Antiepileptic Drugs, 5th Edition



Chemistry, Biotransformation, Pharmacokinetics, and Interactions

Frank J. E. Vajda MD, FRACP

Professorial Fellow, Department of Medicine, University of Melbourne; and Director, Raoul Wallenberg Australian Centre for Clinical Neuropharmacology, St. Vincent's Hospital, Victoria, Australia


Gabapentin (GBP), although designed as a γ-aminobutyric acid (GABA) analog, is not clearly GABAmimetic. First synthesized and tested in animals at Goedecke, in Freiburg, GBP has a simple pharmacokinetic profile, minimal propensity for drug interactions, and a lack of idiosyncratic reactions to date; thus, it is a valuable and safe drug (1,2). It was demonstrated early that GBP was not metabolized extensively either in rodents or in humans and that it penetrates the brain readily (3,4). GBP is 1-(aminomethyl)-cyclohexaneacetic acid. Absorption appears to be dependent on transport by the L-system amino acid transporter. Its elimination half-life is relatively short. It is cleared unchanged by the kidney (5). It is not protein bound, not metabolized, and has no significant drug-drug interactions (6). It is the first antiepileptic drug (AED) since bromide to be eliminated entirely by the kidney, a property shared with vigabatrin (7). It does not induce hepatic oxidation; thus, it may be a drug of choice in acute intermittent porphyria. In addition to its use in epilepsy, GBP has been evaluated in neuropsychiatric and pain disorders to define its psychoactive properties (8).


GBP is a conformationally restricted analog of GABA, not metabolically converted to GABA or its antagonists, nor is it an inhibitor of GABA uptake or degradation. It has higher lipid solubility than GABA (9). Structurally, GBP incorporates GABA into a cyclohexane ring (Figure 29.1). A bitter-tasting crystalline substance with a molecular weight of 171.34, it is highly water soluble (octanol:aqueous pH 7.4 buffer partition coefficient log P = -1.10). It has two negative log of dissociation constant (pKa) values at 3.68 and 10.70 at 25°C and is a zwitterion at physiologic pH (5). Significantly, GBP resembles the bulky hydrophobic amino acids, L-leucine and L-phenylalanine, despite its not having a chiral carbon or an amino group α to the carboxyl group. GBP has a melting point of 165 to 167°C. As confirmed by x-ray structure analysis, the pseudoring configuration of the GABA molecule is integrated into a lipophilic cyclohexane system (10).


Accumulation after multiple dose administration is predictable from single dose data (11,12). After intravenous administration, the pharmacokinetics of GBP is best described by a three-compartment model (10), with half-life values for each phase being 0.1, 0.6, and 5.3 hours, respectively. The contribution of the terminal phase is 90% of the total area under the plasma concentration curve, which may be of significance in penetration of the


blood-brain barrier (13). Bioavailability of GBP is found to be 40% to 60% after oral administration of single 300- to 600-mg doses (10,14), and it is reported to be approximately 35% at a steady dosage of 1,500 mg three times daily. Time of maximum concentration is achieved in 2 to 3 hours. Maximum brain levels are expected after 1 hour after intravenous administration. Volume of distribution is calculated at steady state to be approximately 50 to 58 L (15). The only pharmacokinetic parameter significantly different between genders is maximum concentration, which is higher in women, likely the result of a smaller volume distribution.


FIGURE 29.1. Formulas for gabapentin.


GBP formulations are available as 100-, 300-, 400-, and 800-mg capsules. A liquid syrup form of GBP has limited use in younger children (16). GBP is supplied only for administration orally.


The degree of protein binding is virtually nil for GBP (1,17).


GBP levels in human brain are 80% of those in serum, a finding confirming animal distribution studies (18,19). Concentrations in human cerebrospinal fluid (CSF) are 5% to 35% of plasma levels, and tissue concentrations are approximately 80% of plasma levels (14,20). Ben Menachem and colleagues evaluated penetration of GBP into human CSF and its effects on free and total GABA, homovanillic acid, and 5-hydroxyindoleacetic acid. Five patients were given a single oral dose of GBP, 600 mg (four patients) and 1,200 mg (one patient). Plasma and CSF were collected for 72 hours. CSF:plasma GBP ratios were 0.1 after 6 hours. Free and total GABA concentrations were unchanged, but CSF 5-hydroxyindoleacetic acid and homovanillic acid concentrations increased at 24 and 72 hours (21). A study of simultaneous estimation of influx and efflux blood-brain barrier permeabilities of GBP used microdialysis. Rats were administered intravenous infusions of [14C]GBP to achieve clinically relevant steady-state plasma concentrations. Total brain tissue GBP concentration was significantly higher at steady state than extracellular fluid concentration, owing to intracellular accumulation and tissue binding (22). A comparison of uptake of [3H]GBP with uptake of L-[3H]leucine into rat brain showed that GBP inhibits uptake of certain excitatory amino acids in this synaptosomal preparation (23). Isolation and characterization of a [3H]GBP binding protein from pig cerebral cortex membranes were reported. Purified L-type Ca2+ channel complexes were fractionated. [3H]GBP binding activity closely followed elution of the α2δ subunit (24). GBP was shown to bind most specifically in those areas of the brain where glutamate synapses are predominant (4). Binding of GBP at these sites is not altered by other AEDs, but it is consistently displaced stereospecifically by various other L-amino acids (15,19,20).


