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Hypolipidemic activity of antiepileptic 5-phenylhydantoins in mice
European Journal of Pharmacology, 117 (1985) 135-138
135
Elsevier Short communication H Y P O L I P I D E M I C ACTIVITY OF A N T I E P I L E P T I C 5 - P H E N Y L H Y D A N T O I N S IN M I C E JAMES H. MAGUIRE *, AKULA R. MURTHY and IRIS H. HALL Division of Medicinal Chemistry and Natural Products, School of Pharma~T, Universi(v of North Carolina. Chapel Hill, N C 27514. U.S.A.
Received 29 August 1985, accepted 3 September 1985
J.H. MAGUIRE, A.R. MURTHY and I.H. HALL, Hypolipidemic activity of antiepileptic 5-phenvlhydantoins in mice, European J. Pharmacol. 117 (1985) 135-138. Administration (20 mg/kg i.p.) of antiepileptic 5-phenylhydantoins phenytoin, ethotoin, mephenytoin, and selected metabolites to mice over a period of 16 days produced lower serum concentrations of cholesterol and triglycerides with most of the compounds studied. Several compounds were more effective hypolipidemic agents than clofibrate at 150 mg/kg per day. Several N-alkylated derivatives of the most active compound, 5-ethyl-5-phenylhydantoin, a metabolite of mephenytoin, displayed activities equal to those of the underivatized compound. These in vivo studies suggest that antiepileptic phenylhydantoins, when used in chronic therapy in man, could possibly act as hypolipidemic agents. Hypocholesterolemic
Hypertriglyceremic
Phenytoin
Mephenytoin
Ethotoin
1. Introduction
2. Materials and methods
Studies have indicated the in vivo hypolipidemic effects of a number of cyclic imides of varying chemical structures in rodents (Hall et al., 1983). 5,5-Diphenylhydantoin (phenytoin) and other 5-phenylhydantoins (table 1 and fig. 1) contain a cyclic imide functionality and are used in chronic therapeutic situations to control epilepsies. Recently phenytoin has been reported to increase cholesterol content of serum high-density lipoprotein ( H D L ) in man (Luoma et al., 198~2; Kaste et al., 1983). These observations prompted an investigation of the in vivo hypolipidemic activities of phenytoin, other 5-phenylhydantoin antiepileptics and metabolites. Derivatives similar to those which have previously been shown to be active in the cyclic imide series in mice, i.e. specifically N-substituted derivatives, have been included in this study.
2.1. Chemicals
* To whom all correspondence should be addressed. 0014-2999/85/$03.30 © 1985 Elsevier Science Publishers B.V.
Metabolites
5,5-Diphenylhydantoin (1) and its racemic metabolite, 2, were purchased from Aldrich Chemical Co. (Milwaukee, WI U.S.A.). 5-Phenylhydantoin (4) was available from a previous study (Dudley et al., 1970). 3-Ethyl-5-phenylhydantoin (ethotoin, Peganone ", _3) was extracted with ethyl acetate from crushed tablets and was recrystallized from ethyl acetate/hexane to give a product which was identical with an authentic sample (Dudley et al., 1970). Racemic 5-ethyl-5-phenylhydantoin (6) was prepared and enantiomers of this compound were obtained from resolution of the diastereomeric brucine salts as described by Sobotka et al. (1982). Racemic 5-ethyl-3-methyl-5-phenyihydantoin ~ ) was prepared from racemic (6) via the method of Swiss patent No. 166004 (1934). Racemic compounds _7, 8, _9 and 10 were prepared from the corresponding alkylphenylketones via the method of Henze and Isbell (1954). Racemic 3substituted-5-ethyl-5-phenylhydantoins (11-18) were prepared from racemic_5 via the general
136 ucts, e x t r a c t i o n w i t h d i e t h y l e t h e r a n d p u r i f i c a t i o n o n silica gel c o l u m n s w i t h an e t h y l a c e t a t e e l u e n t p r i o r to r e c r y s t a l l i z a t i o n . C o m p o u n d H
~
R
tained
17 w a s o b -
f r o m _5 b y t h e a d d i t i o n o f m e t h y l vinyl
k e t o n e in t h e p r e s e n c e o f a c a t a l y t i c a m o u n t by' s o d i u m e t h o x i d e . C o m p o u n d 18 w a s p r e p a r e d f r o m 16 Fig. 1. The chemical structure of the 5-phenylhydantoin derivatives described in table 1 and the text.
by oxidation
with potassium
permanganate.
