Physiologic and Metabolic Aspects of Anticonvulsants

Clinical Pharmacology

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'Physiologic and Metabolic Aspects of Anticonvulsants Ichiro Matsuda, MD, PhD, * Akimasa Higashi, MD, PhD, t and Nobuo Inotsume, PhDt.

Epilepsy is a clinically complex phenomenon with various underlying causes. On the basis of different clinical features and types of electroencephalograms, epilepsy has been classified into forms of generalized and partial seizures. 17 A great number of anticonvulsants are available for treating these different types of epilepsy. Therapeutic drug monitoring recently was favored as the method for controlling drug concentrations in the plasma and preventing untoward effects. When these anticonvulsants are prescribed to treat epilepsy in children, careful monitoring is most important because drug metabolism varies depending on maturation and development of body functions. 49 Molecular approaches are also important to elucidate the effectiveness of the drugs for treatment of different seizure disorders and should contribute to a better understanding of body functions.

MOLECULAR ASPECTS OF ANTICONVULSANTS Anticonvulsants can be divided into two categories, as based on mechanisms of action: relatively specific antiepileptic drugs, and relatively nonspecific antiepileptic ones. 13 The first category includes phenytoin, carbamazepine, and valproate, which act by modifying ion conductance in excitable membranes. Sodium and calcium, in particular, have been the focus of attention. The second category includes barbiturates and benzodiazepines, both of which have a general depressing effect on the central nervous system through 'Y-aminobutyric acid (GABA) mediation of CIFrom the Kumamoto University Medical School and Kumamoto University Hospital, Kumamoto, Japan

*Professor of Pediatrics t Associate Professor of Pediatrics :j:Instructor of Pharmaceutical Services

Pediatric Clinics of North America-Vol. 36, No.5, October 1989

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leHIRo MATSUDA ET AL.

channel opening. 13 The following discussion will focus on the calcium channel and the GABA receptor. Calcium Channels and Anticonvulsants The influx of Ca2 + into neurons in response to depolarization is thought to be an important feature of epileptogenesis5 and inhibition of the Ca2 + flux may contribute to the therapeutic action of some anticonvulsants. 46 Ca2 + channels in neural cells play an important role in providing a route for entry of Ca2 + into nerve terminals, to effect neurotransmitter release. There are at least two different types of Ca2 + channels operating intra- and extracellular Ca2 +; voltage-dependent channels and receptor-operated ones. The first channels are opened by membrane depolarization, and the second channels are activated by occupation of neurotransmitter or intercellular second messengers. In some cases both mechanisms are operative. 16 The Ca2 + channels are not homologous; rather, multiple subtypes have been identified in neurons, skeletal and smooth muscles, and other tissues. 16 A differentiation of these subtypes depends on the differences in membrane potential with which the channels are activated, in the tendency to inactivation, and in pharmacologic sensitivity. Although the biochemical basis for the stimulation of neurotransmitter release by intracellular Ca2 + requires further study, phosphorylation of the voltage dependent Ca2 + channel protein through calmodulin-dependent protein kinase seems to be a putative mechanism. 9 Phenytoin in therapeutic concentrations inhibits Ca2 + -calmodulin-dependent protein phosphorylation, in a variety of neuronal and synaptic fractions. 9 Thus, ingestion of phenytoin may cause Ca2 + channel dephosphorylation and thereby inactivation, particularly during intense neuronal activity.70 In addition, phenytoin may possibly interfere with the membrane Ca2 + channel receptor site. 70 The dephosphorylation of cytoskeletal protein and actin also is induced by phenytoin, a condition that may relate to morphologic abnormalities in the somatosensory cortex60 and possibly in others. Other Ca2 + -regulated processes, including release of insulin from islet cells and release of oxytocin and vasopressin from the pituitary gland, are known to be antagonized by phenytoin. 9 A similar action to phenytoin concerning the dephosphorylation of Ca2 + -calmodulin synaptic protein and the impaired release of neurotransmitter from synaptic vesicles is observed with carbamazepine and diazepam, but not with barbiturates, ethosuximide, trimethadione, and valproate. 9 The calcium channel antagonist flunarizine was evaluated in epileptic patients who were poorly controlled with standard drugs. Some of these patients seemed to respond. 56 GABA and Anticonvulsants GABA is a major inhibitory neurotransmitter in the mammalian brain, the dysfunction of which has been implicated in the pathophysiology of seizure disorders.18 The most common mechanism for the postsynaptic inhibitory action of GABA is neuronal hyperpolarization, through activation of the membrane CI- channel. 55 The GABA receptor and the CI- channel reside in one protein complex (GABA receptor-ionophore complex) of the

