SEMINARS I N NEUROLO(;Y-VOLUME

10, NO. 4 DECEMBER I990

Pharmacokinetics of Antiepileptic Drugs Richard D. Scheyer, M.D., and Joyce A. Cramer

centrations that are not fully effective. T h e published, population-based "therapeutic range" is only a target to be used for initial dosing and as an aid to interpreting unexpected clinical responses.'

PHARMACOKINETIC CONCEPTS Drug effect generally correlates better with concentration than with dosage because it depends on achieving the necessary concentration at the effector site. A given concentration does not always have the desired response, but the likelihood of successful seizure control is greater if a target concentration, rather than a specific dosage, is used for initial treatment. ABSORPTION

T h e absorption of the major antiepileptic drugs ranges from approximately 80% (CBZ) to near 100% (VPA). Ingestion of medication concurrent with food alters the timing of VPA and possibly CBZ absorption, but does not affect the completeness of ab~orption.',~Enteric feedings may decrease the bioavailability of PHT.I First-pass hepatic metabolism (the metabolism of a disproportionate amount of absorbed drug during its first pass through the liver in the portal ci~-culation)is not a significant consideration for antiepileptic drugs. T h e limiting factor in antiepileptic drug bioavailability typically relates not to incomplete absorption but to difficulty in ensuring ingestion. Patient compliance is an issue with all medications, but particularly for drugs that must be used chronically and have no immediately obvious beneficial

Department of Neurology, Yale University School of Medicine, New Haven, C o n ~ ~ e c t i c uand t , Epilepsy Center, Department of Veterans Affairs Medical Center, West Ilaven, Connecticut Dr. Scheyer is the Victor Horsley fellow of the Epilepsy Foundation of America. This study was supported by the Epilepsy Foundation of America, the Department of Veterans Affairs Medical Research Service, a n d National Institute of Neurological Disorders a n d Stroke grant NS 06208 Reprint requests: Dr. Scheyer, Neurology Servicel127, Department of' Veterans Affairs Meclical Cellter, 950 Campbell Avenue, West Haven, C T 065 I 6

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Use of the drugs available for the treatment of epilepsy is handicapped by narrow therapeutic indices: toxic effects are apparent at doses only slightly greater than those required for effective control. Hence, it is necessary to administer antiepileptic drugs in carefully adjusted amounts and on optimal schedules to maximize their efficacy. T h e most commonly used antiepileptic drugs (carbamazepine [CBZ], ethosuximide [ESM], phenobarbital [PB], phenytoin [PHT], primidone [PRM], and valproate [VPA]) will be considered. Additional mention will be made of diazepam (DZP) and lorazepam (LZP), drugs used primarily in the treatment of status epilepticus. Antiepileptic drugs are generally given for periods of years or even a lifetime. Doses must be selected that will be well tolerated as well as efficacious. Side effects that might be tolerated for a short course of antibiotic therapy are unacceptable. For some conditions, such as parkinsonism, the effect of medication is apparent within hours or days. Most patients with epilepsy are normal between seizures. It is therefore necessary to initiate a medication regimen that has a good prospect of success and to maintain it for a sufficient period to assess its effectiveness. Pharmacokinetics is the study of how drugs are absorbed, distributed, and eliminated by the body. It may be regarded as the study of what the body does to drugs, as compared to pharmacodynamics, the study of what the drug does to the body. For each drug in an individual patient, there is a "therapeutic window" of concentrations below which it is unlikely to be effective and above which toxic effects may be expected. These limits are not absolute and there may be adverse effects at con-

PHARMACOKINETICS OF ANTIEPILEPTIC DRUGS-SCHEYER,CRAMER

DISTRIB UTION

The apparent volume of distribution (Vd) is defined as:

amount of drug in the body v, = serum (or plasma) concentration Most antiepileptic drugs are renally eliminated as water-soluble metabolites, in some instances following conjugation with glucuronide. Exceptions are acetazolamide, dimethadione, and the bromides, which are themselves renally excreted. Half of a primidone dose may be excreted unchanged by the kidneys.' ELIMINATION

