CHIRALITY 4:142-147 (1992)

Enantioselective Pharmacokinetics of Ethotoin in Humans Following Single Oral Doses of the Racemate WAYNE D. HOOPER, NERIDA J. OSHEA, AND MI SUI QING Department of Medicine, The University of Queensland, Clinical Sciences BuiMng, Royal Brisbane Hospital, Herston, Queensland, Australia

ABSTRACT Racemic ethotoin (lo00 mg) was administered orally as a single dose to six healthy adult volunteers. Blood samples were collected at appropriate times for 120h following the dose. Ethotoin was quantified enantioselectively in plasma using a novel chiral column HPLC procedure. One of the enantiomers of the chiral metabolite, 5-phenylhydantoin,was also quantified in the HPLC method. The G,, and AUCG, values for (+)-(S)-ethotoin were significantly greater than those for (-)-(R)-ethotoin (ratio of mean AUCG, values 0.88), but the elimination half-lives of the isomers were virtually identical [12.35 f 5.15 h for ( - )-(R)-ethotoin;12.28 f 5.34 h for ( + )-(3-ethotoin].Parameters derived from AUC&_, (Cb/ F and V,, /F)also differed slightly between the isomers. The data were interpreted as indicating a small difference in the absorption of the two isomers; it seemed unlikely, in terms of the identical elimination rates, that their metabolic profiles would differ greatly. The 5-phenylhydantoin was eliminated with a significantly longer half-life (18.69 f 6.11 h) than that of ethotoin. Enantioselectivity in the pharmacokinetics of ethotoin is therefore a minor issue. 0 1992 Wiley-Liss, Inc.

KEY WORDS: anticonvulsants, epilepsy, stereoisomers, hydantoins, metabolism, HPLC assay, chiral columns INTRODUCTION Ethotoin (3-ethyl-5-phenylhydantoin; Peganoneb) was introduced into therapy as an anticonvulsant in 1956, and has been shown to have value in treating generalized tonic-clonic and complex partial seizures. Although substantially larger doses are required than for the more commonly used hydantoin anticonvulsant, phenytoin, ethotoin has the major advantage of causing little if any sedation, and no gingival hyperplasia, hirsutism, acne, or hepatitis. Nevertheless ethotoin has never achieved the status of a first-choiceanticonvulsant in the minds of most clinicians, possibly in part because of a variety of reports comparing its efficacy unfavourably with that of phenytoin, as well as the poor pharmacokinetic properties which have been attributed to the drug (notably an inconveniently short half-life4s5and dose-dependent kinetics6s7). Following a recent retrospective evaluation of the efficacy of ethotoin, Biton et a18 concluded that the drug may be a better antiepileptic agent than is generally appreciated, and warrants prospective controlled trials, especially in tonic seizures. Since its introduction into therapy, ethotoin has been available only as the racemate. As is typically the case with older chiral drugs, many workers have overlookedor disregarded the stereochemical issues with this drug. There are no published data concerning the pharmacological properties of the separate enantiomers, and almost no data on the enantiospecific disposition. The enantiomers were shown to be resolvable on an u1acid glycoprotein chiral HPLC c o l ~ m nbut , ~ this was not developed as an analytical method. Recently Inotsume et all0 have extended their earlier GC/MS assay for ethotoin” to include a o 1992 Wiley-Liss, Inc.

