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Clinical pharmacology of mephenytoin and ethotoin.

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Clinical Pharmacology
of Mephenytoin and Ethotoin
Allan S. Troupin, MD, Patrick Friel, BS, Mary Pat Lovely, RN, BS, and Alan J. Wilensky, M D
Effective prescribing of anticonvulsants requires foreknowledge of baseline pharmacokinetic data. Little such information is available about the hydantoins other than phenytoin, although one of them, mephenytoin, is widely
used. Useful pharmacokinetic data should be derived from patients already exposed to anticonvulsants to reflect the
induction of hepatic oxidative enzymes. Single-dose studies of mephenytoin (Mesantoin) and ethotoin (Peganone)
were performed in adult inpatients on stable regimens of other anticonvulsants. Five patients received rnephenytoin, 7 mg per kilogram of body weight. Serial blood sampling was performed rigorously. The time to peak
concentration (TmaX)
for rnephenytoin was 1 hour, with a half-life (T112)
of 7 hours; the TI,, of its metabolite,
5-ethyl-5-phenylhydantion,
was 96 hours. Ethotoin administration was 25 mg per kilogram in 5 patients. Ethotoin
T,,, was 2 hours, with a T,,, of 5 hours. Saliva accurately represented the unbound fraction for all three agents.
Mean salivary levels (as percentage of total levels) were 61% for mephenytoin, 7396 for its metabolite, and 54% for
ethotoin.
The implications for therapy are that following mephenytoin administration, the metabolite 5-ethyl-5phenylhydantoin will provide anticonvulsant effectiveness, with its long half-life producing stable blood levels on
simple dose schedules. Ethotoin, in contrast, has a short half-life and would require divided daily doses to achieve a
steady state. This, rather than pharmacological ineffectiveness, limits its usefulness.
Troupin AS, Friel P, Lovely MP, et al: Clinical pharmacology of mephenytoin and ethotoin.
Ann Neurol 6:410-414, 1979
Recent evolution of the practical science of pharmacokinetics has drawn much of its impetus from the
need to evaluate new anticonvulsant agents. This
interest has tended to overshadow the importance of
gathering the same type of information for other,
older anticonvulsants so that their clinical usefulness
may be maximized. We have accordingly performed
these pharmacokinetic studies of mephenytoin (Mesantoin) and ethotoin (Peganone).
Mephenytoin was first used as an anticonvulsant in
the early 1940s [2, 51 and has recently been reevaluated [lo]. It has been recognized to be a very effective anticonvulsant with few dose-related side-effects
but occasional dangerous idiosyncratic side-effects. It
is demethylated promptly in vivo to 5-ethyl-5phenylhydantoin (Fig l), which is likewise an active
anticonvulsant [ 11. Any pharmacokinetic study of
mephenytoin must include measurement of its active
metabolite as well. Ethotoin was marketed in the
mid-1950s [7] but is not widely used, having acquired
the reputation for being useful only in “mild” epilepsy though it is relatively devoid of side-effects.
Its metabolites are not pharmacologically active
[61.
From the Epilepsy Center, University of Washington School of
Medicine, Seattle, WA.
Accepted for publication Apr 15, 1979.
410
Materials a n d Methods
The patients chosen for these single-dose studies were
all adult, ambulatory volunteers from the outpatient clinic
of the Epilepsy Center of the University of Washington.
Informed consent was obtained from each patient. All had
been treated with various anticonvulsants for many years
but had not received mephenytoin or ethotoin prior to
these studies. There was no change in their ongoing anticonvulsant program either just prior to o r in the course of
the single-dose studies. The patients were all hospitalized
on the Epilepsy Observation Unit for the duration of these
studies.
Serum sampling was performed by heparin-lock technique to minimize the number of individual venipunctures
for each patient. The sampling schedule was chosen for
each drug on the basis of the limited previous knowledge
of their peak times so that an adequate sampling density would be achieved for each individual agent. For
mephenytoin determinations, eight samples were drawn on
the first day, six on the second, four o n the third, and two
on the remaining two days. Patients were brought back for
a single sample o n the eighth day. For ethotoin, eight samples were drawn the first day and two for each of the subsequent three days. Hematological screening batteries
were performed at the beginning and end of the inpatient
phase of each drug protocol. Saliva sampling was per-
Address reprint requests to Dr Troupin, Deparrment of Neurology, Hospital of the University of Pennsylvania, 34th and Spruce
S t s , Philadelphia, PA 19104.