At low concentrations, the decrease in serum concentration per unit time for any medication is proportional to the concentration of medication in the body (dC/dt = - P C, where C serum drug concentration, P = elimination rate constant). At sufficiently high concentrations, the pathways for elimination saturate, and dC/dt = V..,,, the maximum rate of elimination. At low concentrations, dCMt = - P x C' (C' = C). Because the concentration is raised to the first power, this is referred to as first-order elimination; when elimination saturates, dC/dt = - V,, x C"Co= 1). This is referred to as zeroorder elimination. If a drug is eliminated by first-order kinetics, then the fraction of drug eliminated per unit time is the elimination rate constant (P). The half-life (t,,,) is defined as the time required for the elimination of half of the drug. This may be determined by the relation t,,, = 0.693lP. For drugs not eliminated by first-order kinetics, the half-life is a function of drug concentration, increasing with increases in drug level, and is therefore a less useful concept. The elimination rate constant is a function of the apparent volume of distribution and of the clearance, the rate at which drug - is eliminated relative to its c~ncentration.~ If the clearance is known, the steady-state dosing rate may be determined:

dose rates,,,,,, ,I,," (mglday) = clearance (llday) x C,,,,,,

,,,

(mgll)

The half-life helps define the appropriate dosing interval. A common rule of thumb is to make the dosing interval equal to the half-life. For drugs

with narrow therapeutic windows, any alteration in the schedule will cause the concentration to become excessively high or low. Missing a day's dose of a drug with t,,, = 24 hours will expose the patient to the risk of breakthrough seizures (Fig. 1A). If half as much drug is given twice as often, the consequences of missing a dose are greatly reduced (Fig. 1B). Twice daily medication schedules are generally well accepted; patient compliance does not decrease significantly until prescribing four . ~ taking advantage of doses daily is a t t e m ~ t e d By the reduced elimination rate during monotherapy, the physician can usually give even rapidlyexcreted drugs such as CBZ and VPA on twice daily schedules. The elimination half-life determines not only rate of disappearance of drug in the absence of dosing, but also the rate of drug accumulation when a fixed rate of dosing is begun. Thus, 3.3 half-lives are required to reach 90% of the asymp, . totically approached steady-state concentration. To achieve a therapeutic concentration of drug more rapidly, a loading dose is often administered. This dose may be calculated by dividing the desired drug concentration by Vd. DrugS with high lipid solubility (PHT, for example) may require a relamilligram of drug t i v e l ~ large mg/kg ( ) loading kilogram body weight dose in obese patients,g whereas drugs [hat are poorly soluble in lipids (such as PB) may need a relative decrease in mglkg load.

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effect. A significant proportion of breakthrough seizures can be linked to missed doses5 In addition, compliance can be erratic, with improvement just prior to an expected blood-sampling but neglect between visits."

PROTEIN BINDING

For practical purposes, brain concentrations of drug must be inferred from the serum concentrations. For those drugs that are highly bound to serum proteins (such as PHT), the unbound (free) concentration appears to correlate with clinical effect better than the total concentration. When binding is likely to be abnormal, as in renal disease, measurement of free drug concentration can provide clinically important information.I0 The major antiepileptic drugs are restrictively cleared; only the unbound drug is available for hepatic metabolism. If binding is displaced, the free drug concentration will rise transiently. The free drug will redistribute throughout the body in a matter of minutes, equilibrating at a concentration only slightly higher than before. T h e total drug concentration will decrease, reflecting the lower, bound fraction. In one patient, 3 hours following a VPA dose, the free PHT rose from 1.4 to 1.6 pgl ml, while total PHT fell from 14.9 to 12.3 pglml (free fraction rose from 9.3 to 13.0%).11If metabolism is not altered simultaneously, the free concentration will then reequilibrate at the original

415

SEMINARS IN NEUROLOGY

Serum E f f e cLevel tive

V O L U M E 10, NUMBER 4 DECEMBER 1990

A/ '

Dose 0

Missed Dose

*

'

2

1

- - - Tpx ic

7'Effective

I

I

3

5

4 Days I

1

1

6

7 I

I

I nef f e c t i v e

Dose -

Missed Dose

+

8:

1

3

2

B

Figure 1. A: Effect of missed dose. T , hours. Dosing interval = 12 hours.