PHYSIOLOGIC AND METABOLic ASPECTS OF ANTICONVULSANTS

1101

postsynaptic membrane, which also possesses modulatory receptor sites, one being for benzodiazepines and the other being for barbiturates and related depressants and convulsants such as picrotoxin, the convulsant GABA antagonist. The close relationship of the three receptor complexes for GABA, barbiturates, and benzodiazepines has been demonstrated by solubilization in mild detergent of a single molecular species, and the retention of the CI- -dependent interactions at the three sites. 55 The complex consists of four subunits (l2132' a molecular weight (l and 13 subunit being 53,000 and 57,000, respectively. 61 Benzodiazepines as well as barbiturates act to potentiate GABA functions; these are an increase in the CIinflux and subsequent membrane stabilization. 55 Barbiturates enhance the binding of agonist ligands to both GABA and benzodiazepine receptor sites and inhibit the binding of antagonists tb the same sites. 55 Phenytoin may interact with the benzodiazepine receptor site in the GABA receptor-ionophore complex, through which it increases the opening time of CI- channel, thereby prolonging the inhibitory postsynaptic current. 70 Valproate was reported to inhibit dihydropicrotoxin (an analogue of picrotoxin) binding. 55 Another action of valproate is to inhibit GABA transaminase and succinic semialdehyde dehydrogenase, thereby raising the content of GABA in brain tissue. 31

PHARMACOKiNETIC CONSIDERATIONS IN CLINICAL USE OF ANTICONVULSANTS It has been demonstrated clearly that a ratio of plasma drug concentration to a given daily dosage (C/D) of anticonvulsants varies widely iIi each individual, depending on the different drug dispositions, even though the patient takes the drug as prescribed by the physician. 10, 49 Factors to be considered include pharmacogenetics, age"related metabolism, intercurrent disease states, and multiple-drug therapy. Thus, the C/D ratio in children is highly unpredictable and changing compared to such events in adult patients. Therefore, drug monitoring has to be done to maintain plasma concentrations of the drug within the therapeutic range and to avoid levels leading to toxicity. 49

Developmental Aspect of Anticonvulsants Disposition Age-related alterations in the plasma protein-binding affinity of the drug, the content of body water, and development of hepatic biotransformation all relate to the effects of the drug. In the systemic circulation, an equilibrium between free (or unbound to plasma protein) and bouIid drug will be established. Only the free drug can cross the biologic membrane and react with specific receptor for a pharmacologic response. As listed in Table 1, each antiepileptic drug has its own characteristics of proteinbinding affinity ranging from 0 to 95 pet cent. Physical characteristics of plasma protein also are associated with protein binding affinity. Taburet et al. reported that the range of protein binding of phenobarbital was 10 to

..... .....

= t-:)

Table 1. Pharmacokinetics of Antiepileptic Drugs

Bioavailable fraction (F) Time to peak concentration (Tm~; hr) Volume of distribution (Vd; 11kg) Neonates Adults Half-life (T'I2; hr) Neonates Infants Children Adults Protein bound percentage in plasma Neonates Adults and Children Minimum effective concentration (J.Lg/ml) Toxic concentration (J.Lg/ml) Active metabolite Renal excretion (%)