T h e s t r u c t u r e s o f c o m p o u n d s _7-18 w e r e c o n f i r m e d b y N M R s p e c t r o s c o p y (60 M H z ) a n d p u r i t i e s w e r e a s c e r t a i n e d b y e l e m e n t a l a n a l y s e s (C, H, N), all o f w h i c h w e r e w i t h i n + 0.40% o f t h e o r y .
p r o c e d u r e o f D u d l e y et al. (1970) b y a l k y l a t i o n o f _5 w i t h t h e a p p r o p r i a t e alkyl h a l i d e in a n h y d r o u s d i m e t h y l f o r m a m i d e w i t h p o t a s s i u m c a r b o n a t e as base. C o m p o u n d s 11-18 after isolated after the addition
of water
to t h e r e a c t i o n m i x t u r e s , re-
covery of precipitated products and
subsequent
r e c r y s t a l l i z a t i o n , o r in t h e c a s e o f n o n - s o l i d p r o d -
2.2. Hypolipidemic ~kcreens C o m p o u n d s w e r e e v a l u a t e d in CF~ m a l e m i c e (-30 g) a c c o r d i n g to t h e m e t h o d o f Hall et al. (1983), w h e r e b y 20 m g / k g i.p. d o s e s w e r e g i v e n d a i l y in 1% c a r b o x y m e t h y l c e l l u l o s e for 16 d a y s .
TABLE 1 Hypolipidemic activities of substituted hydantoins in mice (n = 6) at 20 mg/kg per da5 i.p. Compound
Percent control (X -+ S.D.) C9 "
!(R=C6H s,R'=H) 2 (R = 4-OH-C6H 5, R ' - H) _3(R =H, R ' = C 2 H s ) 4(R = R'= H) 5 (R = C2H s, R'= CH~) 6 (R = C2H 5, R'= H) 6a (R)-(-)-6 6h (S)-(+)-6 7 (R = CH~, R'= H) 8 (R = 1-C~H,> R'= H) 9 (R = 2 - C 3 H 7, R'= H) 10(R=I-C4H, ~,R'=H) 11 (R = C 2 H 5 , R ' = C 2 H s ) 1 2 ( R = C 2 H 5,R'=I-C)HT) 1 3 ( R = C 2 H s,R'=I-C4H,~) 14 (R = C2H~, R'= 1-CsHll) 15 (R = C2H 5, R'= CH2C6H5) 16 (R = C2H 5, R'= CH2CH2CHzOH) 17(R =C2H 5,R'=CH2CH2COCH)) 18 (R = C:H 5, R'= CH2CH2COOH) Hydantoin Clofibrate (150 mg/kg per day) Control (1% carboxymethylcellulose)
75+5"d 70-+4 * 85+4" 100-+7 102-+7 89_+5 66_+6 * 72+7 * 84+6 79_+7 72-+3 81 -+5" 97-+6 84_+7 113-+6 74-+4 * 81 +6 * 61 -+5 * 101+6 81 _+6 * 79-+6 * 88 -+4 100 -+6
('l~, " 74--+4" 79+3 * 67±5" 90-+6 83-+7 74_+4 * 59+5 * 56_+6 * 79_+6 * 73-+5 * 73+_2 * 77+6" 67_+4 * 81 + 6 " 76+7" 64+4 " 75-+7 * 56+4 * 81_+5" 70-+ 5 * 67-+5 * 87 -+ 5 100 + 5
TGI6 • 84+6 80+ 5 * 60_+4" 88-+5 62-+6 * 57+3 * 54-+4 * 59-+3 * 60-+5 * 74-+4 * 64-+5 * 84+4" 62-+3 * 59+5" 74+5" 85 + 3 * 60-+5 * 56_+4 * 71 -+5" 68-+4 * 69_+5 * 75 + 5 * 100 -+6
" Cholesterol plasma levels expressed as percent of control at day 9, 128 mg/dl; b cholesterol plasma levels expressed as percent of control at day 16, 130 mg/dl; ': triglyceride plasma levels expressed as percent of control at day 16, 137 mg/dl: * P ~<0.001 Student's t-test: N = 6.
