Pharmacology: Pharmacodynamics: 300 & 400 mg: Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation.
Gabapentin was tested in radioligand binding assays at concentrations up to 100 μM and did not exhibit affinity for a number of other common receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, atrychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with batrachotoxinin A 20-alpha-benzoate. Furthermore, Gabapentin did not alter the cellular uptake of dopamine, noradrenaline, or serotonin.
600 mg: Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but its mechanism of action is different from that of several other active substances that interact with GABA synapses including valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists, and GABA prodrugs. In vitro studies with radiolabeled gabapentin have characterized a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may relate to anticonvulsant and analgesic activity of gabapentin and its structural derivatives. The binding site for gabapentin has been identified as the alpha 2-delta subunit of voltagegated calcium channels.
Gabapentin at relevant concentrations does not bind to other common drug or neurotransmitter receptors of the brain including GABAA, GABAB, benzodiazepine, glutamate, glycine or N-methyl-d-aspartate receptors.
Gabapentin does not interact with sodium channels in vitro and so differs from phenytoin and carbamazepine. Gabapentin partially reduces responses to the glutamate agonist Nmethyl-D-aspartate (NMDA) in some test systems in vitro, but only at concentrations greater than 100 μm, which are not achieved in vivo. Gabapentin slightly reduces the release of monoamine neurotransmitters in vitro.
Pharmacokinetics: 300 & 400 mg: All pharmacological actions following Gabapentin administration are due to the activity of the parent compound; Gabapentin is not appreciably metabolized in humans.
Absorption: 300 & 400 mg: Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of Gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200,, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of Gabapentin (14% increase in AUC and Cmax).
600 mg: Following oral administration, peak plasma gabapentin concentrations are observed within 2 to 3 hours. Gabapentin bioavailability (fraction of dose absorbed) tends to decrease with increasing dose. Absolute bioavailability of a 300 mg capsule is approximately 60 %. Food, including a high-fat diet, has no significant effect on gabapentin pharmacokinetics. Gabapentin pharmacokinetics are not affected by repeated administration.
Distribution: 300 & 400 mg: Less than 3% of Gabapentin circulates bound to plasma protein. The apparent volume of distribution of Gabapentin after 150 mg intravenous administration is 58±6 L (Mean ±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of Gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
600 mg: Gabapentin is not bound to plasma proteins and has a volume of distribution equal to 57.7 litres. In patients with epilepsy, gabapentin concentrations in cerebrospinal fluid (CSF) are approximately 20 % of corresponding steady-state trough plasma concentrations.
Gabapentin is present in the breast milk of breast-feeding women.
Metabolism: There is no evidence of Gabapentin metabolism in humans. Gabapentin does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.
Elimination: 300 & 400 mg: Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.
600 mg: Gabapentin is eliminated unchanged solely by renal excretion. The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours.
In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearacne.
Gabapentin is removed from plasma by haemodialysis. Dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended.
Linearity/Non-linearity: 600 mg: Gabapentin bioavailability (fraction of dose absorbed) decreases with increasing dose which imparts non-linearity to pharmacokinetic parameters which include the bioavailability parameter (F) e.g. Ae%, CL/F, Vd/F. Elimination pharmacokinetics (pharmacokinetic parameters which do not include F such as CLr and T1/2), are best described by linear pharmacokinetics. Steady state plasma gabapentin concentrations are predictable from single-dose data.