preliminary resolution of the enantiomers on a Chiralcel CA-1 HPLC column. These authors showed pharmacokinetic profiles of the separate enantiomers in one subject following a single oral dose of racemic ethotoin,lo which is to our knowledge the only report to date on enantioselective pharmacokinetics in humans. Although there are very few data on the enantioselective pharmacokinetics of ethotoin, there have been some elegant and informative studies of stereochemical factors in the metabolism of the drug in dogs and humans.12,13The major metabolic pathways were shown to be 4’-hydroxylation in the phenyl ring, and N-deethylation; a total of 11 metabolites were detected in human urine.13 There are no data concerning the stereochemistry of the phenolic metabolite formed by 4’-hydroxylation, but the N-dealkylation leads to some interesting stereochemical consequences. Thus, while both enantiomers of ethotoin are susceptible to the loss of the N-ethyl group, the ( - )-(R)-enantiomerof the product (5-phenylhydantoin) is a substrate for a dihydropyrimidinase enzyme, l4,l5 which converts it to ( - )-(R)-2-phenylhydantoicacid. The (3-enantiomer of 5-phenylhydantoin is not a substrate for the dihydropyrimidinase, but racemizes in vitro,16 and probably in vivo, and is thus also capable of yielding ( - )-(R)-Zphenylhydantoic acid. We report here a novel enantiospecific HPLC assay for ethotoin, and the results of pharmacokinetic studies following Received for publication August 19, 1991; accepted November 13, 1991. Address reprint requests to Dr.W. D. Hooper, Department of Medicine, Clinical Sciences Building, Royal Brisbane Hospital, Herston Qld 4029, Australia.

PHARMACOKINETICS OF ETHOTOIN

single oral doses of the racemate in 6 healthy adult human volunteers.