137 Control values were obtained by injecting vehicle only, 1% carboxymethylcelluiose, and were compared with those obtained by treatment with clofibrate as a standard at the therapeutic dose of 150 m g / k g per day. Blood samples were obtained from the mice on days 9 and 16 via tail vein bleeding. Serum cholesterol levels were determined by the method of Ness et al. (1964). Serum triglyceride levels were determined on day 16 using a commercial kit (Bio-Dynamics/bmc No. 348201 single vial triglycerides).
3. Results Hydantoin anticonvulsants phenytoin (1), ethotoin Q) and mephenytoin (_5), when administered to mice at 20 m g / k g per day for 16 days, demonstrated variable but significant reductions in both serum cholesterol and triglyceride levels as shown in table 1. The racemic phenolic metabolite of phenytoin, 5-(4-hydroxyphenyl)-5-phenylhydantoin (2), and racemic dealkylated metabolites of ethotoin (4_) and mephenytoin (6) were administered similarly, and compounds 2 and -6 demonstrated reduced serum cholesterol and triglyceride levels. Based upon the activity of racemic 5-ethyl5-phenylhydantoin (-6), enantiomers 6a and 6b were studied and found to have essentially the same hypotriglyceridemic activity as -6, but were more effective hypocholesterolemic agents than the racemic compound -6 (table 1). Racemic 5-alkyl-5-phenylhydantoins (_7-10) also displayed hypocholesterolemic and hypotriglyceridemic activities similar to those observed for racemic 5-ethyl-5-phenylhydantoin (_6). Of the N-3-alkylated derivatives of (_6), only compound 16 possessed activity equal to 6a or 6b, while the other compounds (11-15, 17, 18) generally had lower activities (table 1). Compounds 11, 12 and 15 afforded greater than 35% reduction of serum triglyceride levels. The parent compound, hydantoin, also displayed good activities, suggesting that the unsubstituted hydantoin ring system is responsible for a portion of the observed activity. A number of the hydantoin derivatives demonstrated more potent hypolipidemic activity at 20
m g / k g per day than clofibrate at 150 m g / k g per day in mice after 16 days dosing. 4. Discussion Hypocholesterolic and hypotriglyceridemic activities of hydantoin antiepileptics phenytoin (!% ethotoin (_3) and mephenytoin (_5) were observed in an in vivo screening test. Similarly, racemic metabolites of antiepileptics 1 and _5, of which 6 is an active metabolite, also demonstrated such activity. Racemic 5-ethyl-5-phenylhydantoin (6) and its enantiomers were selected for further studies based upon their activities (table 1). Those studies confirm similar activity in rats in lowering serum lipids as well as increasing HDL cholesterol (unpublished data). These data would suggest that the antiepileptic agents and some of their metabolites (!-_6) might demonstrate hypolipidemic activity similar to the standard agent clofibrate. Luoma et al. (1982) first demonstrated increases in HDL cholesterol in phenytoin-treated patients, and indicated a positive correlation between phenytoin plasma levels and HDL cholesterol levels in females, with suggestions that similar trends might be occurring in males. Kaste et al. (1983) have similarly reported increases in HDL cholesterol content in patients after 21 months on a dose of the drug that achieved average plasma levels of 5 /~g/ml. Both studies suggest that the observed effects of phenytoin therapy are consistent with reduced risk of coronary heart disease, a possible beneficial effect of phenytoin therapy. The present animal study indicates that hydantoin derivatives possess significant hypolipidemic activity lowering both serum cholesterol and triglyceride levels. For this reason, further studies would seem warranted as to the mechanism of action of hydantoin derivatives in the rodent models, and to their possible hypolipidemic effects when used in chronic antiepileptic therapy in man. Acknowledgements Research was supported by Grant HL25680,National Heart, Lung and Blood Institute. We thank Dr. Kenneth H. Dudley for a gift of 5-phenylhydantoin and Patricia Day for her technical assistance.
