Antiepileptic Drugs, 5th Edition

Phenobarbital and Other Barbiturates

56

Methylphenobarbital

Mervyn J. Eadie MD, PhD*

Wayne D. Hooper PhD**

* Emeritus Professor, Department of Medicine, University of Queensland; and Honorary Consultant Neurologist, Royal Brisbane Hospital, Brisbane, Queensland, Australia

** Director, Center for Studies in Drug Disposition, University of Queensland, Royal Brisbane Hospital, Brisbane, Queensland, Australia

Two N-methyl barbituric acid derivatives were introduced as antiepileptic agents during the past 70 years, but only methylphenobarbital, which appeared in 1932 (1), remains in much use. Metharbital, first used in 1948, never became popular. It was discussed in earlier editions of this book (2), but is not considered further here. Methylphenobarbital is reputedly as effective as phenobarbital as an antiepileptic agent in humans, and is useful in the same types of epilepsy. There has been some interest in its pharmacokinetics and metabolism, especially their stereospecific aspects (3, 4, 5).

CHEMISTRY

Methylphenobarbital [mephobarbital, methylphenobarbitone, Mebaral (Sanofi Winthrop, New York, NY) Prominal], chemically 5-ethyl-l-methyl-5-phenylbarbituric acid, is the N-methylated analog of phenobarbital (Figure 56.1). It is a weakly acidic, white crystalline powder, pKa 7.8, molecular weight 246.26, and is more lipid soluble than phenobarbital. It usually is supplied as a racemic mixture [i.e., as equal parts of the (R) (-)- and (S) (+)-enantiomers]. In what follows, methylphenobarbital should be taken to refer to the racemic substance, except where an individual enantiomer is specified; sometimes the prefix rac- is added to emphasize that the racemate is meant.

METHODS OF DETERMINATION

The earliest methods for measuring N-methylphenobarbital and its desmethylated derivative in biologic materials were ultraviolet spectrophotometric assays (6, 7, 8). Nitration, followed by thin-layer chromatography, was used to resolve methylphenobarbital from phenobarbital (9). Various gas-liquid chromatographic techniques were developed for measuring methylphenobarbital and phenobarbital (10) without derivatization (11), or as ethyl (12) or butyl derivatives (13). Gas chromatography-mass spectrometry provides specific measurement of methylphenobarbital and phenobarbital in the same sample of biologic material (14, 15, 16, 17). Methylphenobarbital and phenobarbital can be measured at biologic concentrations without prior derivatization using high-performance liquid chromatography with ultraviolet detection (18). These chromatographic methods measure total methylphenobarbital—that is, the sum of the concentrations of the drug's two enantiomers. The value obtained is not correctly regarded as that of “racemic” methylphenobarbital; the concentrations of the two enantiomers in plasma rarely are equal (see later). In the following discussion, the result of such assays are expressed in terms of (R+S)-methylphenobarbital. Chiral separation chromatographic methods have been used for the measurement of the individual isomers of the drug (5,19,20).

ABSORPTION, DISTRIBUTION, AND ELIMINATION

Absorption

Clinicians have long known that the molar dose of racmethylphenobarbital required to produce a given biologic effect is approximately twice that for phenobarbital. In urine from three humans, methylphenobarbital plus derived phenobarbital accounted for only 50% to 60% of the methylphenobarbital dose (6). It therefore sometimes was

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assumed that only approximately 50% of an oral methylphenobarbital dose was absorbed. It is now known that in humans some 35% of a rac-methylphenobarbital dose is excreted in urine as the (R)- (predominantly) and (S)-enantiomers of a previously unidentified p-hydroxyphenyl glucuronide derivative (5,21). In two volunteers, the absolute bioavailability of oral methylphenobarbital was 75% (22). Hooper and Qing (23) pointed out that (R)-methylphenobarbital has a high oral clearance and is likely to undergo significant presystemic elimination, which may explain the incomplete oral bioavailability of the racemic drug.

 

FIGURE 56.1. Metabolic pathways for (R)-methylphenobarbital (Ia) and (S)-methylphenobarbital (Ib). The (R)-enantiomer undergoes formation of phenolic (V), diol (VII), and O-methylcatechol (VIII) derivatives or may be demethylated to phenobarbital (II). The (S)-enantiomer is demethylated to phenobarbital, which may then undergo N-glucosidation or be oxidized to phenolic (III), diol (IV), or O-methylcatechol (VI) products. (From Hooper WD, Eadie MJ. Mephobarbital. In: Resor SJ Jr, Kutt H, eds. The medical treatment of epilepsy. New York: Marcel Dekker, 1992:363-370, with permission.)