143

Only one of the metabolites of ethotoin, 5-phenylhydantoin, was available to us (as the racemate). This compound was previously separated on a (3-cyclodextrin column. l 7 Using pure compounds, or plasma standards prepared with drug-free MATERIALS AND METHODS human plasma, we were able to demonstrate that ethotoin and Clinical Protocol Six healthy adult volunteers (5 males, 1 female) participated 5-phenylhydantoin could be assayed concurrently using the in these studies. The experimental protocol was approved by technique described. However, in almost all of the plasma samthe University of Queensland Medical Research Ethics Commit- ples obtained from the volunteers, there was a small peak tee (St. Lucia, Queensland, Australia), and each subject gave which appeared as a shoulder on the later-eluting 5-phenylinformed consent to participate in the study. The subjects' ages hydantoin peak (see Results). ranged from 25 to 45 years. All were in excellent health, were Characterization of the Ethotoin Enantiomers within the community norms for weight/height ratio, and none was taking any medication immediately prior to, or at the time The enantiomers of ethotoin were separated on a preparative of the clinical study. At recruitment all subjects had physical scale using a semipreparative P-cyclodextrin column (25 cm examinations, provided medical histories, and gave blood sam- long, 1 cm id.; ASTEC). For this work the mobile phase was ples for measurement of clinical biochemistry and haematology 2% acetonitrile in phosphate buffer with a flow rate of 3 ml/ parameters, which were confirmed to be within normal ranges. min. Single injections of 200 pg of racemic ethotoin gave satisNone of the participants was a smoker. factorily resolved peaks. The eluent fractions containing the Each subject received a single lo00 mg oral dose of racemic resolved enantiomers were separately collected, and fractions ethotoin as two 500 mg tablets (Peganone@,Abbott Laborato- from multiple injections were pooled. The pooled eluents were ries, Chicago, IL) with water at approximately 8 A.M. following adjusted to pH 3, and extracted with chloroform. Evaporation an overnight fast. Blood samples (G3ml) were collected by of the chloroform gave a residue of which a portion was reconmeans of an indwelling venous cannula before dosing, and at stituted in HPLC mobile phase, and rechromatographed to deapproximately 0.33, 0.67, 1.0, 1.5, 2, 3, 4,5, 6, 8, 10, and 12 h termine the ratio of enantiomers. It was necessary to repeat the after the dose. Further samples were obtained by separate preparative separation in order to obtain a sample of the enantivenipunctures at approximately 24, 32, 48, 72, 96, and 120 h. omer (approx. 2 mg) which was approximately 98Y0 pure in Food was allowed 3 h after the dose. Meals were not standard- terms of peak area ratios. We used a Perkin Elmer model ized, and subjects engaged in their normal activities other than 241MC polarimeter to show that the first eluting ethotoin enanduring the first 12 h. Plasma was separated immediately after tiomer was levorotatory. The specific rotation could not be blood collection, and was stored at - 20°C until assayed. reliably determined because the sample, while chromatographically pure, probably contained residues from the evaporation of relatively large volumes of solvent. The specific rotation of Assay of Ethotoin ( - )-(I?)-ethotoinwas recorded previously l7 as - 88". The abEthotoin was analysed by a chiral column HPLC procedure solute configuration has been determined, l7 and for all of the using the (achiral) anticonvulsant zonisamide (1,2-benzisoxanalogous 5-phenylhydantoins which have been documented azole-3-methanesulfonamide;Parke Davis Pty. Ltd., Sydney, the levorotatory enantiomer had the (I?)-configuration.17,18 Australia) as the internal standard. The internal standard (1.0 pg in 0.5 ml methanol) was added to each assay tube, and the Pharmacokinetic and Statistical Analyses solvent removed under an air stream. Plasma (0.5 ml; subject specimen or calibration standard) was added, and briefly agiAll plasma concentration-time data were analysed by tated using a vortex mixer. Dichloromethane (5 ml) was added, model-independent pharmacokinetic methods. Peak plasma and the tube shaken vigorously by hand for 2 min. Following concentration (&ax) and time to reach peak concentration centrifugation, the aqueous layer and precipitated proteins (Tmax)were determined by inspection of the raw data. Area were aspirated to waste, and the organic solvent was trans- under the concentration-time curve from time zero to time t ferred to a clean, tapered test tube.The solvent was removed (AUC,,.J was determined by trapezoidal rule, where t was the under a gentle air stream at room temperature, and the residue last time at which drug concentration was measurable. The was taken up in HPLC mobile phase (100 pl), an aliquot (10-30 extrapolated area, AUCf-, , was obtained from the expression PI) of which was injected into the HPLC. C/h,, in which C was the drug concentration at time t and h, Chromatography was carried out on a Cyclobond I p-cy- was the elimination rate constant, i.e., the slope of the line of clodextrin analytical column (Advanced Separation Technolo- best fit to the approximately log-linear terminal elimination gies, Whippany, NJ), which was immersed in a water bath held phase. AUCS, was the sum of AUCS, and AUC,- . Eliminaat a constant temperature of 32°C. We used a Waters model 510 tion half-life (t,h)was 0.693/hZ,and apparent total body clearpump, a Rheodyne 7120 injector, and a Waters model 481 ance (C&/F) was derived from the quotient enantiomer dose/ absorbance spectrophotometer, the signal from which was pro- AUCG, . The bioavailability, F, was not known, since only an cessed by a Shimadzu C-R3A integrator. The mobile phase was oral formulation was available. The ratio of apparent volume 6% (v/v) acetonitrile in phosphate buffer (0.067 M; pH 5.0) with of distribution ( Vara) of each enantiomer to its availability to a flow rate of 0.7 mlimin. The absorbance of the effluent was the systemic circulation (F)was calculated as enantiomer dose/ monitored at 205 nm, and quantification was in terms of peak (A, x AUC&,). area ratios. The enantiomers of ethotoin were separated on a Differences between the pharmacokinetic parameters for the preparative scale (see below) and we then confirmed that the two enantiomers of ethotoin were tested for significance using first eluting peak corresponded to the ( - )-(I?)-enantiomer. the Wilcoxon paired data test.