PB

PMD

PHT

0.9-1.0 1-3

0.9-1.0 1-3

0.85-0.95 4-7

0.9-1.0 0.6-0.75

0.65

0.73-1.2 0.6

67-99 40-70 40-70 50-120

10-12 10-12

10-30 50-55 10

<20 6

15-105* 2-7* 12-22* 18-30*

74-90 90 5

30-40 None

12 Phenobarbital, PEMA

20 None

20-40

40

<5

CBZ

VPA

ESM

DZP

CZP

NZP

0.85-0.9 3(1-5)

1.0 1-3

3-7

1-2

1-2

0.5-5

1.1-2.6 0.8-1.8

0.2-0.4 0.2-0.4

0.6

1.8-2.1 1.6-3.2

2-6

1.5-3

8-27 2.5-15

40-400 10-12

15-25

6-15 8-15

30-50 40-60

20-30

19-60

24-40

75(50-90) 4

90-95 40-50

0 40

96

>0.5

82 0.02

95 0.04

0.07 Yes

0.18 Yes

2

<1

8-12 Carbamazepine 10,11epoxide <1

100 Several (minor activity) <5

100 None

10-20

Ndes methyl DZP 2

Key: PB, phenobarbital; PMD, primidone; PHT, phenytoin; CBZ, carbamazepine; VPA, valproate; ESM, ethosuximide; DZP, diazepam; CZP, clonazepam; NZP, nitrazepam; PEMA, phenylethylmalondiamide. *Exhibits saturation kinetics.

PHYSIOLOGIC AND METABOLIC ASPECTS OF ANTICONVULSANTS

1103

30 per cent in neonates, compared with 45 to 50 per cent in adults. 69 A similarly diminished protein-binding proportion in neonates was noted with other antiepileptic agents, including phenytoin. 12 This is attributable not only to lower plasma protein concentrations in the neonate but also to some as yet undefined differences between fetal and adult albumin or to a competition for drug binding sites by bilirubin and fatty acids. 64 The lack of binding capacity results in elevation of free drug concentrations in the circulation, a condition that would lead to toxic syndrome in some patients. In addition, other drugs taken simultaneously can interfere with protein binding by displacing antiepileptics from protein-binding sites, as discussed later. Thus, if there is a nontherapeutic response or clinical toxicity but the total concentration of antiepileptics is within the therapeutic range, one must consider the possibility of altered protein binding. Generally speaking, the protein binding status can be assumed indirectly by measuring salivary drug concentration. However, this is only the case when the drug has an ionization constant (pKa) that is significantly different from plasma or salivary pH, as is the case with phenytoin (pKa = 9.2); otherwise the salivary drug concentration will not be a good indicator of free drug levels, such as that seen with phenobarbital (pKa = 7.2). In the latter case, correction for individual differences in salivary pH is required. 45 Because direct urinary excretion of the drug in an unchanged form is limited in case of most anti epileptics (see Table 1), elimination of the drug is associated mainly with the activity of drug-metabolizing enzyme systems in hepatic microsomes (biotransformation). Through biotransformation, the drugs are conjugated with glucuronic acid or sulfate, lead to formation of water-soluble metabolites, and are readily excreted into the urine. For example, parahydroxyphenytoin, which is a major metabolite of phenytoin and the conjugate with glucuronic acid, increases its water solubility almost 100-fold. 58 The activity of hepatic biotransformation is immature in neonates and 'the maximal activity occurs from age 1 to 10 years. Subsequently the activity declines gradually as the child progresses through puberty. Drug disposition in adolescents after puberty is generally similar to that in adults. 49,64 The developmental pattern of hepatic drug-metabolizing enzyme is responsible for the biologic half-life of phenobarbital in the circulation; that is, 67 to 99 h in neonates, 40 to 70 h in infants and children, and 50 to 120 h in adults. 64 In the case of phenytoin, the term half-life does not seem appropriate because the drug is metabolized by zero-order kinetics, which means that above a certain drug level, biotransformation of the drug becomes independent of its concentration. Thus, a very small increment in dose may result in a clinically significant elevation of plasma drug levels. Under the saturation point of the biotransformation, however, the drug will be metabolized in a similar manner of first-order kinetics. After biotransformation, metabolites of drugs such as biotransformed primidone, carbamazepine, and diazepam retain the pharmacologic activity (see Table 1). The size of body compartments, including total body water content, fat tissue, and muscle mass, are other factors affecting drug disposition. The mean of apparent distribution volume of anticonvulsants is larger in infants and young children than in adults. 48 For example, a distribution