GBP is an artificial amino acid, and it was postulated that passage of GBP across cell membranes required facilitated transport by one of the saturable dose transport systems, ordinarily concerned with L-leucine and L-phenylalanine transport (4,25). The reason for the lack of proportionality after an oral dose was thought to be that GBP and the amino acids were mutually inhibitory and concentration dependent.


No data are available on the transplacental passage of GBP in humans. It is not known whether the drug is safe in pregnancy, hence it is not used extensively. Data on breast milk have not been reported.


GBP is well absorbed in rats and dogs, with an elimination half-life of 2 to 3 hours and 3 to 4 hours, respectively. After intravenous administration, similar blood and brain concentrations were obtained in rats after a short distribution phase. More than 93% of [14C]GBP was eliminated renally, as unchanged substance. Biotransformation to N-methyl GBP was found only in dogs (5,26). Pharmacokinetics was linear in the range of 400 to 500 mg/kg intravenously in rats, not sex dependent or changed on multiple dosage (3). Colonic GBP absorption in dogs was poor and consistent with membrane transport rate-limiting absorption of hydrophilic AEDs (27).


Although oral absorption of GBP has been reported to saturate at doses >1,500 mg/day, other investigators report that high doses of GBP are absorbed and can be effective (28). Other reports suggest that bioavailability is 57% with a single


dose of 300 mg and decreases to 35% with 1,600 mg three times daily (29). Data are conflicting on the effect of food on enhancement of absorption (1). High protein intake has been associated with increased GBP absorption. Both L-leucine and L-phenylalanine may compete with the intestinal transport of GBP. In 10 volunteers receiving a single dose of GBP 600 mg, after fasting and after a high-protein meal, maximum concentration was significantly increased and time to maximum concentration was significantly shorter after protein consumption (30). In another study after fasting or after a protein meal, pharmacokinetic parameters showed no statistically significant differences (31).


Renal clearance of GBP is linearly related to creatinine clearances (30,32). Because GBP elimination is affected by disease- and age-related decreases in renal function, dosage guidelines are based on renal function (33). In patients with renal impairment, peak plasma GBP levels are increased. After a single oral dose of GBP, elimination half-life increased to 16 hours in patients with a mean creatinine clearance of 41 mL/min and to 43 hours with a mean creatinine clearance of 13 mL/min. GBP is removed by hemodialysis.. A maintenance dose after dialysis should provide steady-state plasma concentrations comparable to those attained in the setting of normal renal function (34). A case of successful hemodialysis and hemoperfusion for treatment of valproate and GBP poisoning was reported (35). The elimination half-life of GBP in monotherapy is approximately 6 to 9 hours (11,22,36). Steady-state plasma concentrations of GBP can be reached within 1 to 2 days in patients with normal renal function (1,3,11,14).


To investigate the influence of prolonged GBP administration on liver enzyme activity, a controlled trial of GBP was carried out using antipyrine clearance as a model for enzyme induction. None of the antipyrine parameters were affected by GBP administration (10). Because GBP is not metabolized in humans, neither isoenzymes nor genetic factors operating to give rise to metabolic differences among individuals are known or expected. In humans, no metabolites were found. (10,11).


Observations to date have not disclosed major differences in GBP kinetics between children and adults (1,39).


Old age is associated with decreased renal function; hence elimination of GBP by the kidney is impaired in elderly (33). GBP should be used cautiously and in reduced doses. GBP does not require routine laboratory monitoring, and because of lack of enzyme induction or alteration of metabolism of other drugs, it may represent an alternative to conventional drugs in the management of older patients (40). Morris recommends investigation of renal function parameters in patients who have experienced GBP toxicity at low blood levels. These patients include the elderly and those with known renal disease (16).