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RESULTS

All subjects tolerated the single 1O , OO mg dose of ethotoin well. The only side-effect encountered was a transient visual disturbance in all subjects, described as a sensation of increased brightness of light, especially in a dimly lit room. This commenced within 1 h of dosing and lasted for up to 2 h. Under the chromatographic conditions described, the ethotoin enantiomerseluted at 10.2 (levo)and 10.8 (dextro)min, and zonisamide at 12.9 min. The enantiomers of 5-phenylhydantoin were well separated from ethotoin, at 8.7 and 9.3 min. A specimen chromatogram for the reference compounds is shown in Figure la. Figure l b shows a chromatogram from the analysis of a spiked plasma standard containing racemic 5-phenylhydantoin and racemic ethotoin. A chromatogram from analysis of a plasma sample from a subject is illustrated in Figure lc. The peak interfering with the later-elutingisomer of 5-phenylhydantoinwas present at similar levels in almost all postdose samples up to 48 h from the subjects; it was absent in predose samples and in samples beyond 48 h. This raised the suspicion that the interference was drug-related,but its identity was unknown. As a consequence, quantification of only the earlier-eluting 5-phenylhydantoin isomer was possible. The assay had excellent linearity for each enantiomer of ethotoin over the concentration range 0.1-75 pg/ml; the lower limit of quantification was 0.1 pg/ml. Accuracy and precision were determined using spiked standards at several concentrations, and were within the range of 6-8%. When racemic standards were assayed at each of 5 different concentrations, the ratio of determined concentrationsfor the two enantiomers was invariably within the range of 1.00 f 0.05. Comparable performance was achieved with calibration standards with respect to quantification of the two enantiomers of 5-phenylhydantoin. Figure 2 shows the mean concentration-time profiles in the group of 6 subjects for the enantiomers of ethotoin and for the one enantiomer of 5-phenylhydantoinwhich could be quantified. There was a small but consistent difference between the concentrations of the two ethotoin enantiomers, with the ( + )-(8-isomer having higher concentrations at virtually all (a)

(b)

(C)

T m (h)

Fig. 2. Mean (n =6) plasma concentration-time profiles for (+)-(3-ethotoin (solid circles), ( - )-(R)-ethotoin (open circles), and one enantiomer of 5-phenylhydantoin (solid triangles). The intersubject variability was so low that standard error bars were contained within the symbols for most points. The inset shows the same data on a logarithmic concentration scale.

times and in all subjects. Despite this difference the profiles of the two enantiomers were closely parallel, and in particular their elimination rates appeared very similar. The profile of 5-phenylhydantoin,with an abnormally delayed peak concentration, clearly showed that this metabolite was still being formed from its precursor until around 24 h. It was significant, in the light of published accounts of nonlinear kinetics of ethotoin, that all three species showed excellent log-linear terminal elimination phases. The calculated pharmacokinetic parameters for ( - )-(R)-ethotoin,( + )-(3-ethotoin, and 5-phenylhydantoin are shown in Tables 1, 2, and 3, respectively. Statistical comparison of the results for the two ethotoin enantiomers showed that they differed significantly with respect to and AUCgm (see Table 2 for P values). Differences of marginal statistical significance were found for C& / F and V,, / F (Table 2). There were no differences for Tma, h,, and tlh.The 5-phenylhydantoin was characterized by a substantially longer elimination half-life than the ethotoin enantiomers (Table 3). DISCUSSION

i3

I

0

10

I

I

I

20

0

10

20

L

I

,

0

10

I

20

Time (mid

Fig. 1. Chromatograms for analysis of (a) pure reference compounds; (b) plasma spiked with racemic ethotoin (each enantiomer 31.25 pg/ml) and racemic 5-phenylhydantoin (each enantiomer 6.25 pg/ml); and (c) plasma sample from a volunteer (12 h postdose). The doublet numbered 1 corresponds to 5-phenylhydantoin, that numbered 2 to ethotoin [( -)-(R)-enantiomer elutes first], and peak 3 is zonisamide.