=

24 hours. Dosing interval

level. However, the total concentration of drug will be lower than previously. If this phenomenon is not recognized, and the drug dose is altered to maintain the original total serum concentration, the patient may develop signs or symptoms of toxicity. Free levels should be measured if there is a question of active drug concentration. Representative pharmacokinetic parameters are listed in Table 1. ENZYME INDUCTION AND INHIBITION

416

4 Days

CBZ, PB, and P H T are inducers of the hepatic microsomal cytochrome P450 enzymes responsible for the metabolism of many endogenous and pharmaceutical compounds. Administration of these inducing agents may have widespread metabolic effects. Production of endogenous compounds such as steroids is generally compensated for by intrinsic homeostatic feedback mechanisms, but dosage increases may be necessary for medications.12

5 =

6

7

24 hours. B: Effect of missed dose. TI,

=

24

Conversely, VPA is an inhibitor of many oxidative reactions. Thus, the addition of VPA can cause elevated concentrations of inhibited drugs, requiring dosage reduction. Less commonly, other drugs may induce or inhibit the metabolism of antiepileptic drugs. Representative examples are presented in Table 2. SERUM DRUG CONCENTRATIONS

Antiepileptic drug levels may be obtained for a number of purposes: (1) to estimate a drug's pharmacokinetics for individual patients, especially to determine if a patient has reached steady state and to guide dose adjustments; (2) to assess compliance; (3) to assess the reason for breakthrough seizures; or (4) to determine if an alteration in neurologic status might be caused by the medication. To help establish if a breakthrough seizure is due to inadequate drug concentration, or if a possible adverse effect might be due to a drug,

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Seru111Level

PHARMACOKINETICS OF ANTIEPILEPTIC DRUGS-SCHEYER,CRAMER Table 1. Pharmacokinetic Summary* Oral Bioavailability (%)

Drug

Carbamazepine

75-85

Diazepam

80-1 00

Ethosuximide Lorazepam Phenobarbital

Unbound Fraction (%)

25

V, (Llkg) 0.8-2

t ~ (hours) ,

Target Range i~glml)

Usual Dosing (mglkglda~)

6-1 2 t -

10-20 15-40 -

8-36t$ 30-60t

1

1.1

1 00

100

0.7

93

10

1.O

30-60t 8-25

40-1 00 -

100

50

0.5

96

15-30

12-1 2 0 t

10-20

Phenytoin

90-985

10

0.7

Primidone

92

70-1 00

0.6-0.9

Valproate

100

5-35t

.12-.25

2-4 5-1 0

8-20t

6-1 2 t

10-20

8-1 6$

50-1 25

15-45

'Data from Levy et al;36Gilman et al;23and many other sources. tSee text. +Values are for monotherapy. Values lower if receiving enzyme inducers. 5Jusko et a1.37 I/lncreaseswith concentration.

REPRESENTATIVE DRUGS PHENOBARBITAL

PB metabolism follows straightforward linear pharmacokinetics. The steady-state concentration is proportional to dosage. A long half-life of 4 to 5 days in adults permits once-daily dosing and minimizes the effect of an occasional missed dose. The long half-life also leads to the necessity for a load-

ing dose if a therapeutic level must be reached rapidly. T h e usual target range of PB is 15 to 30 kg/ ml, although many patients tolerate levels over 40 ~ g l m lin chronic therapy with gradual dose increases. Although PB is a potent inducer of cytochrome P450 enzymes, and in animals induces its own metabolism, autoinduction does not seem to be significant in man.I3 PB induction of CBZ and VPA metabolism may require dose increases to maintain desired drug concentration. PRM has independent antiepileptic properties. It is also converted to the active anticonvulsants phenylethylmalonamide and PB.I4 T h e concentrations of these metabolites gain increased importance when PRM metabolism is induced by PHT or CBZ. During polytherapy, the PBIPRM ra-

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the serum sample should be obtained at the time of symptoms. For most other purposes, the morning trough (predose) level should be measured. 'This will usually provide the most reproducible concentration, allowing the detection of altered ingestion or metabolism.