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ICHIRO MATSUDA ET AL.

volume of phenytoin is expanded roughly one and a half times in infants. Accordingly, by a simple calculation, at least an initial dosage with 50 per cent increment (per kg of body weight) is required to reach the identical plasma drug level in infants. The summary of pharmacokinetic parameters of standard antiepileptics shown in Table 1 has proven useful for treatment of epileptic patients. Clinical Factors and Drug Disposition

Drug Interactions. Since drug metabolizing enzyme systems in the hepatic microsomes are not designed to recognize specific drugs, they act on compounds in a similar structure. When certain drugs are prescribed concomitantly, they are hydroxylized by the same enzyme system and there will be clinically significant interactions, as competition for metabolizing sites on the enzyme system. Phenytoin has a low affinity for microsome enzymes; thus, when one ingests an additional drug with a greater affinity for the microsomal enzyme than phenytoin, the plasma phenytoin concentration will elevate. Such drug interactions, in addition to unknown mechanisms, will be responsible for elevation of plasma levels of phenytoin, phenobarbital, and carbamazepine, when simultaneously administered with isoniazid, cimetidine, chloramphenicol, and erythromycin. 36. 49, 57 Another potential mechanism of drug interaction is induction of the drug-metabolizing enzyme system in hepatic microsomes and alteration of protein-binding affinity when the drugs are ingested concomitantly. Phenobarbital and carbamazepine elevate the activity of the hepatic microsomal P 450 drug-metabolizing enzyme system, through which plasma levels of phenytoin, valproate, and carbamazepine (given with phenobarbital) are lowered in case of simultaneous administration. 64 Most recently, reductions of plasma phenytoin levels were noted in a leukemic child treated with anticancer drugs, including vincristine, 6-mercaptopurine, methotrexate, and prednisolone, any of which is thought to be a potential inducer of hepatic microsomal enzyme. 29 Valproate is known to interfere with protein binding by displacing phenytoin from its plasma proteinbinding sites, resulting in elevation of free phenytoin levels and the acceleration of its pharmacodynamic reaction. 36 Similarly, salicylate administration also is associated with elevation of plasma free levels of phenytoin and valproate. 36 The reported interactions of anticonvulsants are summarized in Table 2. It must be kept in mind that both the additional administration of drugs that elevate the plasma level of the originally prescribed anticonvulsant and the discontinuation of drugs that lower the anticonvulsant level are potentially toxic in some clinical cases. Disease State and Anticonvulsants Generally speaking, plasma protein-binding affinity is significantly diminished in patients with renal and hepatic disorders. 58 Phenytoin and valproate have a higher affinity to the protein-binding site in the range of 90 to 95 per cent (see Table 1). Thus, attention should be given not to the total but rather to the free phenytoin or valproate level in patients with renal or hepatic disease. 58 In addition, as drug-metabolizing enzyme in the

Table 2. Effect of Concurrent Drugs on Serum Concentrations of Antiepileptic Drugs CONCURRENT DRUGS

AED

PB

PMD

PHT

PB

t

PMD

~

PHT

~

CBZ

~

~

~

VPA

~

~

~

CBZ

VPA

~

t t

~

U

ESM

Salicylate

U ~

~

Isoniazid (INH)

t t t

Cimetidine

Chloramphenicol

t

t

t t

t

Erythromycin

t

U

~

ESM

t : Serum concentrations are t : Serum concentrations are

elevated because of enzyme inhibition. reduced because of enzyme induction. U: Unbound concentrations may be higher; a reduction in daily dose ingested may be required. Key: AED, antiepileptic drug; PB, phenobarbital; PMD, primidone; PHT, phenytoin; CBZ, carbamazepine; VPA, valproate; ESM, ethosuximide .

