0 w
Cl (f)
x
5.0
4.0
w-
o
~ ~ en
8
(fJ-g . hrlml)
(1)
AUC o->8 t
(fJ-g . hrlml)
---
Smokers R. S. N. S. F. C. S. M. Nonsmokers S. R. J. I. R. P. E. R.
l.18 1.46 1.61 2.28
± ± ± ±
l.89* 1.06 2.19 11.5
0.07 0.07 0.10 0.09
0.02 0.01 0.02 0.01
9.9 9.9 6.9 7.7
138 141 121 123
± ± ± ±
33 14 21 17
44.54 41.97 38.15 39.51
40.09 40.71 37.00 34.37
3.64 0.46 6.13 69
± ± ± ±
17.20 2.8 24.8 476
0.13±0.02 0.13 ± 0.05 0.08 ± 0.02 0.06 ± 0.01
5.3 5.3 8.7 11.6
174 114 241 235
± ± ± ±
43 42 50 40
NS
NS
19.74 32.08 22.39 29.68 4.64/6>
James W. Crow, Ph.D., Pedro Lain, M.D., Felix Bochner, M.D., * Don W. Shoeman, Ph.D., and Daniel L. Azarnoff, M.D. Kansas City, Kan. Clinical Pharmacology-Toxicology Center, Departments of Medicine and Pharmacology, University of Kansas Medical Center, College of Health Sciences and Hospital
The hypnotic, glutethimide (2-ethyl-2phenylglutarmide, Doriden), is extensively metabolized to several more polar compounds. Glucuronidated metabolites excreted in the urine account for 92% to 94% of the administered drug. The two enantiomers of glutethimide (G) are metabolized differently; the dextro form produces a 4-hydroxyglutaramide ring substitution, whereas the levo forms a I-hydroxy substitution on the ethyl side chain. 12 When large amounts of the racemate are administered to selected animals and man, significant Supported by Grant GM 15956 from the United States Public Health Service. Received for publication Nov. 16, 1977. Accepted for publication June 6, 1977. Reprint requests to: Daniel L. Azarnoff, M.D., Clinical Pharmacology Center, University of Kansas Medical Center, Rainbow Blvd. at 39th, Kansas City, Kan. 66103. 'National Health and Medical Research Council of Australia Fellow in Clinical Pharmacology.
458
quantities of both 4-hydroxy-2-ethyl-2-phenylglutaramide (4-HG) and 2-(/-hydroxyethyl)2-phenylglutaramide can be identified in the urine. After long-term administration of smaller amounts of the racemic mixture to a 75-yr-old man, larger amounts of the 4-HG metabolite than of the I-hydroxy metabolite have been observed. 17 G has a half-life (tV2) of approximately 6 hr in man and produces sleep within 20 min of administration which lasts for 6 to 8 hr. Central nervous system depressed eye movements are detectable for only 2.5 hr after dosing, which suggests that this effect may not necessarily parallel venous drug concentrations. 6 With the use of the rotarod test, 4-HG administration to mice produced a sedative effect equal to or greater than that of the parent compound. The presence of this active metabolite has been used to explain the long duration and erratic recur-
Volume 22 Number 4
rence of coma observed in G overdosage in man.I,8 Our study was designed to investigate the pharmacokinetics of multiple therapeutic doses of G and the relationship between the level of G and 4-HG in plasma on selected performance tests in normal volunteers. Materials and methods
Subjects. Twelve healthy volunteers were selected and trained daily (except on weekends) on a computer-generated tracking test l6 for 12 days until a steady-state level of performance was reached. During the course of the study 3 volunteers dropped out during the training period, I had substances in plasma that interfered with the assay of G, and I did not reach steady-state performance. Thus, the data from 7 subjects (4 male and 3 female) were available for the analysis of performance and those from 8 (5 male and 3 female) for pharmacokinetic modeling. The subjects varied in age from 24 to 29 (mean, 25) yr and in weight from 57 to 90 (mean, 60) kg. The training period for the other performance tests included only the last two predrug days. Alcohol