The absorption half-time of (R+S)-methylphenobarbital after oral intake was 1.4 (24), 0.48, and 0.38 hour (22). Mean values (n = 6) of 0.20 hour and 0.94 hour were obtained for the (R)- and the (S)-enantiomers, respectively (5). Values for the time to maximum concentration (Tmax) for plasma (R+S)-methylphenobarbital levels have been 2.5 to 7 hours (24), and for the (R)- and the (S)-enantiomers, 2.29 ± 1.03 hours (mean ± standard deviation) and 3.50 ± 1.52 hours, respectively (5). In young adult women and men and in elderly women and men, the Tmax values for the (R)-enantiomer were 3.82 ± 1.67, 2.62 ± 1.48, 4.74 ± 1.56, and 4.17 ± 1.62 hours, respectively; the corresponding figures for the (S)-enantiomer were 5.96 ± 3.84, 17.3 ± 10.6, 9.18 ± 6.73, and 8.43 ± 3.24 hours (23).

Distribution

The calculated apparent volume of distribution (Vd) of rac-methylphenobarbital in humans (24) and dogs (25) exceeds that of total-body water. Such values and the known lipophilicity of the drug suggest that it may achieve higher concentrations in tissues (particularly adipose tissue and brain) than in plasma. In rats, brain methylphenobarbital levels were eight times those in blood (11). The (R)-isomer is more readily taken up than the (S)-isomer by the brains of Wistar rats, although the latter isomer has the more potent anesthetic effect (26). Values for the apparent Vd of (R+S)-methylphenobarbital have been 1.9 and 2.1 L/kg in two dogs (25), and in humans 153.5 and 188.3 L (22), and between 49 and 246 L (mean, 132 L) (24). The latter values assumed that the orally administered drug was fully bioavailable. In one human, the Vd of (R+S)-methylphenobarbital was 246 L and that of phenobarbital (administered separately on another occasion) 25.9 L (24). Assuming complete oral bioavailability, in healthy adults the Vd of (R)-methylphenobarbital averaged 5.32 ± 3.33 L/kg and the Vd of (S)-methylphenobarbital averaged 1.73 ± 0.31 L/kg (5). As mentioned previously, the (R)-enantiomer may not be fully bioavailable orally.

In vitro, 47% ± 2% of (R)-methylphenobarbital and 34% ± 2% of (S)-methylphenobarbital is bound to albumin (27). In human plasma, ~67% of the (R)-enantiomer and ~59% of the (S)-enantiomer were protein bound, with 41% and 29%, respectively, being bound to albumin (27). The percentage bound was slightly lower in young adults than in the elderly. The binding was not concentration dependent or influenced by plasma phenobarbital concentrations within the methylphenobarbital concentration range of 1 to 5 mg/L.

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Elimination

Biotransformation

Methylphenobarbital undergoes biotransformation to phenobarbital (25), which might be metabolized further (e.g., to p-hydroxyphenobarbital and the dihydrodiol metabolite of phenobarbital) (28). Kunze et al. (18) and Hooper et al. (14) identified an additional major biotransformation pathway for the drug in humans, namely, aromatic hydroxylation. Both the meta and the para isomers of the hydroxylated product were identified in urine. The former appeared to be an artifact, probably formed from a postulated dihydrodiol derivative under conditions of acid hydrolysis of the glucuronide (and perhaps other conjugates). Treston et al. (29) identified small amounts of an O-methylcatechol derivative of methylphenobarbital in urine.

Kupfer and Branch (4) and Jacqz et al. (3) showed that methylphenobarbital undergoes a polymorphic pattern of metabolism that appears to be coregulated with that of mephenytoin (methoin). In subjects categorized either as extensive or as poor metabolizers of mephenytoin, Kupfer and Branch (4) showed that the extensive metabolizers excreted 2.5% to 48% of a racemic methylphenobarbital dose in urine as its p-hydroxyphenyl derivative over 8 hours, whereas the poor metabolizers excreted less than 1% of the dose in this form. Lim and Hooper (5) and Hooper and Qing (23) showed that (R)-methylphenobarbital is metabolized mainly by aromatic hydroxylation (the pathway that is coregulated with mephenytoin hydroxylation); the (S)-enantiomer is mainly oxidatively dealkylated to phenobarbital through cytochrome P450 (CYP) isoenzyme CYP2B6 activity (30), although a small amount of hydroxylation occurs (Figure 56.1). The metabolic products may undergo conjugations as well as further biotransformations. It is not clear whether methylphenobarbital, like phenobarbital (31), undergoes N-glucosidation.