The pharmacokinetics of ethotoin have received relatively little study hitherto, despite the fact that the drug has been in clinical use for more than 30 years. All of the published studies, except the brief report of Inotsume et al., lo have used analytical methods which did not resolve the optical isomers of ethotoin; as a consequence their conclusions must be interpreted with considerable caution. In addition to this problem, there are conflicting data in the published reports, with respect to questions of the elimination half-life of the drug and the possibility of dose dependency in its kinetics. In the present study we have shown a slight, but statistically significant difference between the enantiomers of ethotoin for some of their pharmacokinetic parameters. Most notably, differences existed for Gaand AUC@, , and to a lesser extent for those parameters which were derived from AUC@, (i.e., clearance and apparent volume of distribution). There was no

145

PHARMACOKINETICS OF ETHOTOIN

TABLE 1. Pharmacokineticparameters for (-)-(R)-ethotoin following oral administration of 1,000 mg of racemic drug Volunteer Parameter (units) Weight (kg) cmx(wlml) T,,, (h) AUC, I (pg/rnl.h) (h-9 4,z (h) CJ!,JF (liter/h/kg) KJF (liter/kg)

1

2

3

4

60 31.5 1.0 564 0.0841 8.24 0.015 0.18

72 24.4 1.5 420 0.0824 8.41 0.017 0.21

72 22.2 1.0 316 0.0668 10.37 0.022 0.33

85 33.8 3.0 590 0.0469 14.79 0.010 0.21

54

62 29.1 2.0 880

0.0320 21.69 0.009 0.28

6

Mean

(SD)

83 18.7 1.5 287 0.0656 10.57 0.021 0.32

26.6 1.67 510 0.0663 12.35 0.016 0.26

(5.8) (0.75) (220) (0.0203) (5.15) (0.005) (0.06)

“Female.

TABLE 2. Pharmacokinetic parameters for (+)-(S)-ethotoin following oral administrationof 1,000 mg of racemic drug Volunteer Parameter1

1

2 ~~

cmax

Tmax

AUC, k,

L

4’2

CkIF KrJF

35.0 1.5 636 0.0838 8.27 0.013 0.16

~

25.0 2.0 449 0.0830 8.35 0.015 0.18

5

6

Mean

(SD)

pb

31.9 2.0 920 0.0310 22.33 0.009 0.29

24.1 1.5 368 0.0699 9.92 0.016 0.23

30.4 1.83

(5.9) (0.68) (218) (0.0204) (5.34) (0.004) (0.06)

0.031 0.500 0.031 0.625 0.688 0.062 0.062

4

3 ~~~~~~

~~

27.2 1.0 386

0.0635 10.92 0.018 0.28

~~

38.9 3.0 721 0.0500 13.87 0.008 0.16

580 0.0635 12.28 0.013 0.22

%its as shown in Table 1. bP value for comparison of results for (+ Fethotoin with those for (-)-ethotoin using Wilcoxon paired data test.

TABLE 3. Pharmacokineticparameters for one enantiomer of 5-phenylhydantoinfollowing oral administration of 1,000 mg of racemic ethotoin

cmx

Tmax

AUC, 4 2

1

2.9 12.0 118 0.0413 16.76

2.4 24.5 93 0.0635 10.92

2.4 10.0 100 0.0443 15.65

1.5 8.0 68 0.0325 21.31

1.0 24.0 68 0.0220 31.54

2.0 27.87 82 0.0434 15.97

2.0 17.73 88

0.0412 18.69

(0.7) (8.66) (20) (0.0138) (7.11)

‘Units as shown in Table 1.

difference in the elimination rates. The most likely explanation of these pharmacokinetic differences would be a small difference in the extent of absorption of the two enantiomers. While this seems somewhat surprising for a drug with relatively low clearance (well below the level at which a first pass clearance would be expected), it would certainly account fully for the observed pharmacokinetic outcomes. An alternate explanation to which we have given careful attention is that the differences are apparent but not real, and could result from an analytical artifact if the assay method were biased in favour of the second eluting enantiomer. Although the two enantiomers are not quite resolved to baseline (Fig. l),our careful review of the results of analyzing racemic standards has shown that the assay does not show a bias in favour of one enantiomer; the