Table 2. Selected Clinically Significant Drug Interactions Interacting Drug

Affected Drug

CBZ

VPA

Interaction

CBZ increases VPA metabolism

C BZ

Warfarin

CBZ may increase warfarin metabolism

Cimetidine

PHT

Cimetidine inhibits PHT metabolism

Erythromycin

CBZ

Erythromycin inhibits CBZ metabolism

Folic acid

PHT

Folic acid supplementation increases PHT metabolism

PB

CBZ

PB increases CBZ metabolism

PB

VPA

PB increases VPA metabolism

PHT

Theophylline

PHT increases theophylline metabolism PHT increases cyclosporine metabolism

PHT

Cyclosporine

PHT

VPA

PHT increases VPA metabolism

PHT

Warfarin

PHT increases warfarin metabolism

Propoxyphene

CBZ

Propoxyphene inhibits CBZ metabolism

VPA

CBZ

VPA inhibits CBZ-epoxide metabolism

VPA

PB

VPA inhibits PB metabolism

VPA

PHT

VPA displaces PHT binding

Verapamil

CBZ

Verapamil inhibits CBZ metabolism

417

SEMINARS IN NEUROLOGY

Km = 8.4 ug'ml

-

Vmax = 494 mg/day NaPHT

-

Sodium Phenytoin (mg/day) Figure 2. Steady-state concentration versus dose (46 year old man).

PHENYTOZN

If a drug is eliminated by other than firstorder metabolism, the time required for elimination of half the drug accumulated in the body will depend on the concentration of drug in the body. For PHT, the "half-life," nominally 24 hours, may range from 8 hours to 3 days in a young, healthy patient, and longer in an elderly patient or one with significant hepatic disease. Because of this variability, it is generally unwise to think in terms of PHT half-life. Although the target concentration may be established several days after beginning therapy, it is advisable to recheck the concentration in 2 to 4 weeks to be sure that the concentration does not gradually rise, causing delayed toxicity. The usual target range is 10 to 20 pglml total PHT and 1 to 2 pglml free PHT. Many patients tolerate and require higher levels to maintain seizure control. When the administered PHT dose approaches the elimination capacity of the liver, small changes in dose may lead to large changes in steady-state concentration (Fig. 2). Once a level of 10 pglml has been reached, further increases in daily dosage should usually be in increments of only 50 mglday. The extreme sensitivity to dosage changes means that small changes in drug bioavailability must be considered. In addition to possibly different formulations obtained from different manufacturers, even drug from a single manufacturer may vary. Dilantin Infatabs and suspension are measured in milligrams of PHT. T h e Kapseal and intravenous formulations, however, are measured in milligrams of the sodium salt: 100 mg of phenytoin is equiv-

alent to 108 mg of phenytoin sodium; this difference is enough to cause toxicity or loss of seizure control if the formulations are interchanged. Approximately 10% of PHT is unbound in normal individuals. Because PHT, like most acidic drugs, is bound primarily to albumin, patients with decreased albumin concentration, whether from malnutrition, hepatic failure, or renal disease, will have an increased fraction of unbound PHT. Displacement of PHT o r alteration in the molecular conformation of albumin is caused by the presence of "uremic toxins."16 Patients with uremia will have significantly higher unbound fraction than patients with nephrotic syndrome at similar albumin concentrations. In patients with altered binding, the free concentration has been shown to correlate better with CSF concentrations than does the total concentration.1° In addition to disease states, concurrent administration of aspirin or VPA may decrease PHT binding.17.18The ratio of unbound to total drug is increased in both of these circumstances. During concurrent administration of VPA, the free fraction of PHT may vary significantly as the VPA concentration changes during the inter-dose inter~ a l . l ' . Patients '~ receiving both VPA and PHT may benefit from more frequent administration of both drugs. Three or four daily doses of VPA may be necessary to reduce fluctuations in free PHT concentration. PHT is a potent inducer of cytochrome P450 enzymes (Table 2). In the presence of PHT co-