.... .... o

(Jl

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ICHIRo MATSUDA ET AL.

liver is impaired in chronic hepatic disorders, this must be taken into account when prescribing antiepileptics. 59 The rate of elimination of phenytoin is approximately twice as high in the febrile disease, whereas the metabolism of phenobarbital remains intact. 37

MODIFICATION OF BODY FUNCTION AND METABOLISM BY ANTICONVULSANTS Elevated blood concentrations of standard anticonvulsants above the therapeutic range may induce adverse effects in epileptic children, including nystagmus, lethargy, ataxia, and sometimes an increase in seizure frequency.32 Other untoward effects found in patients on anticonvulsants for an extended time and whose drug concentrations have been controlled in the therapeutic range are disturbed bone metabolism,7. 34, 39, 53 liver dysfunction sometimes associated with Reye-like syndrome,4, 6, 30 immunomodification,2, 3, 65 nutritional deficiency (including vitamin D,19, 33, 35, 38 vitamin K,8 and vitamin E 24 ), teratogeneity,26 and others. Disturbed Bone Metabolism Epileptic children on prolonged anticonvulsant medication (mostly phenobarbital and phenytoin) often develop rickets and osteomalasia. Factors involved appear to be total dose of the drugs ingested during therapy, and in addition, sunlight exposure, physical activity, and probably individual susceptibility to the drugs. 7, 19, 34, 39, 53 Common laboratory findings are hypocalcemia, hypophosphatemia, hypocalciuria, as well as elevated serum alkaline phosphatase and immunoreactive parathyroid hormone levels. All of these observations can be explained by vitamin D deficiency, as is evidenced by decreased serum 25-hydroxyvitamin D (25-0H D) levels in these patients. 19, 33, 35, 38 Decreased serum calcitonin leveP5 and metabolic acidosis are observed occasionally42, 50 and may be factors related to bone demineralization. There is an unusual response of renal absorption of phosphorus for exogenous parathyroid hormone noticed in some epileptic children on anticonvulsants, thereby representing a feature of pseudohypoparathyroidism type n. l l , 43 Clinical and experimental studies have shown that anticonvulsant therapy is associated with induction of hepatic microsomal mixed function of oxidase enzyme system, a condition through which biologically active vitamin D appears to be rapidly catabolized. 19 One surprising finding was normal or even elevated levels of 1,25 dihydroxyvitamin D (1,25 [OH]2 D) (the most biologically active form of vitamin D), instead of a decrease in precursor 25-0H D leve1. 33 This may be related to renal stimulation of the synthesis of this more active form by hyperparathyroidism or by the anticonvulsant itself. 38 This observation in the patient may support the idea that 25-0H D itself may play an important role in bone formation. Reversal of all biochemical and radiologic abnormalities can be achieved with oral administration of either a supraphysiologic dose of vitamin D at 25 f,Lg per