racemic standards always were assayed to have values within 5% of each other, usually well within, and there was no consistent finding of a higher result for either isomer. Thus there is no evidence that inadequate chromatographic resolution would account for our results. Another possible analytical explanation of the result would be a cochromatographing peak, possibly from another metabolite, (and therefore not seen in standards). This cannot be discounted with our present data, although we have no indication of peak shouldering even when ethotoin concentrations are quite low. In addition to this, we note that in the only other report of a single-dosepharmacokinetic study with ethotoin in which an enantioselective assay was used, lo exactly the same pattern of results was obtained, with the ( + )-(9-enantiomer having slightly higher concentrations than

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HOOPER ET AL.

the (- )-(R)-enantiomerat all time points. That study involved only one subject,but was performed with a completely different analytical method than we used, which strengthens our belief that our finding is not a result of analytical artifact. Our results for ethotoin are closely analogous to those reported previously for vigabatrin, whose enantiomers showed even greater differences for & and AUC, but negligible differences in terminal elimination half-life. l9 Stereoselectivity in drug absorption is not unknown, but is not an issue for the great majority of chiral drugs.20*21 It may be important when one isomer has a much higher metabolic clearance than the other, giving rise to a stereoselective first pass or when a drug resembles endogenous compounds and is carried by active transport processes, as happens with L-dopa.% However these processes often result in major differences in the uptake of enantiomers, much greater than we have observed for ethotoin, for which the ratio of AUC&m values was 0.88. We are not able on the basis of our present data to propose a mechanism for this difference in the apparent uptake of the enantiomers of ethotoin. The elimination kinetics of ethotoin were previously reported to be nonlinear following a single oral dose of 30 mg/kg in humans.6*7This finding was not reproduced by two other groups of workers, in patients with comparable plasma levels of the drug. However, in a more recent study Meyer et a1.26 administered doses of 500, 1,500, and 2,500 mg of ethotoin to healthy volunteers and found that the AUC values were not proportional to dose, but were greater at higher doses than predicted from the lower doses, indicating probable saturation of elimination pathways. Perhaps as a consequence of this nonlinearity in kinetics, there has been a controversy regarding the elimination half-life of this drug. Browne and Szabo2 have recently analyzed this nicely in terms of Michaelis-Menten kinetics. They noted that clinical acceptance of the drug has been hampered by the information in the manufacturer's package insert which states that ethotoin should be administered 4-6 times daily. Their analysis, based on extrapolation of results of single dose kinetic studies to the chronic dosing situation, suggested that a three times daily regimen would be rational. Although our single dose studies at only one dose level (approximately 15 mg/kg) showed excellent linear elimination profiles, they shed no light on the possibility of nonlinear kinetics at higher doses. Our finding of a mean elimination half-life of about 12 h for each enantiomer adds weight to the suggestion of Browne and Szabo that the drug could be administered less frequently than is currently recommended. We note here also that there was moderate intersubject variability in our small group of subjects, which implies that larger groups should be studied in order to adequately define the population variability. Some aspects of stereoselectivity in the metabolism of ethotoin have been studied previously. 12J3 Our finding of no difference in the elimination rates of the enantiomers of ethotoin suggests that the isomers are not subject to markedly different metabolic profiles. The possibility of racemization of ethotoin in vivo must be considered, since racemization has been shown to occur for some hydantoins in vitro, specifically and has 5-phenylhydantoin and 3-methyl-5-phenylhydantoin, been proposed as a probable component of the metabolism of 5-phenylhydantoin in vivo. l6 Although racemization of 475