At doses of 4.8 g/day, bioavailability was estimated to be 35% (11). At doses of 300 to 600 mg three times daily, trough plasma concentrations were generally in the range of 1 to 10 µg/mL (10,15). After multiple oral doses of GBP, dose linearity was demonstrated (41). After a single dose of 300 mg (capsule), plasma concentrations of 2.7 µg/mL were obtained in 2 to 3 hours. After oral administration of 300 mg every 8 hours, peak plasma levels averaged 4 µg/mL. Because of individual variability in absorption and excretion of GBP, some patients do not develop significantly elevated plasma GBP levels until they are receiving high doses. A possible therapeutic range is of the order of 1 to 4 µg/mL. A value of 10 µg/mL without clinical toxicity may be grounds for discontinuation of the drug, if no therapeutic response has been achieved. Although in general four elimination half-lives are required to reach steady-state levels after starting treatment or after dose modification, there is suggestive evidence that the duration of action of GBP may be longer than predicted from its half-life, but multiple doses are still needed to maximize gastrointestinal absorption (1,42). In one major study, mean GBP levels in plasma were higher in responders than in nonresponders, and higher drug levels were related to increased efficacy of the drug (43). Improved seizure control tended to correlate with dose (44). Mattson suggests that for AEDs in which correlation between blood concentrations and clinical outcome is less clear, such as GBP, other indirect measures such as determination of serum GABA concentration or magnetic resonance spectroscopy may prove useful (45).


Data are insufficient to recommend routine monitoring of GBP levels, although there is a possibility that measurement of plasma levels may be useful in high-dose treatment to


identify the level beyond which further dose increases fail to be absorbed (Table 29.1) (1,46, 47, 48).


Pharmacokinetic Parameter



2-3 h (dose-dependent)

Oral bioavailability

<60% (35%-60%)


2-3 h

Cmax after single dose of 300 mg

2.5-3.0 µg/mL



Plasma protein binding


Vd standardized for weight

0.65-1.4 L/kg


6-7 h


100-300 mL/min

Renal elimination

Proportional to creatinine clearance

Dose frequency

3 per day

Enzyme induction


Tmax, time to maximum effect; Cmax, maximum plasma concentration; Vd, volume of distribution; h, hours. From Perucca E. The clinical pharmacokinetics of the new antiepileptic drugs. Epilepsia 1999;40(suppl 9):S7-S13; Wong MO, Eldon MA, Keane WF, et al. Disposition of gabapentin in anuric subjects on hemodialysis. J Clin Pharmacol1995;35:622-626; Gram L. Pharmacokinetics of new antiepileptic drugs. Epilepsia 1996;37 (suppl 6):S12-S16, with permission.


GBP neither induces nor inhibits hepatic microsomal enzymes, nor does it affect the plasma concentrations of most concurrently administered AEDs (11,15,46). Other AEDs have no effect on GBP pharmacokinetics (1). In animal studies, an augmentation of the antiepileptic effects of vigabatrin by GBP was demonstrated in guinea pig hippocampal slices. The combination of GBP and vigabatrin simultaneously decreased the repetition rate of epileptiform field potentials to a level significantly different from the effect by vigabatrin alone (49). In a study of 12 healthy women receiving 2.5 mg of norethisterone acetate and 30 µg ethinyl estradiol daily for three consecutive menstrual cycles, concurrent GBP administration did not alter the pharmacokinetics of either hormone. Thus, GBP is unlikely to cause contraceptive failure (50).

GBP may conceivably interact with drugs excreted predominantly by renal mechanisms. Most of the absorbed GBP, approximately 10% of lamotrigine, and 50% of absorbed felbamate are excreted unchanged in the urine; thus, a potential exists for GBP interaction with these drugs at a renal site (15). Interaction of GBP with felbamate has been reported. In a retrospective pharmacokinetic study of felbamate, 18 patients were taking felbamate and GBP simultaneously. Eleven patients were taking these two drugs alone. The mean half-life of felbamate in this cohort was almost 50% higher than in patients receiving felbamate monotherapy, probably as a result of 37% lower clearance (51). Concomitant administration of GBP has not affected the plasma concentrations of carbamazepine or of its epoxide metabolite, phenobarbitone, phenytoin, or valproate. (32,37,52, 53, 54). These results are consistent with the effects of GBP observed in clinical studies (43,44) and other interaction studies related to the newer AEDs (36).

A case report indicated that GBP added to three AEDs (phenytoin, carbamazepine, and clobazam) caused a clinically significant rise in phenytoin plasma levels and signs of phenytoin toxicity. After cessation of GBP, levels of phenytoin returned to normal. Rechallenge with GBP caused further evidence of toxicity and a rise in phenytoin levels (55). Interactions of GBP have been reported with an antacid containing aluminum and magnesium hydroxide (56), which decreased the concentration of GBP by 15%; this interaction was not thought to be of clinical significance (15). Cimetidine also caused a similar effect, by a renal mechanism (11). The lack of clinically significant drug interactions is one of the drug's most favorable characteristics, contributing to its safety.


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