138
References Dudley, K.H., D.L. Bius and T.C. Butler. 1970, Metabolic Fates of 3-ethyl-5-phenylhydantoin (Ethotoin, Peganone), 3-methyl-5-phenylhydantoin and 5-phenylhydantoin, J. Pharmacol. Exp. Ther. 175, 27. Hall, I.H.. P.J. Voorstad, J.M. C h a p m a n and G.H. Cocolas, 1983. Antihyperlipidemic activity of phthalimide analogues in rodents, J. Pharm. Sci. 72. 845. Henze. H,R. and A.F. Isbell, 1954, Research on substituted 5-phenylhydantoins, J. Am. Chem. Soc. 76, 4152. Kaste, M., A. Muuronen, E.A. Nikkila and P.J. Neuvonen, 1983, Increase of low serum concentrations of high-density
lipoprotein (HDL) cholesterol in TIA-patients treated with phenytoin, Stroke 14, 525. Luoma, P.V., V.V. Myllyl~ and E. Hokkanen, 1982, Relationship between plasma high-density lipoprotein cholesterol and anticonvulsant levels in epileptics, J. Cardiovasc. Pharmacol. 4, 1024. Ness, A.T., J.V. Pastewka and A.C. Peacock, 1964, Evaluation of a recently reported stable Liebermann-Burchard reagent and its use for the direct determination of serum total cholesterol, Clin. Chim. Acta 10, 229. Sobotka, H., M.F. Holzman and J. Kahn, 1932, Optically active 5,5'-disubstituted hydantoins, J. Am. Chem. Soc. 54, 4697.
135
Elsevier Short communication H Y P O L I P I D E M I C ACTIVITY OF A N T I E P I L E P T I C 5 - P H E N Y L H Y D A N T O I N S IN M I C E JAMES H. MAGUIRE *, AKULA R. MURTHY and IRIS H. HALL Division of Medicinal Chemistry and Natural Products, School of Pharma~T, Universi(v of North Carolina. Chapel Hill, N C 27514. U.S.A.
Received 29 August 1985, accepted 3 September 1985
J.H. MAGUIRE, A.R. MURTHY and I.H. HALL, Hypolipidemic activity of antiepileptic 5-phenvlhydantoins in mice, European J. Pharmacol. 117 (1985) 135-138. Administration (20 mg/kg i.p.) of antiepileptic 5-phenylhydantoins phenytoin, ethotoin, mephenytoin, and selected metabolites to mice over a period of 16 days produced lower serum concentrations of cholesterol and triglycerides with most of the compounds studied. Several compounds were more effective hypolipidemic agents than clofibrate at 150 mg/kg per day. Several N-alkylated derivatives of the most active compound, 5-ethyl-5-phenylhydantoin, a metabolite of mephenytoin, displayed activities equal to those of the underivatized compound. These in vivo studies suggest that antiepileptic phenylhydantoins, when used in chronic therapy in man, could possibly act as hypolipidemic agents. Hypocholesterolemic
Hypertriglyceremic
Phenytoin
Mephenytoin
Ethotoin
1. Introduction
2. Materials and methods
Studies have indicated the in vivo hypolipidemic effects of a number of cyclic imides of varying chemical structures in rodents (Hall et al., 1983). 5,5-Diphenylhydantoin (phenytoin) and other 5-phenylhydantoins (table 1 and fig. 1) contain a cyclic imide functionality and are used in chronic therapeutic situations to control epilepsies. Recently phenytoin has been reported to increase cholesterol content of serum high-density lipoprotein ( H D L ) in man (Luoma et al., 198~2; Kaste et al., 1983). These observations prompted an investigation of the in vivo hypolipidemic activities of phenytoin, other 5-phenylhydantoin antiepileptics and metabolites. Derivatives similar to those which have previously been shown to be active in the cyclic imide series in mice, i.e. specifically N-substituted derivatives, have been included in this study.