0364-5134/79/110410-05$01.25 @ 1978 by Allan S. Troupin
Mephenytoin
Ethotoin
Peg anone
?
H
H
0
Mesantoin
d
Phenytoin
Dilantin
d
H
5-Ethyl-5-phenylhydantoin
F i g 1 . Structures of the three commercially available hydantoin
anticonvulsants and 5-ethyl-5-phenylhydantoin,the pharmacologically actizle demethylation product of mephenytoin.
formed for the patients taking ethotoin at o r near the time
of peak concentration. Mephenytoin saliva samples, on the
other hand, were taken from 5 different outpatients on
stable, long-term dosage so both mephenytoin and 5ethyl-5-phenylhydantoin could be assayed simultaneously.
Blood samples were spun promptly and serum was separated and frozen for subsequent simultaneous analysis.
Saliva samples were similarly separated and frozen. The
serum and saliva level determinations were all performed
by gas-liquid chromatography with flame-ionization detection, utilizing flash-heater ethylation for mephenytoin and
5-ethyl-5-phenylhydantoin [3] and silylation for ethotoin
[ll]. Day-to-day coefficients of variation are 3% for
mephenytoin, 292 for 5-ethyl-5-phenylhydantoin,and
12% for ethotoin. Saliva determinations were carried out
as previously described [9].
Ethotoin data for each subject were analyzed by an
iterative computer method using a one-compartment open
model with first-order absorption. Half-lives (T1d of
mephenytoin and 5-ethyl-5-phenylhydantoinwere calculated for each subject using linear regression of log concentration versus time following peak concentration.
Doses administered were 7 mg per kilogram of body
weight for the 5 patients receiving mephenytoin, rounded to
the nearest 100 mg tablet, and 25 mg per kilogram for the 5
receiving ethotoin, rounded to the nearest 250 mg tablet.
These doses were chosen in an attempt to provide a single
total daily dose. O n e patient, who was taking carbamazepine as her routine anticonvulsant, was given single
doses of ethotoin, mephenytoin, and phenytoin on separate
occasions for comparison. H e r phenytoin dose was likewise
7 mgper kilogram, rounded to the nearest 100 mg capsule.
Results
Regression of computer-predicted concentrations
versus observed concentrations yielded correlation
coefficients greater than 0.90 for those subjects receiving each drug. Mean serum mephenytoin and
5-ethyl-5-phenylhydantoin levels are shown on a
semilogarithmic plot in Figure 2. The time to appearance of peak serum concentrations (T,,,)
for
mephenytoin was 1.0 hour (Table). Low levels of the
metabolite were apparent as early as 1/2 hour following mephenytoin administration. T h e apparent T,,,
was 27 hours, but in fact, nearly identical maximum
5-ethyl-5-phenylhydantoinconcentrations persisted
in serum between 14 and 33 hours after the dose.
The constant formation of this metabolite from the
parent compound mephenytoin, which was present
for a full day following the single dose, does not allow
estimation of a T,,, according to the classic definition. In addition, this constant formation with associated distribution does not permit estimation of a
clearly defined distribution phase. The mean TI,, for
mephenytoin was 6.8 hours, while that for 5-ethyl5-phenylhydantoin was 95.8 hours (Table).
The single-dose kinetics of ethotoin are simpler
(Fig 3). The T,,, for mean concentrations was 1.5
hours, with a median T,,, of 2.0 hours among the 5
patients (Table). The data are best fitted to a singlecompartment open model (Fig 3) with a mean TI,, of
5.1 hours. First-order absorption rate constants for
ethotoin were 0.39 to 2.42 hours-'. Dose dependency was not seen over a wide range of serum
concentrations, despite a previous report [8].
