Pharmacology: Mode of action: Gabapentin is structurally related to the neurotransmitter GABA; however, gabapentin and its metabolites do not bind to GABA (A) or GABA (B) receptors or influence the degradation or uptake of GABA. The analgesic action of gabapentin has been demonstrated in animal models of analgesia where gabapentin prevented allodynia and hyperalgesia. Pain related responses in neuropathic pain models and in peripheral inflammation models were prevented or decreased by gabapentin. Immediate pain-related behaviors were not altered.
The mechanism by which gabapentin exerts its analgesic effects is unknown. It has been suggested the mechanism of action may be by gabapentin preventing thrombospondin from binding to alpha-2 delta-1 (a receptor involved in excitatory synapse formation). The anticonvulsant action of gabapentin has been demonstrated in animal test systems; however, the mechanism by which gabapentin prevents seizure activity is unknown.
Summary of Pharmacodynamics and Pharmacokinetics: Absorption: Gabapentin bioavailability is not dose-proportional. That is, as the dose is increased, bioavailability decreases.
Gabapentin is absorbed from the gastrointestinal tract by means of a saturable mechanism. After multiple dosing peak plasma concentrations usually occur within 2 to 3 hours of a dose and a steady state within 1 to 2 days.
Absolute bioavailability of gabapentin capsules is approximately 60%.
Distribution: Gabapentin is distributed into breast milk.
It is widely distributed throughout the body but binding to plasma proteins is minimal. It has a volume of distribution equal to 57.7 liters.
Metabolism: Gabapentin is excreted unchanged in the urine, and is not appreciably metabolized.
Excretion: The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours.
The renal clearance of gabapentin was 150 mL/min.
Fecal: 10% to 23%.
Renal: 76% to 81%.
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 clearance.