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tio will increase. PRM levels are usually 6 to 12 pg/ ml in monotherapy and 4 to 6 ~ g l m in l polytherapy with enzyme-inducing drugs. Derived PB levels are low in monotherapy, often approximately equal to the PRM concentration, but typically 20 to 40 pglml in polytherapy. Both PB and PRM levels should be monitored in patients receiving PRM. Relative elevations in PRM levels, especially in polytherapy, suggest recent extra doses superimposed on a more chronic history of low compliance. In monotherapy, the PRM levels often are equal to or higher than derived PB levels because of the slow conversion to this metabolite. If increased PB levels are necessary, they should be achieved by increasing PRM dose rather than by adding PB co-medication. If parenteral therapy is necessary, a stable PB level may be maintained by substituting approximately 60 mg of PB for every 250 mg of daily PRM.I5 The same ratio is used for rapid oral crossover between the two medications.

VOLUME 10. NUMBER 4 DECEMBER I990

PHARMACOKINETICS OF ANTIEPILEPTIC DRUGS-SCHEYER.CRAMER

CARBAMAZEPZNE

CBZ elimination is approximately linear. CBZ is oxidatively metabolized, but the intermediate thus formed (carbamazepine- 10,11-epoxide) has therapeutic and toxic effects similar to those of the parent drug." CBZ epoxide is then further oxidized to an inactive diol metabolite. Unlike other antiepileptic drugs, CBZ's induction of its own metabolism is not negligible. CBZ metabolism doubles with chronic therapy, the induction being largely completed during the first 1 to 2 weeks.22The half-life decreases from 36 hours, following the initial dose, to 10 to 20 hours with chronic the rap^.'^ An additional decrease of halflife to 8 to 12 hours may be observed during comedication with PHT or PB. This decrease in CBZ concentration is paralleled by a rise in the relative concentration of carbamazepine-l 0 , l l -epoxide. The epoxide concentration also increases when its metabolism to inactive CBZ-diol is blocked by an enzyme-inhibiting drug, such as VPA. During combination therapy, the target concentration of CBZ is decreased from 6 to 12 pglml to 4 to 8 pglml. Although it is a potent inducer of its own metabolism, CBZ at usual concentrations appears to be a slightly less potent inducer of other drugs than is PHT.24,25 CBZ protein binding is relatively stable, with 20 to 25% of drug unbound. Slight increases in this unbound fraction may be expected during comedication with VPA and in the setting of hepatic ~ ~ . ~ changes ~ are of lesser or renal f a i l ~ r e . These clinical importance than for PHT because of the lesser binding. For example, if 15% of bound PHT is displaced from albumin, the free fraction will rise from 10 to 24%; if 15% of bound CBZ is displaced, the free fraction will rise from 25 to only 36%.

E THOSUXZMZDE

ESM metabolism is linear. The rate of elimination decreases markedly with age. The half-life is 30 hours in children and 60 hours in adults. Dosage, in mglkg, may need to be decreased as patients age, and once-daily dosing is possible in adults. The target range is 40 to 100 pglml, with significantly superior control of simple absence seizures at higher levels.28

VPA elimination is approximately linear. A small decrease in rate of elimination is apparent at clinically applicable concentrations, but this is relatively minor in degree.2gThe most significant factor affecting VPA pharmacokinetics is saturable protein binding. At very low concentrations, 95% of serum VPA is bound to albumin. Only 5% is available for transport into the central nervous system and for metabolism by the liver. Cerebrospinal fluid concentration correlates with free plasma concentration.1° As concentration increases, the fraction of unbound drug rises to greater than The relatively constant free drug 30% (Fig. 3).30,31 elimination means that total drug concentration rises less than linearly with dosage. The more important, but less frequently measured, free drug concentration rises approximately linearly with dosage.1° VPA metabolites are believed to be hepatotoxic and may be neurotoxic as well. The production of the hepatotoxic 4-ene-VPA metabolite becomes more prominent at higher VPA concent r a t i ~ n s . ~ T target he range is 50 to 125 pglml, with the lower concentrations effective for simple absence and the higher concentrations often necessary for other seizure types.

Total VPA (&/liter)

Figure 3. Free versus total valproate (VPA). (From Scheyer et aL3' Reprinted with permission.)