intake was not allowed after the ninth day of the training period and caffeinecontaining beverages (coffee, tea, cocoa, and colas) after the eleventh day. Compliance was monitored only by verbal questioning. On day 12, 500 mg of G was administered orally every 8 hr. The subjects fasted from 8 P.M. on day 12 until noon on day 13, at which time they received a standard lunch. On the morning of day 13, the fourth and final dose of 500 mg of G was administered. Blood samples were taken just prior to administration of the last dose, every 2 hr for 4 hr, and every hour for 6 hr more. Performance was evaluated just before the last dose and every 2 hr for 10 hr at times corresponding with the blood sampling. On days 14 and 15 blood samples were drawn and performance was measured once in the morning and once in the evening. On day 16, these were repeated only once. Psychomotor tests Based on reports that they were affected by various central nervous system depressants, the
Glutethimide and 4-0H glutethimide
459
following tests were selected to evaluate each subject's psychomotor performance: Tracking test. A Digital Equipment Corporation PDP- 12 computer was implemented to generate an apparently moving set of parallel lines whose direction was randomly determined by sampling a white noise generator. 16 Each subject was instructed to position a cross-hair cursor under joy stick control in the middle of the parallel (tracking) lines. The subjects were allowed a 0.25 in preview of the track which had an apparent speed of 33 in/min with 0.75 in between the lines. Each trial consisted of two 7-min tests separated by a 20-sec rest period. Two thousand sample points were collected during each I4-min sampling period. The standard deviation of the error (SDE) was calculated according to Equation I for each of the two 7-min trials and the average of these two values used to define the volunteer's performance at each test period: SDEi= [
Ieln
)2]y.
(I e j -n-
(1)
where e j is the jth sample distance, n = 1000, and i = the number of any sample period, I, 2 ... ,7. Each individual's performance was tested 5 to 7 different times after receiving the last dose of G (Fig. I). Preliminary evaluation made it obvious that it would be necessary to provide motivation to achieve and maintain steady-state performance. Accordingly, the subjects lost a portion of the compensation they would receive for participating in the study as a function of their performance, i.e., the better their performance during their training and experimental periods, the greater their monetary reward. Card sorting. A board was placed on the table in front of the volunteer with slots containing the ace, 2, 3, 4, 5, 6, 7, and 8 from a deck of cards. The same cards in all suits were separated from another deck of cards and shuffled 3 times. The deck of 32 cards was handed face down to the subjects and they were instructed to turn each card in sequence as rapidly as possible with the preferred hand and place it in the slot matching its face value. Three trials were done at each test period. The number of errors and
460
Crow et al.
Clinical Pharmacology and Therapeutics
8.0'
7.0
•
6.0 w
Cl (f)
x
5.0
4.0
w-
o
~ ~ en
8
(fJ-g . hrlml)
(1)
AUC o->8 t
(fJ-g . hrlml)
---
Smokers R. S. N. S. F. C. S. M. Nonsmokers S. R. J. I. R. P. E. R.
l.18 1.46 1.61 2.28
± ± ± ±
l.89* 1.06 2.19 11.5
0.07 0.07 0.10 0.09
0.02 0.01 0.02 0.01
9.9 9.9 6.9 7.7
138 141 121 123
± ± ± ±
33 14 21 17
44.54 41.97 38.15 39.51
40.09 40.71 37.00 34.37
3.64 0.46 6.13 69
± ± ± ±
17.20 2.8 24.8 476
0.13±0.02 0.13 ± 0.05 0.08 ± 0.02 0.06 ± 0.01
5.3 5.3 8.7 11.6
174 114 241 235
± ± ± ±
43 42 50 40
NS
NS
19.74 32.08 22.39 29.68 4.64/6>