Half-Life

Terminal half-life values for (R+S)-methylphenobarbital in individual subjects were 47.9 and 52.2 hours (22) and 34 and 47 hours (32). The first-dose mean half-life of (R+S)-methylphenobarbital was 49.0 ± 18.8 hours in four adults not receiving other drugs, but 19.6 ± 5.0 hours in five adults taking various drugs, mainly anticonvulsants (24). Lim and Hooper (5) showed that the mean half-life of the (R)-enantiomer was 7.50 ± 1.70 hours and that of the (S)-enantiomer was much longer (69.8 ± 14.8 hours). These (R+S)-methylphenobarbital half-life values represent the means of individual enantiomer values, and are potentially misleading (23). The derived phenobarbital had a half-life of 98.0 ± 19.7 hours.

Hooper and Qing (23) showed that the half-life of (R)-methylphenobarbital in young men (3.05 ± 1.68 hours) was shorter than in young women (6.94 ± 4.16 hours), elderly men (10.66 ± 7.70 hours), and elderly women (9.64 ± 5.07 hours). For (S)-methylphenobarbital, the half-life in young men again was shorter (50.5 ± 20.1 hours) than in the other groups (means of 85.4, 95.1, and 96.4 hours, respectively).

Clearance

The total-body clearance of orally administered (R+S)-methylphenobarbital averaged 1.85 ± 0.70 L/hr in noninduced subjects and 5.84 ± 2.70 L/hr in presumably induced subjects (24). After intravenous dosage of rac-methylphenobarbital, clearance values of 2.21 and 2.50 L/hr for the pooled enantiomers were obtained in two subjects (22). In six noninduced volunteers, the mean oral clearance was 0.47 ± 0.18 L/kg/hr for the (R)-isomer and 0.017 ± 0.001 L/kg/hr for the (S)-isomer (5). The former value is high enough to suggest that the (R)-enantiomer may undergo some presystemic elimination. The first-dose oral clearance of (R)-methylphenobarbital (169.9 ± 55.2 L/hr) was higher in young men than in healthy young women (45.1 ± 39.2), elderly men (35.0 ± 29.4), and elderly women (57.4 ± 57.7). Simultaneously measured oral clearances of (S)-methylphenobarbital (~1.1 to 1.6 L/hr) did not show appreciable differences related to age or sex (23).

Renal Excretion

Renal excretion of unmetabolized (R+S)-methylphenobarbital accounts for approximately 1.5% to 3.0% of an oral dose of the drug, with approximately 8% to 25% of the dose being excreted as phenobarbital (24). Possibly the urine collection may not have gone on long enough to determine the full amount of phenobarbital that ultimately would have been excreted by this route. p-Hydroxymethylphenobarbital accounts for 30% to 35% of the total dose and appears in human urine mainly as the phenolic glucuronide conjugate of the (R)-enantiomer (22). Lim and Hooper (5) found that 24.8% ± 2.3% of the oral dose of rac-methylphenobarbital was excreted in urine as (R)-p-hydroxymethylphenobarbital and 3.6% ± 2.0% as (S)-p-hydroxymethylphenobarbital. Again, the period of urine collection (at least 12 days) may not have been long enough to determine the full extent of the hydroxylation of the (S)-enantiomer.

INTERACTIONS WITH OTHER DRUGS

Any interaction that has been described for phenobarbital (Chapter 53) is likely to occur when methylphenobarbital provides the source of phenobarbital. Methylphenobarbital may contribute an additive sedative effect if coprescribed with other drugs with sedative properties. It probably possesses

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antiepileptic activity in its own right (see later), as well as by virtue of the phenobarbital it produces. When given with other appropriate antiepileptic drugs, it may produce additive antiepileptic effects. The degree of antiepileptic effect of the individual enantiomers of methylphenobarbital is not established.