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medication, CBZ and VPA concentration/dose ratios are reduced and the apparent half-lives are The effect PHT On PB is less clear. Competitive inhibition of PB metabolism appears more significant than any induction effect. PHT does not induce its own metabolism to any significant extent.lg In addition to its effect on other antiepileptic drugs, PHT induces the metabolism of warfarin, theophylline, and cyclosporine, resulting in increased dosage requirements of these drugs (Table 2). Steroid metabolism is also increased; patients receiving oral contraceptives may require formulations with higher estrogen dosage to maintain efficacy.12.20

SEMINARS I N NEUROLOGY

DZP, because of its extremely high lipid solubility, is able to penetrate the blood-brain-barrier rapidly and is a drug of choice for status epilepticus. As a consequence of this solubility, it redistributes extensively into the body's lipid stores. T h e relatively poorer perfusion of these tissues results in a period of 20 to 30 minutes before the CNS concentration becomes ineffective. Following equilibration, the apparent volume of distribution of unbound DZP of 133 Llkg greatly exceeds the total body volume.33 LZP is less lipid soluble than DZP and has less dramatic redistribution. It may have a longer duration of action. T h e lower lipid solubility may also cause it to have a slower onset of a ~ t i o n . ~ ' DZP undergoes N-dealkylation (t,,, = 20 to 45 hours) to the active metabolite N-desmethyldiazepam, which has an elimination half-life of 44 to 62 hours. Hence, repetitive dosing may lead to the accumulation of sedating concentrations of parent drug and metabolite. T h e anticonvulsant effect of DZP for most seizure types is present only at the high concentrations achieved following an intravenous bolus." Chronic dosing of DZP is not generally employed in the treatment of epilepsy.

COMMENT T h e requirement for long-term, often lifelong, treatment of epilepsy makes concurrent treatment with other medications inevitable. If possible interactions are foreseen, deleterious effects can be minimized. The pharmacokinetic concepts discussed are appropriate only so long as the patient complies with dosing instructions. Epilepsy patients have been shown to take only 75% of their doses as pre~ c r i b e dMedication .~ dosing is not necessarily consistent even when drug levels are in the target range. Microelectronic compliance monitoring has demonstrated significantly reduced dosing between clinic visits, and has linked breakthrough seizures to missed doses5 Compliance assessment, and intervention as necessary, must be a part of antiepileptic drug prescribing. Awareness of antiepileptic drug pharmacokinetics aids in the choice of appropriate drug and permits the design of an optimal dosage schedule for each patient. By anticipating possible drug interactions, or alterations in metabolism, the physician may often avert adverse effects and brcakthrough seizures.