ethotoin was not explicitly demonstrated in those earlier studies, it remains a possibility which requires further study with purified enantiomers in quantities greater than we currently have available. That the concentrations of the enantiomers in vivo remained different for extended periods in our studies argues against racemization occurring to a significant extent. An admitted shortcoming of the present study is our inability to assay both enantiomers of 5-phenylhydantoinin subject plasma samples, and our uncertainty as to whether the enantiomer measured (the first eluting in this HF'LC system) was the levorotatory isomer. It was clear from the chromatograms that the concentrations of the two enantiomers of 5-phenylhydantoin were approximately equal in all samples, despite our inability to assign reliable quantification to the later peak. In terms of the documented racemization of this compound,l6 one would anticipate equivalent concentrationsof the enantiomers, and we therefore strongly suspect that our findings for the one enantiomer are applicable to both, though this has not been rigorously demonstrated. There could be some tendency for this metabolite to accumulate in plasma with chronic dosing, given its longer elimination half-life, but the relatively low plasma levels seen in the single dose situation suggest that steady-state concentrations should not be high in relation to those of ethotoin. In terms of clinical effects, the peculiar visual disturbances caused by ethotoin in all of our volunteers have been reported and described well by Meyer et al. 26 Since the effect was transient it is unlikely to pose serious difficulties in single dose experiments. This study adds to our understanding of the pharmacokinetics of this anticonvulsant drug, by providing the first detailed information on enantioselectivity. There are, however, still a number of important questions unanswered and, as a consequence of recent suggestions that the drug could find an improved application in therapy, we believe that further study of its pharmacokinetics and metabolism is desirable. ACKNOWLEDGMENTS

This work was supported by a Project Grant from the National Health and Medical Research Council of Australia. The authors wish to thank Dr.M.L. Bullpitt for clinical oversight of the volunteers who participated in these studies. We are grateful also to Abbott Australasia Pty. Ltd., and their parent company of Deerfield, Illinois, for supplying the Peganones tablets and the reference samples of racemic ethotoin and 5-phenylhydantoin. We thank Parke-DavisPty. Ltd., Sydney, Australia for the gift of zonisamide. LITERATURE CITED 1. Livingstone, S. The use of Peganone (AC 695) in the treatment of epilepsy. J. Pediak. 49:728-732, 1956. 2. Browne, T.R., Szabo, G.K. A pharmacokinetic rationale for three times daily administration of ethotoin (peganone@). J. Clin. Phannacol. 29.270-271, 1989. 3. Schwade, E.D., Richards, R.K., Everett, G.M. Peganone, a new antiepileptic drug. Dis. New. Syst. 17:155-158, 1956. 4. Yonekawa, W.. Kupferberg, H.J., Cantor, F. A gas chromatographicmethod for the determination of ethotoin (3-ethyl-5-phenylhydantoin)in human plasma. In: Clinical Pharmacology of Anti-Epileptic Drugs. Schneider, H., Jam, D., Gardner-Thorp, C.. Meinardi, H., Sherwin, A.L., eds. Berlin: Springer-Verlag, 1975 115121.