PHYSIOLOGIC AND METABOLIC ASPECTS OF ANTICONVULSANTS

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day (10,000 IV per day),7 calcidiol (25-0H D) at 10 to 45 ILg per day,66 or calcitriol (1,25[OH]2D) at 0.25 to 0.751Lg per day.27 Liver Dysfunction and Reye-like Syndrome Hepatic disorders in patients on anticonvulsants include elevated levels of hepatic enzymes, reversible hyperammonemia, toxic hepatitis, and Reyelike syndrome. The latter three are associated with the drug valproate. The incidence of these abnormalities is higher in polytherapy than monotherapy of valproate6, 30 and possibly in patients with malnutrition. 44 Several factors are involved in the development of valproate-induced hepatic injury; carnitine deficiency seems to be a major factor, This idea was based on findings that patients on valproate plus phenytoin and phenobarbital have significantly higher blood ammonium levels and significantly lower free carnitine levels than patients on phenytoin and phenobarbital only. After carnitine supplementation, the carnitine levels reverted to normal and the ammonium levels fell. 54 Additional clinical observations and animal experiments support this idea,4, 68 Secondary carnitine deficiency is potentially induced by increased conversion of free carnitine to acylcarnitine (consumption of free carnitine), and increased urinary excretion of acylcarnitine associated with decreased reabsorption of free carnitine in the tubulus. 44 Millington et al. identified valproylcarnitine in patients ingesting valproate, although this does not seem to be prominent acylcarnitine excreted. 47 Carnitine acts as a vehicle to transport long-chain fatty acids into the mitochondria for energy production and to eliminate short-chain acyl moieties from the mitochondria after conversion to acylcarnitine from acyl COA.67 Since short-chain acyl CoA acts as a toxic substance in the mitochondria, the conversion of acylmoieties to carnitine form seems to be necessary for a recovery of free CoA level in the mitochondria for maintaining its function normally,67 In addition, there is a direct toxic effect of valproate for oxidative phosphorylation. 21 It is well known that carnitine deficiency associated with mitochondrial dysfunction induces metabolic acidosis, hypoglycemia, disturbed ureagenesis, and impaired fatty acid metabolism. 67 Thus, secondary carnitine deficiency and postulated mitochondrial dysfunction could result in hyperammonemia as a moderate effect or Reye-like syndrome as a severe effect in the patients taking valproate, either as separate or interrelated processes. L-Carnitine supplementation may lead to improvement. 44, 54 Immunomodification by Anticonvulsants Phenytoin potentially is associated with both cellular and humoral immunoabnormalities in epileptic children. A suppression of cellular immunity is evidenced by a lower responsiveness for delayed skin hypersensitivity, 23, 65 depressed mitogen-induced activation of lymphocytes,3, 14, 51, 65 and decreased total peripheral lymphocyte or T-cell population40 in patients on anticonvulsants. Actual effects of phenytoin on immune systems of these patients are difficult to assess, however. Drug effects underlying pathogenesis of epilepsy and genetic factors are all possibly responsible for abnormalities. Higashi et al. 23 and Gabourel et al. 14 observed abnormal delayed

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ICHIRO MATSUDA ET AL.

skin reactions and T-cell response in epileptic patients not ingesting antiepileptics. Serum phenytoin concentrations seem to be an additional factor linked to immunodeficiency as total lymphocyte counts are reduced in patients with toxic levels of phenytoin (20-90 /Jog per ml)40 but are unchanged in cases of therapeutic levels. 22. 62 Although evidence is now lacking, zinc deficiency,l, 24, 25, 28 induced by phenytoin in association with its chelating activity, may be linked to the suppression of cellular immunity. The close relationship between zinc deficiency and cellular immunodeficiency was noted in clinical and experimental studies. 20 Suppression of humoral immunity is assumed by JgA deficiency in epileptic patients65 and impaired antibody production in murine species 41 given phenytoin. This JgA deficiency is linked to expression of the HLAA2 antigen. 15 Autoimmune disease as evidenced by lupus-like syndrome2, 63 and autoimmune thyroiditis 52 also are cases of immunomodification by anticonvulsants. Although a direct relationship between production of antinuclear or antithyroid antibodies and anticonvulsants has not been proven, a discontinuation of ethosuximide and phenytoin and replacement with other compounds can lead to a normalization of antibody formation and clinical features in these patients. 2, 52, 63