Phenobarbital is a well known inducer of certain hepatic microsomal isoenzymes, namely, CYP2B1, CYP2B2, CYP2C6, and CYP3A (33). Methylphenobarbital intake might be expected to cause similar induction both by virtue of the phenobarbital to which it is biotransformed, and also directly (33). In patients, Lander et al. (34) found no interactions between methylphenobarbital and concurrently taken phenytoin or carbamazepine. Phenytoin, carbamazepine, and sulthiame dosage had no statistically significant effects on the relationship between plasma levels of parent methylphenobarbital or derived phenobarbital and methylphenobarbital dose (24). Valproate intake causes a progressive and sustained rise in plasma phenobarbital levels, and a lesser rise in plasma (R+S)-methylphenobarbital levels, in people taking methylphenobarbital (35).

 

FIGURE 56.2. Relationship between steady-state plasma levels of (R + S)-methylphenobarbital and derived phenobarbital and dose of rac-methylphenobarbital in a group of treated epileptic patients. (From Eadie MJ, Bochner F, Hooper WD, et al. Preliminary observations on the pharmacokinetics of methylphenobarbitone. Clin Exp Neurol1978;15:131-144, with permission.)

RELATIONSHIP OF PLASMA CONCENTRATION TO SEIZURE CONTROL

Therapeutic Plasma Concentrations

When methylphenobarbital is taken on a long-term basis, steady-state plasma concentrations of phenobarbital become substantially higher than plasma methylphenobarbital levels. For clinical purposes, it usually is sufficient to use plasma phenobarbital levels as a guide to the therapeutic situation (Chapter 54) and to ignore simultaneous plasma methylphenobarbital levels.

Relationship of Dose to Plasma Concentration

Simultaneous steady-state plasma concentrations of both (R+S)-methylphenobarbital and derived phenobarbital are linearly related to the dose of methylphenobarbital (Figure 56.2). No comparable data are available for plasma levels of the individual enantiomers. A methylphenobarbital dosage of 3 to 4 mg/kg/day produces a mean steady-state plasma

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phenobarbital level of 15 mg/L, and a dosage of 5 mg/kg/day a level of 20 mg/L. The relationship between simultaneous steady-state plasma phenobarbital and (R+S)-methylphenobarbital levels in the same patients is shown in Figure 56.3. Plasma phenobarbital levels between 10 and 20 mg/L (values commonly encountered in treating epilepsy) average 7 to 10 times simultaneous (R+S)-methylphenobarbital levels. However, at higher plasma methylphenobarbital levels, plasma phenobarbital levels tend to be proportionately less than at lower methylphenobarbital levels. Kupferberg and Longacre-Shaw (15) stated that plasma phenobarbital levels averaged 20 times those of (R+S)-methylphenobarbital.

 

FIGURE 56.3. Relationship between simultaneous steady-state plasma levels of (R + S)-methylphenobarbital and derived phenobarbital in epileptic patients treated with rac-methylphenobarbital. (From Eadie MJ, Bochner F, Hooper WD, et al. Preliminary observations on the pharmacokinetics of methylphenobarbitone. Clin Exp Neurol 1978;15:131-144, with permission.)

 

FIGURE 56.4. Relationship between steady-state plasma level of phenobarbital and phenobarbital dose (left) and between steady-state phenobarbital level and rac-methylphenobarbital dose (right), each in two subjects who took different doses of the drugs at different times. (From Eadie MJ, Lander CM, Hooper WD, et al. Factors influencing plasma phenobarbitone levels in epileptic patients. Br J Clin Pharmacol 1977;4:541-547, with permission.)

In the individual, steady-state plasma phenobarbital levels up to at least 30 mg/L, and also (R+S)-methylphenobarbital plasma levels (36), appear linearly related to the methylphenobarbital dose (Figure 56.4). When phenobarbital itself is taken, the relationship in the individual between steady-state plasma phenobarbital level and phenobarbital dose appears curvilinear (37).

The methylphenobarbital dose (expressed relative to body weight) that produces a given plasma phenobarbital level decreases with age (37). To achieve a plasma phenobarbital level of 15 mg/L, a person younger than 15 years of age requires a mean daily methylphenobarbital dose of 4 mg/kg, and someone older than 40 years one of 2 mg/kg. For a given methylphenobarbital dose (corrected for body weight), men tend to have average plasma phenobarbital levels some 5 mg/L higher than women.