PHARMACOKINETICS OF ETHOTOIN 5. Troupin, AS., Friel, P., Lovely, M.P., Wilensky, A.J. Clinical phmacology of mephenytoin and ethotoin. Ann. Neurol. 6410-114, 1979. 6. Lund, M., Sjo, O., Hvidberg, E.F. Plasma concentrations of ethotoin in epileptic patients. In: Clinical Pharmacology of Anti-Epileptic Drugs. Schneider, H., Janz, D., Gardner-Thorpe, C., Meinardi, H., Sherwin, A.L., eds. Berlin: Springer-Verlag, 1975:lll-114. 7. Sjo, O., Hvidberg, E.F., Larsen, N.-E., Lund, M., Naestoft, J. Dose-dependent kinetics of ethotoin in man. Clin. Exp. Pharmacol. Physiol. 2185-192, 1975. 8. Biton, V., Gates, J.R., Ritter, F.J., Loewenson, R.B. Adjunctive therapy for intractable epilepsy with ethotoin. Epilepsia 31:43M37, 1990. 9. Hermansson, J., Eriksson, M. Direct liquid chromatographic resolution of acidic drugs using a chiral a1-acid glycoprotein column (Enantiopacn). J. Liquid Chromatogr. 9621439, 1986. 10. Inotsume, N.. Fujii,J., Honda, M., Nakano, M. Stereoselectiveanalysis of the enantiomers of ethotoin in human serum using chiral stationary phase liquid chromatography and gas chromatography-mass spectrometry. J. Chromatogr. 428.402-407, 1988. 11. Inotsume, N.. Higashi, A., Kinoshita, E., Matsuoka, T., Nakano, M. Rapid and sensitive determination of ethotoin as well as carbamazepine, phenobarbital, phenytoin and primidone in human serum. J. Chromatogr. 3 8 3 : 1 6 171, 1986. 12. Dudley, K.H., Bius, D.L., Butler, T.C. Metabolic fates of 3-ethyl-5-phenylhydantoin (ethotoin, peganone), 3-methyl-5phenylhydantoin and 5-phenylhydantoin. J. Pharmacol. Exp. Ther. 17527-37, 1970. 13. Bius, D.L., Yonekawa, W.D., Kupferberg, HJ., Cantor, F., Dudley, K.H. Gas chromatographic-mass spectrometric studies on the metabolic fate of ethotoin in man. Drug Metab. Dispos. 822S229, 1980. 14. Dudley, K.H., Butler, T.C., Bius, D.L. The role of dihydropyrimidinase in the metabolism of some hydantoin and succinimide drugs. Drug Metab. Dispos. 210S112, 1974.

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15. Dudley, K.H., Roberts, S.B. Dihydropyrimidinase: stereochemistry of the metabolism of some 5-alkylhydantoins. Drug Metab. Dispos. 613S139, 1978. 16. Dudley, K.H., Bius, D.L. Buffer catalysis of the racemization reaction of some 5-phenylhydantoins and its relation to the in vivo metabolism of ethotoin. Drug Metab. Dispos. 434CL348.1976. 17. Dudley, K.H., Bius, D.L. The synthesis of optically active 5phenylhydantoins (1).J. Heterocyclic Chem. 10:17S180, 1973. 18. Maguire, J.H. Some structural requirements for resolution of hydantoin enantiomers with a j3-cyclodextrin liquid chromatography column. J. Chromatogr. 387453458, 1987. 19. Haegele, K.D., Schechter, P.J. Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S-enantiomer. Clin. Pharmacol. Ther. 40:581-586,1986. 20. Tucker, G.T., Lennard, M.S. Enantiomer specific pharmacokinetics. P h macol. Ther. 453W329, 1990. 21. Campbell, D.B. Stereoselectivity in clinical pharmacokinetics and drug development. Eur. J. Drug Metab. Pharmacokinet. 151W125, 1990. 22. Eichelbaum, M. Pharmacokinetic and pharmacodynamic consequences of stereoselective drug metabolism in man. Biochem. Pharmacol. 3793-96, 1988. 23. Borgstrom, L., Nyberg, L., Jonsson, S., Lindberg, C., Paulson. J. Pharmacokinetic evaluation in man of terbutaline given as separate enantiomers and as the racemate. Br. J. Clin. Pharmacol. 24%56, 1989. 24. Lim, W.H., Hooper, W.D. Stereoselectivemetabolism and pharmacokinetics of racemic methylphenobarbital in humans. Drug Metab. Dispos. 17212217, 1989. 25. Wade, D.N., Mearrick, P.T., Moms, J.L. Active transport of L-dopa in the intestine. Nature (London) 242463465, 1973. 26. Meyer, M.C., Holcombe, B.J., Burckart, G.J., Raghow, G., Yau. M.K. Nonlinear ethotoin kinetics. Clin. Pharmacol. Ther. 3 3 B 3 3 4 , 1983.

Enantioselective pharmacokinetics of ethotoin in humans following single oral doses of the racemate.

Racemic ethotoin (1000 mg) was administered orally as a single dose to six healthy adult volunteers. Blood samples were collected at appropriate times...
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