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16. Greenberg DA: Calcium channel and calcium channel antagonists. Ann Neurol 21:317330, 1987 17. Gumit RJ: Diagnostic difficulties and treatment implications. Epilepsia 28 (suppI3):9-13, 1987 18. Haefely WE: GABA and the anticonvulsant action of benzodiazepine and barbiturates. Brain Res Bull 5 (suppl 2):873-878, 1980 19. Hahn TJ: Drug-induced disorders of vitamin K and mineral metabolism. Clin Endocrinol Metab 9:107-129, 1980 20. Hansen MA, Fernandes G, Good RA: Nutrition and immunity: Influence of diet on autoimmunity and role of zinc in the immune response. Ann Rev Nutr 2:151-177,1982 21. Hass R, Chir B, Stumpf DA: Inhibitory effects of sodium valproate on oxidative phosphorylation. Neurology 31:1473-1476, 1981 22. Higashi A, Ikeda T, Akaboshi I, et al: Lymphocyte counts in children treated with phenytoin. Lancet ii:44, 1976 23. Higashi A, Matsuda I, Sinosuka S, et al: Delayed cutaneous hypersensitivity in children with severe multiple handicaps treated with phenytoin. Eur J Pediatr 129:273-278, 1978 24. Higashi A, Tamari H, Ikeda T, et al: Serum zinc and vitamin E concentrations in handicapped children treated with anticonvulsants. Dev Pharmacol Ther 5:109-111, 1982 25. Higashi A, Chen C, Matsuda I: Zinc status and delayed cutaneous hypersensitivity in handicapped children treated with anticonvulsants. Dev Pharmacol Ther 10:30-35, 1987 26. Holmes LB: Teratogenic effects of anticonvulsant drugs. J Pediatr 112:579-581, 1988 27. Hunt P, Wa-Chen ML, Handal N, et al: Bone disease induced by anticonvulsant therapy and treatment with calcitriol (1,25-dihydroxyvitamin K3)' Am J Dis Child 140:715-718, 1986 28. Ikeda T, Higashi A, Matsukura M, et al: Hair copper and zinc concentrations in handicapped children treated with anticonvulsants. Dev Pharmacol Ther 6:381-387, 1983 29. Jarosinski PF, Moscow JA, Alexander MS, et al: Altered phenytoin clearance during intensive chemotherapy for acute lymphoblastic leukemia. J Pediatr 112:996-999, 1988 30. Jeavons PM: Non-dose-related side effects of valproate. Epilepsia 25 (suppl):S50-55, 1984 31. Johnston D: Valproic acid: Update on its mechanisms of action. Epilepsia 25 (suppl 1) SI-S4, 1984 32. Johnston MV, Freemen JM: Pharmacologic advance in seizure control. Pediatr Clin North Am 28:179-194, 1981 33. Jubitz W, Haussler MR, McCain TA, et al: Plasma 1,25 dihydroxy vitamin K levels in patients receiving anticonvulsant drugs. J Clin Endocrinol Metab 44:617-621, 1977 34. Kruse K: On the pathogenesis of anticonvulsant-drug-induced alterations of calcium metabolism. Eur J Pediat 138:202-205, 1982 3.5. Kruse K, Suss A, Busse M, et al: Monomeric serum calcitonin and bone turnover during anticonvulsant treatment and in congenital hypothyroidism. J Pediatr 111:.57-63, 1987 36. Kutt H: Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 2.5 (suppl 2):S118-S131, 1984 37. Leppik IE, Fisher J, Kreil R, et al: Altered phenytoin clearance with febrile illness. Neurology 36: 1367-1370, 1986 38. Levinson JC, Kent CN, Worth GK: Anticonvulsant induced increase in 25-hydroxyvitamin D3-la hydroxylase. Endocrinology 101:1898-1901, 1977 39. Lifshitz F, Maclaren NK: Vitamin K-dependent rickets in institutionalized, mentally retarded children receiving anticonvulsant therapy. I. A survey of 288 patients. J Pediatr 83:612-620, 1973 40. Mac Kinney AA, Vyas R: The assay of diphenyl hydantoin effects in growing lymphocytes. J Pharmacol Exp Therap 186:37-41, 1973 41. Margaretten NC, Warren RP: Effect of phenytoin on antibody production: use of a murine model. Epilepsia 28:77-80, 1987 42. Matsuda I, Takekoshi Y, Shida N, et al: Renal tubular acidosis and skeletal demineralization in patients on long-term anticonvulsant therapy. J Pediatr 87:202-205, 1975 43. Matsuda I, Takekoshi Y, Tanaka M, et al: Pseudohypoparathyroidism type II and anticonvulsant rickets. Eur J Pediatr 132:303-308, 1979

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Department of Pediatrics Kumamoto University Kumamoto 860, Japan