Pharmacology: Pharmacodynamics: Mechanism of Action: Lamotrigine is a use-dependent blocker of voltage gated sodium channels. It produce a use- and voltage-dependent block of sustained repetitive firing in cultured neurons and inhibits pathological release of glutamate (the amino acid which plays a key role in the generation of epileptic seizures), as well as inhibiting glutamate-evoked bursts of action potentials.
Pharmacokinetics: Absorption: Lamotrigine is rapidly and completely absorbed from the gut with no significant first pass metabolism. Peak plasma concentrations occur approximately 2.5 hours following administration. Maximum plasma concentration is slightly delayed after food but the extent of absorption is unaffected. The pharmacokinetics is linear up to 450mg, the highest single dose tested. There is considerable inter-individual variation in steady state maximum concentrations but within an individual concentrations vary very little.
Distribution: Lamotrigine binding to plasma proteins is about 55%. It is very unlikely that displacement from plasma proteins would result in toxicity. The volume of distribution is 0.92 to 1.22 l/kg.
Metabolism: UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of Lamotrigine. Lamotrigine induces its own metabolism to a modest extent depending on dose. However, there is no evidence that Lamotrigine affects the pharmacokinetics of other AEDs and data suggest that interactions between Lamotrigine and drugs metabolized by cytochrome P450 enzymes are unlikely to occur.
Elimination: The apparent plasma clearance in healthy subjects is approximately 30mL/min. Clearance of Lamotrigine is primarily metabolic with subsequent elimination of glucuronide conjugated material in urine. Less than 10% is excreted unchanged in the urine. Only about 2% of Lamotrigine-related material is excreted in feces. Clearance and half-life are independent of dose. The apparent plasma half-life in healthy subjects is estimated to be approximately 33 hours (range 14 to 103 hours).
The half-life of Lamotrigine is greatly affected by concomitant medication. Mean half-life is reduced to approximately 14 hours when given with enzyme-inducing drugs such as carbamazepine and phenytoin and is increased to a mean of approximately 70 hours when coadministered with sodium valproate alone.
Linearity: The pharmacokinetics of Lamotrigine is linear up to 450mg, the highest single dose tested.