2.1. Chemicals
* To whom all correspondence should be addressed. 0014-2999/85/$03.30 © 1985 Elsevier Science Publishers B.V.
Metabolites
5,5-Diphenylhydantoin (1) and its racemic metabolite, 2, were purchased from Aldrich Chemical Co. (Milwaukee, WI U.S.A.). 5-Phenylhydantoin (4) was available from a previous study (Dudley et al., 1970). 3-Ethyl-5-phenylhydantoin (ethotoin, Peganone ", _3) was extracted with ethyl acetate from crushed tablets and was recrystallized from ethyl acetate/hexane to give a product which was identical with an authentic sample (Dudley et al., 1970). Racemic 5-ethyl-5-phenylhydantoin (6) was prepared and enantiomers of this compound were obtained from resolution of the diastereomeric brucine salts as described by Sobotka et al. (1982). Racemic 5-ethyl-3-methyl-5-phenyihydantoin ~ ) was prepared from racemic (6) via the method of Swiss patent No. 166004 (1934). Racemic compounds _7, 8, _9 and 10 were prepared from the corresponding alkylphenylketones via the method of Henze and Isbell (1954). Racemic 3substituted-5-ethyl-5-phenylhydantoins (11-18) were prepared from racemic_5 via the general
136 ucts, e x t r a c t i o n w i t h d i e t h y l e t h e r a n d p u r i f i c a t i o n o n silica gel c o l u m n s w i t h an e t h y l a c e t a t e e l u e n t p r i o r to r e c r y s t a l l i z a t i o n . C o m p o u n d H
~
R
tained
17 w a s o b -
f r o m _5 b y t h e a d d i t i o n o f m e t h y l vinyl
k e t o n e in t h e p r e s e n c e o f a c a t a l y t i c a m o u n t by' s o d i u m e t h o x i d e . C o m p o u n d 18 w a s p r e p a r e d f r o m 16 Fig. 1. The chemical structure of the 5-phenylhydantoin derivatives described in table 1 and the text.
by oxidation
with potassium
permanganate.
T h e s t r u c t u r e s o f c o m p o u n d s _7-18 w e r e c o n f i r m e d b y N M R s p e c t r o s c o p y (60 M H z ) a n d p u r i t i e s w e r e a s c e r t a i n e d b y e l e m e n t a l a n a l y s e s (C, H, N), all o f w h i c h w e r e w i t h i n + 0.40% o f t h e o r y .
p r o c e d u r e o f D u d l e y et al. (1970) b y a l k y l a t i o n o f _5 w i t h t h e a p p r o p r i a t e alkyl h a l i d e in a n h y d r o u s d i m e t h y l f o r m a m i d e w i t h p o t a s s i u m c a r b o n a t e as base. C o m p o u n d s 11-18 after isolated after the addition
of water
to t h e r e a c t i o n m i x t u r e s , re-
covery of precipitated products and
subsequent
r e c r y s t a l l i z a t i o n , o r in t h e c a s e o f n o n - s o l i d p r o d -
2.2. Hypolipidemic ~kcreens C o m p o u n d s w e r e e v a l u a t e d in CF~ m a l e m i c e (-30 g) a c c o r d i n g to t h e m e t h o d o f Hall et al. (1983), w h e r e b y 20 m g / k g i.p. d o s e s w e r e g i v e n d a i l y in 1% c a r b o x y m e t h y l c e l l u l o s e for 16 d a y s .