The mean percentages of free mephenytoin,
ethotoin, and phenytoin [9] in serum, as determined
by equilibrium dialysis, were compared to the relative concentration of the same drug in saliva and expressed as a percentage of the simultaneous serum
concentration (see the Table). The salivary levels for
all three hydantoins represent a good measure of unbound drug in serum. Mean salivary levels were
61.1% for mephenytoin, 72.5% for its metabolite,
Troupin et al: Mephenytoin and Ethotoin
411
Pharmacokinetic Determinations for Various Anticonvulsants
No. of
Patients
Mean
Free Percenta
Mean
Salivary Percenta
5.11 (0.72)
6.81 (0.44)
95.84 (14.02)
5
5
58.8 (13.7)
59.6 (10.1)
68.1 (7.7)
54.2 (11.8)
61.1 (10.0)
72.5 (11.5)
16.95h
6'
10.0 ( 0 . 8 ) C
9.1 (1.7)"
Drug
Tmax
Median
(hr)
TI,, (hr)
Ethotoin
Mephenytoin
5-Ethyl-5-phenylhydantoin
Phenytoin
2.0
1.0
27.0
2.0"
Mean
Values in parentheses are standard error about the mean.
"Expressed as percentage of total serum concentration.
'One patient (see Fig 4).
'From Troupin and Friel [9].
4.0-1
I
I
2
1
3
4
5
6
7
8
Time (days)
F i g 2. Semilogarithmic plot of mean serum concentrations of
mephenytoin (solid circles) and S-ethyl-5-phenylhydan~oin
(open circles) following a single oral dose o f 7 mg per kilogram of body weight in 5 patierits.
30 1
2o
,f..,
\
6
12
18
24
30
and 54.2% for ethotoin. T h e free ethotoin concentration in serum was approximately half the total concentration, while the unbound 5-ethyl-5-phenylhydantoin was about two-thirds the total concentration.
Free mephenytoin levels are similar. The difference
between these relatively high free drug percentages
and the low phenytoin free drug percentage is striking.
The single patient who received all three hydantoin anticonvulsants had a phenytoin T,,,,, of 2.0
hours with a T,,2of 17.0 hours (see the Table). These
values correspond well to previously reported data
for patients who have reached full enzyme induction at this dose. A comparison of the kinetic profile
for all three drugs in this single patient is shown in
Figure 4.
Time (hours)
F i g 3. Semilogarithmic plot of mean serum concentrations of
ethotoin in 5 patientr following single oral dose of 25 mg per
kilogram of body weight.
Discussion
Accurate prescribing of anticonvulsants is best performed with foreknowledge of kinetic data. The re-
412 Annals of Neurology Vol 6 No 5 November 1979
Ethotoin
25 m g l kg
2
1
10
Phenytoin
a1
2
1
I
1
3
Mephenytoin
2
7 mglkg
3
7mglkg
I
4
5
6
7
8
Time (days)
F i g 4. Arithmetic plots of serum levels o f ethotoin, phenytoin,
mephenytoin, and its metabolite 5-ethyl-5-phenylbydantoin
(Nirvanol) in the same patient following single oral doses of
the respective drugs i n consecutive weekj.
sults affect the prediction of time to achieve steady
state, the calculation of dosing intervals, and the relationship of time of peak appearance in serum to
dose-related side-effects. To be clinically useful,
studies need to be done on patients who have been
treated with similar drugs over a prolonged period to
the point of maximum induction of hepatic metabolism for those classes of drugs. During 1977, 140,000
prescriptions for mephenytoin were written in the
United States (Ferris AJ: personal communication,
1978); so few ethotoin prescriptions were written
that the data were not retrievable. If one considers
that mephenytoin has a reputation for being a
dangerous anticonvulsant with few dose-related
side-effects, while ethotoin has few side-effects and
no reputation for danger, some reason for the difference in their relative utilization should be sought.
The fact that mephenytoin is a clinically useful
drug has been documented elsewhere [lo] and is
further attested to by its continued use. Although
mephenytoin itself has anticonvulsant properties, its
active metabolite is actually the clinically effective
agent. Its gradual conversion from mephenytoin accounts for both the lack of an obvious distribution
phase and the stable level achieved over a prolonged
period. The very long half-life (four days) allows for
ease in dosing, with few fluctuations during the day
and little penalty for irregularities in dose-taking
within the day. True mephenytoin, on the other
hand, has little relationship to the course of antiepileptic therapy. With long-term administration it
represents less than 10% of the total mephenytoin
plus metabolite level in serum, and even its short
peak time usually has little bearing on the distribution of side-effects during the day [lo]. If saliva sampling is done carefully, it yields an accurate estimate
of the free percentage of both in serum. No drug
interactions involving mephenytoin o r 5-ethyl-5phenylhydantoin has as yet been described at the
level of binding to serum proteins, although saliva
testing might be a convenient way to evaluate this.