REFERENCES 1. Kutt H . Phenytoin: relation of plasma concentration to seizure control. In: Woodbury DM, Penry JK, Pippinger CE, eds. Antiepileptic drugs, 2nd ed. New York: Raven Press, 1982:241-56 2. Fischer J H , Barr AN, Paloucek FP, et al. Effect of food on the serum concentration profile of enteric-coated valproic acid. Neurology (Cleve) 1988;38: 1319-22 3. Tedeschi G, Ceriraud B, Guyot M, et al. Influence of food o n carbamazepine absorption. In: Dan1 M, Gram L, Penry J K , eds. Advances in epileptology: XIlth Epilepsy International Symposium, New York: Raven Press, 198 1:563-7 4. Nishimura LY, Armstrong EP, Plezia PM, Iacono KP. l n fluence of enteral feedings o n phenytoin sodiuni absorption from capsules. Drug Intell Clin Pharm 1988; 22: 130-3 5. Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessrnent technique. JAMA 1989;26 1 :3273-7 6. Cranier J A , Scheyer K, Mattson K. Compliance declines between clinic visits. Arch Intern Med 1!)90; 150: 150910 7. Cloyd J C , Leppik IE. Primidone: absorption, distribution, excretion. In: Levy R, Mattson R, bleldrum B, et al, eds. Antiepileptic Drugs, 3rd e d . New York: Kaven Press, 3989:391-400 8. Wilkinson GR. Clearance approaches in pharmacology. Pharmacol Rev 1987;39: 1-47 9. Abernethy DK, Greenblatt L v . Phenytoin disposition in obesity: determination of loading dose. Arch Neurol 1985;42:468-7 1 10. Levy RH. Monitoring of free valproic acid levels? T h e r Drug Monit 1980;2:199-201 11. Scheyer RD, C r a n ~ eJrA , Mattson KH. Valproate induced variable phenytoin binding. (Abstr.). Epilepsia 1989; 30:647 12. Mattson RH, Cramer JA. Epilepsy, sex hormones, and antiepileptic drugs. Epilepsia 1985;26 (Suppl I):S4051 13. Browne T R , Evans JE, Szabo G K , et al. Studies with stable isotopes 11: phenobarbital pharmacokinetics d u r ing monotherapy. J Clin Pharmacol 198.5;25:51-8 14. Baumel I, Gallagher B, Mattson R. Phe~~ylethylmalonamide. An important metabolite of pl-imidor~e.Arch Neurol 1972;27:34-4 1 15. Olesen OV, Dam h.1. T h e metabolic conversion of primidone (Mysoline) to phenobarbitone in patients urider long-terrn treatment. Acta Neurol Scand 1967;43:34856 16. Mabuchi H , Nakahashi H. A major inhibitor of phenytoin binding to serum protein in uremia. Ncphron 1988; 48:310-4 17. Fraser DG, Ludden T M , Evens KP, Suthcrland EW. Displacement of phenytoin from plasma binding sites by salicylate. Clin Pharmacol 'I'her 1980;27: 16.5-9 18. Mattson RH, Cramer JA, Williamson PD. Novelly RA. Valproic acid in epilepsy: clinical a n d pharmacological effects. Ann Neurol 1978;3:20-5 19. Yuen GI, Bell KL), 1-udden T M . Phenytoin cumulation profiles. Res Commun Cheni Pathol Ph,irrnacol 1983; 42:355-68 20. Mattson RH, Cranier JA, Darney PL), Nafrolin F. Use of oral contraceptives by women with epilepsy. JAMA 1986;256:238-40 21. Kerr BM, Levy RH. Carbamazepine: carbama7epine epoxide. In: Levy RH, Dreifuss FE, Mattson RH, Meldrum BS, eds. Antiepileptic drugs, 3rd ed. New York: Raven Press, 1989:505-20 22. Mikati MA, Browne T R , Collins JF. T h e VI\ Cooperative Study Group No. 118. Time course of carbamazepine autoinduction. Neurology (Cleve) 1989;39:592-4 23. Gilman AG, Goodrnan LS, Rall 'FW, Muracl F. T h e Phar-

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BENZODIAZEPINES

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PHARMACOKINETICS OF ANTIEPILEPTIC DRUGS-SCHEYER,CRAMER

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n~acologicalbasis of therapeutics, 7th ed. New York, Macmillan, 1985 Mattson RH, Cramer JA. Disinduction of valproate metabolism: timing and magnitude of change. In: Chadwick D, ed. Fourth International Symposium o n Sodium Valproate and Epilepsy. London: Royal Society of Medicine Services, 1989: 138-42 Patsalos PN, Duncan JS, Shorvon SD. Effect of the removal of individual antiepileptic drugs o n antipyrine kinetics in patients taking polytherapy. Br J Clin Pharmacol 1988;26:253-9 Mattson GF, Mattson RH, Cramer JA. Interaction between valproic acid and carbamazepine: a n in vitro study of protein binding. T h e r Drug Monit 1982; 4:181-4 Morselli PL. Carbamazepine: absorption, distribution and excretion. In: Levy RH, Mattson RH, Meldrum BS, et al, eds. Antiepileptic drugs, 3rd ed. New York: Raven Press, 1989:473-90 Sherwin AK, Robb JP, Lechter M. Improved control of epilepsy by monitoring plasma ethosuximide. Arch Neurol 1973;28: 178-83 Bowdle TA, Patel I H , Levy RH, Wilensky AJ. Valproic acid dosage and plasma protein binding a n d clearance. Clin Pharmacol T h e r 1980;28:486-92