TABLE 1 Hypolipidemic activities of substituted hydantoins in mice (n = 6) at 20 mg/kg per da5 i.p. Compound
Percent control (X -+ S.D.) C9 "
!(R=C6H s,R'=H) 2 (R = 4-OH-C6H 5, R ' - H) _3(R =H, R ' = C 2 H s ) 4(R = R'= H) 5 (R = C2H s, R'= CH~) 6 (R = C2H 5, R'= H) 6a (R)-(-)-6 6h (S)-(+)-6 7 (R = CH~, R'= H) 8 (R = 1-C~H,> R'= H) 9 (R = 2 - C 3 H 7, R'= H) 10(R=I-C4H, ~,R'=H) 11 (R = C 2 H 5 , R ' = C 2 H s ) 1 2 ( R = C 2 H 5,R'=I-C)HT) 1 3 ( R = C 2 H s,R'=I-C4H,~) 14 (R = C2H~, R'= 1-CsHll) 15 (R = C2H 5, R'= CH2C6H5) 16 (R = C2H 5, R'= CH2CH2CHzOH) 17(R =C2H 5,R'=CH2CH2COCH)) 18 (R = C:H 5, R'= CH2CH2COOH) Hydantoin Clofibrate (150 mg/kg per day) Control (1% carboxymethylcellulose)
75+5"d 70-+4 * 85+4" 100-+7 102-+7 89_+5 66_+6 * 72+7 * 84+6 79_+7 72-+3 81 -+5" 97-+6 84_+7 113-+6 74-+4 * 81 +6 * 61 -+5 * 101+6 81 _+6 * 79-+6 * 88 -+4 100 -+6
('l~, " 74--+4" 79+3 * 67±5" 90-+6 83-+7 74_+4 * 59+5 * 56_+6 * 79_+6 * 73-+5 * 73+_2 * 77+6" 67_+4 * 81 + 6 " 76+7" 64+4 " 75-+7 * 56+4 * 81_+5" 70-+ 5 * 67-+5 * 87 -+ 5 100 + 5
TGI6 • 84+6 80+ 5 * 60_+4" 88-+5 62-+6 * 57+3 * 54-+4 * 59-+3 * 60-+5 * 74-+4 * 64-+5 * 84+4" 62-+3 * 59+5" 74+5" 85 + 3 * 60-+5 * 56_+4 * 71 -+5" 68-+4 * 69_+5 * 75 + 5 * 100 -+6
" Cholesterol plasma levels expressed as percent of control at day 9, 128 mg/dl; b cholesterol plasma levels expressed as percent of control at day 16, 130 mg/dl; ': triglyceride plasma levels expressed as percent of control at day 16, 137 mg/dl: * P ~<0.001 Student's t-test: N = 6.
137 Control values were obtained by injecting vehicle only, 1% carboxymethylcelluiose, and were compared with those obtained by treatment with clofibrate as a standard at the therapeutic dose of 150 m g / k g per day. Blood samples were obtained from the mice on days 9 and 16 via tail vein bleeding. Serum cholesterol levels were determined by the method of Ness et al. (1964). Serum triglyceride levels were determined on day 16 using a commercial kit (Bio-Dynamics/bmc No. 348201 single vial triglycerides).