There was initial clinical interest in the use of
ethotoin following its introduction [ 71, although the
drug has fallen into subsequent disuse. The metabolites of ethotoin are not active, so one is dealing with
a single pharmacologically effective agent. The present studies demonstrate that ethotoin has an early
peak concentration in serum, which is probably not
of great clinical importance in view of its relative
absence of dose-related side-effects. With a half-life
of less than 6 hours, it would be necessary to administer this drug at least four times per day in order
to keep fluctuations between peak and trough serum
levels less than 100%. Even so doing, relatively large
doses are necessary to keep the minimum level prior
Troupin et al: Mephenytoin and Ethotoin
413
to the next dose within the therapeutic range of 15 to
SO p g per milliliter [4].These facts explain why the
usual dose of ethotoin is five to six times the usual
dose for phenytoin or mephenytoin. The bound portion of ethotoin in serum represents only half of the
total drug available in serum, a situation analogous to
that of mephenytoin and 5-ethyl-5-phenylhydantoin.
Saliva gives an accurate measure of binding for
ethotoin also, and no known interactions have been
described for this drug.
The clinical implications of these studies are that
mephenytoin is a convenient drug to administer because stable 5-ethyl-5-phenylhydantoinlevels can be
achieved without a compulsive regimen. Plateau
levels are reached in two to four weeks. In view of its
effectiveness and relative freedom from dose-related
side-effects, ease of administration tends to promote
good compliance and make it an operationally successful anticonvulsant. Ethotoin, on the other hand,
is quite difficult to manage on a daily basis, with consequent less ethusiastic compliance and a tendency
for recurrent seizures. This diminished usefulness of
ethotoin as a practical anticonvulsant is a result of its
pharmacokinetic properties rather than its strictly
pharmacological properties.
Supported in part by National Institutes of Health Contract
NOI-NS-6-2341, awarded by the National Institute of Neurological and Communicative Disorders and Stroke, US Public Health
Service, Department of Health, Education, and Welfare.
414 Annals of Neurology
Vol 6 No 5
References
1. Butler TC, Waddell WJ: Metabolic demethylation of 3methyl, 5-ethyl, 5-phenylhydantoin (Mesantoin).J Pharmacol
Exp Ther 104:229-308, 1952
2. Clein NW: New anticonvulsant in the treatment of epilepsy (3
methyl, 5,5 phenylaethylhydantoin) (Hydantal). Preliminary
report. Northwest Med 44:210-212, 1945
3. Friel P, Troupin AS: Mephenytoin: determination by flashheater ethylation, in Pippenger CE, Penry JK, Kutt H (eds):
Antiepileptic Drugs: Quantitative Analysis and Interpretation. New York, Raven, 1978, pp 352-354
4. Larsen NE, Naestoft J: Quantitative determination of ethotoin in serum by gas chromatography. J Chromatogr 92:157161, 1974
5. Loscalzo AE: Treatment of epileptic patients with a combination of 3 methyl, 5,5 phenylethylhydantoin and phenobarbital. J Nerv Ment Dis 101:537-544, 1945
6. Pippenger CE: Appendix 1, in Pippenger CE, Penry JK, Kutt
H (eds): Antiepileptic Drugs: Quantitative Analysis and Interpretation. New York, Raven, 1978, pp 321-333
7. Schwade ED, Richards RK, Everett GM: Peganone, a new
antiepileptic drug. Dis Nerv Syst 17:155-158, 1956
8. Sjo 0, Hvidberg EF, Larsen NE, et al: Dose-dependent kinetics of ethotoin in man. Clin Exp Pharmacol Physiol 2:185192, 1975
9. Troupin AS, Friel P: Anticonvulsant levels in saliva,
serum, and cerebrospinal fluid. Epilepsia 16:223-227,
1975
10. Troupin AS, Ojemann LM, Dodrill CB: Mephenytoin: a reappraisal. Epilepsia 17:403-414, 1976
11. Yonekawa W, Kupferberg HJ, Cantor F: A gas chromatographic method for the determination of ethotoin (3-ethy1,
5-phenylhydantoin) in human plasma, in Schneider H, Janz D,
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1975, pp 115-122
November 1979
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