Relationship of Plasma Concentrations to Therapeutic and Toxic Effects

No data are available for the therapeutic range of plasma levels of (R+S)-methylphenobarbital or for the individual

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enantiomers. The conventional therapeutic range of plasma phenobarbital levels (15 to 30 or 10 to 40 mg/L) usually proves a reasonable guide to the antiepileptic effects of methylphenobarbital, although it probably underestimates the total antiepileptic activity present. Dose-determined toxic effects of methylphenobarbital correlate reasonably well with plasma phenobarbital levels. No information is available correlating plasma levels of the methylphenobarbital enantiomers with toxic effects of the drug.

Pharmacologic Aspects of Clinical Use

Steady-state plasma levels of (R+S)-methylphenobarbital (half-life approximately 2 days) should apply approximately 8 to 10 days after the most recent dosage change; steady-state conditions for the (R)-enantiomer would be expected after approximately 36 hours, and for the (S)-enantiomer after approximately 15 days. From the clinical point of view, the derived phenobarbital is likely to take approximately 2 to 3 weeks to attain steady-state after a methylphenobarbital dosage change.

Both (S)-methylphenobarbital and phenobarbital are rather slowly eliminated, and their steady-state plasma levels show relatively little fluctuation over 12-hour or even 24-hour dosage intervals, when the drug is taken only once a day (35). Plasma levels of the short half-life (R)-enantiomer might be expected to show appreciable interdosage fluctuation under “steady-state” conditions.

Pregnancy and Lactation

Plasma phenobarbital levels tend to fall during the course of pregnancy and to rise again in the puerperium at constant daily methylphenobarbital doses (38). Kaneko et al. (39) have obtained some evidence suggesting that methylphenobarbital is a teratogen in humans. Surprisingly, methylphenobarbital could not be found in the breast milk of women taking the drug (40).

Dose Required to Achieve a Given Plasma Concentration

Intravenous loading doses of methylphenobarbital (15 to 35 mg/kg) have been given to control convulsions in neonates (41), but the drug is better suited to long-term use than to single-dose intake.

Children require average oral methylphenobarbital doses of 5 mg/kg/day, young adults ones of 4 mg/kg/day, and adults older than 40 years of age, ones of 2 mg/kg/day to achieve a mean plasma phenobarbital level of 15 mg/L (24). If higher doses of methylphenobarbital are indicated, steady-state plasma phenobarbital levels can be expected to increase in proportion to the dose increment made.

Toxicity

It is difficult to distinguish between the toxicity of methylphenobarbital and that of its metabolite, phenobarbital (whose toxic manifestations are described in Chapter 56). Most of the toxic effects seen in patients taking methylphenobarbital involve depression of central nervous system function, usually manifested as drowsiness, intellectual blunting, decreased concentration, and irritability.

PHARMACODYNAMICS

Reinhard (42) tabulated the results of a number of studies in which methylphenobarbital appeared to protect against maximal electroshock seizures in the mouse, rat, and cat and against minimal electroshock seizures and pentylenetetrazol-induced seizures in the mouse and rat. Unfortunately, the investigators often have not determined whether phenobarbital had formed in the biologic systems in which they studied methylphenobarbital. After single doses of methylphenobarbital in rats, immediate protection against maximal electroshock seizures correlated better with brain (R+S)-methylphenobarbital than with levels of phenobarbital (13). Methylphenobarbital inhibits N-methyl-D-aspartate-mediated responses, but only at supratherapeutic concentrations (43).

With the exception of the work of Buch et al. (26), the biologic effects of the individual enantiomers of methylphenobarbital are still to be explored.

CONCLUSION

Methylphenobarbital often has been regarded as a more expensive and less completely absorbed but equally effective alternative to phenobarbital. However, accumulating pharmacokinetic and clinical pharmacologic data indicate that it is well absorbed after oral administration, may enter the brain more readily than phenobarbital, and possesses a useful antiepileptic effect in its own right. It has the advantage over phenobarbital that in the individual patient it produces plasma phenobarbital levels that vary in direct proportion to drug dose.

CONVERSIONS: METHYLPHENOBARBITAL

Conversion factor:

CF = 1,000/mol. wt. = 1,000/246.3 = 4.06

Conversion:

(mg/L) or (µg/mL) × 4.06 = µmol/L

(µmol/L)/4.06 = mg/L or µg/mL

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ACKNOWLEDGMENTS

The authors thank the editors and copyright owners of the British Journal of Clinical Pharmacology and Clinical and Experimental Neurology for permission to reproduce Figures 56.2,56.3 and 56.4 from previously published work; and Marcel Dekker, Inc. for permission to reproduce Figure 56.1.

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