3. Results Hydantoin anticonvulsants phenytoin (1), ethotoin Q) and mephenytoin (_5), when administered to mice at 20 m g / k g per day for 16 days, demonstrated variable but significant reductions in both serum cholesterol and triglyceride levels as shown in table 1. The racemic phenolic metabolite of phenytoin, 5-(4-hydroxyphenyl)-5-phenylhydantoin (2), and racemic dealkylated metabolites of ethotoin (4_) and mephenytoin (6) were administered similarly, and compounds 2 and -6 demonstrated reduced serum cholesterol and triglyceride levels. Based upon the activity of racemic 5-ethyl5-phenylhydantoin (-6), enantiomers 6a and 6b were studied and found to have essentially the same hypotriglyceridemic activity as -6, but were more effective hypocholesterolemic agents than the racemic compound -6 (table 1). Racemic 5-alkyl-5-phenylhydantoins (_7-10) also displayed hypocholesterolemic and hypotriglyceridemic activities similar to those observed for racemic 5-ethyl-5-phenylhydantoin (_6). Of the N-3-alkylated derivatives of (_6), only compound 16 possessed activity equal to 6a or 6b, while the other compounds (11-15, 17, 18) generally had lower activities (table 1). Compounds 11, 12 and 15 afforded greater than 35% reduction of serum triglyceride levels. The parent compound, hydantoin, also displayed good activities, suggesting that the unsubstituted hydantoin ring system is responsible for a portion of the observed activity. A number of the hydantoin derivatives demonstrated more potent hypolipidemic activity at 20
m g / k g per day than clofibrate at 150 m g / k g per day in mice after 16 days dosing. 4. Discussion Hypocholesterolic and hypotriglyceridemic activities of hydantoin antiepileptics phenytoin (!% ethotoin (_3) and mephenytoin (_5) were observed in an in vivo screening test. Similarly, racemic metabolites of antiepileptics 1 and _5, of which 6 is an active metabolite, also demonstrated such activity. Racemic 5-ethyl-5-phenylhydantoin (6) and its enantiomers were selected for further studies based upon their activities (table 1). Those studies confirm similar activity in rats in lowering serum lipids as well as increasing HDL cholesterol (unpublished data). These data would suggest that the antiepileptic agents and some of their metabolites (!-_6) might demonstrate hypolipidemic activity similar to the standard agent clofibrate. Luoma et al. (1982) first demonstrated increases in HDL cholesterol in phenytoin-treated patients, and indicated a positive correlation between phenytoin plasma levels and HDL cholesterol levels in females, with suggestions that similar trends might be occurring in males. Kaste et al. (1983) have similarly reported increases in HDL cholesterol content in patients after 21 months on a dose of the drug that achieved average plasma levels of 5 /~g/ml. Both studies suggest that the observed effects of phenytoin therapy are consistent with reduced risk of coronary heart disease, a possible beneficial effect of phenytoin therapy. The present animal study indicates that hydantoin derivatives possess significant hypolipidemic activity lowering both serum cholesterol and triglyceride levels. For this reason, further studies would seem warranted as to the mechanism of action of hydantoin derivatives in the rodent models, and to their possible hypolipidemic effects when used in chronic antiepileptic therapy in man. Acknowledgements Research was supported by Grant HL25680,National Heart, Lung and Blood Institute. We thank Dr. Kenneth H. Dudley for a gift of 5-phenylhydantoin and Patricia Day for her technical assistance.
138
References Dudley, K.H., D.L. Bius and T.C. Butler. 1970, Metabolic Fates of 3-ethyl-5-phenylhydantoin (Ethotoin, Peganone), 3-methyl-5-phenylhydantoin and 5-phenylhydantoin, J. Pharmacol. Exp. Ther. 175, 27. Hall, I.H.. P.J. Voorstad, J.M. C h a p m a n and G.H. Cocolas, 1983. Antihyperlipidemic activity of phthalimide analogues in rodents, J. Pharm. Sci. 72. 845. Henze. H,R. and A.F. Isbell, 1954, Research on substituted 5-phenylhydantoins, J. Am. Chem. Soc. 76, 4152. Kaste, M., A. Muuronen, E.A. Nikkila and P.J. Neuvonen, 1983, Increase of low serum concentrations of high-density
lipoprotein (HDL) cholesterol in TIA-patients treated with phenytoin, Stroke 14, 525. Luoma, P.V., V.V. Myllyl~ and E. Hokkanen, 1982, Relationship between plasma high-density lipoprotein cholesterol and anticonvulsant levels in epileptics, J. Cardiovasc. Pharmacol. 4, 1024. Ness, A.T., J.V. Pastewka and A.C. Peacock, 1964, Evaluation of a recently reported stable Liebermann-Burchard reagent and its use for the direct determination of serum total cholesterol, Clin. Chim. Acta 10, 229. Sobotka, H., M.F. Holzman and J. Kahn, 1932, Optically active 5,5'-disubstituted hydantoins, J. Am. Chem. Soc. 54, 4697.