Lamotrigine clearance

Because of the possibility of increased seizure frequency, discontinuance of lamotrigine should be done gradually over a period of 2 weeks. Addition of DVP to lamotrigine therapy reduces lamotrigine clearance and increases steady-state plasma lamotrigine concentrations by 50% (AHFS, 2000). Conversely, steady-state plasma concentrations of lamotrigine are de-... 

Tran TA, Leppik IE, Blesi K, Sathanandan ST, Remmel R. Lamotrigine clearance during pregnancy. Neurology 2002 59 251-5. 

Weintraub D, Buchsbaum R, Resor SR, Hirsch L J, Effect of antiepileptic drug comedication on lamotrigine clearance. Arch Neurol (2005) 62, 1432-6,... 

Not fully understood. It is thought that valproate reduces lamotrigine glu-curonidation by competitive inhibition, which results in a decreased lamotrigine clearance.Raised lamotrigine levels have been implicated in the development of rash. Increased valproate clearance may be due to enzyme induction. Tremor may be the result of a pharmacodynamic interaction. ... 

The apparent clearance of lamotrigine is affected by the coadministration of AEDs. Lamotrigine is eliminated more rapidly in patients who have been taking hepatic enzyme inducing antiepileptic drugs (ElAEDs), including carbamazepine, phenytoin, phenobarbital, and primidone. 

Metabolism/Excretion - Lamotrigine is approximately 55% bound to human plasma proteins. Following multiple administrations to healthy volunteers taking no other medications, lamotrigine induced its own metabolism resulting in a 25% decrease in half-life and a 37% increase in plasma clearance. 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

In 103 children with cranial diabetes insipidus, 3 children who started or had an increase in dose of lamotrigine needed a larger dose of desmopressin, suggesting an effect on the renal tubule or on drug clearance (76). Lamotrigine also increased desmopressin dosage requirements in two other children with cranial diabetes insipidus (78). 

Induction of the glucuronidation of several drugs, including lamotrigine by oral contraceptive steroids (OCSs), has been observed (134). The formation clearance to the acyl glucuronide of diflunisal increased from 3.01 mL/min in... 

Enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) may increase the clearance ot lamotrigine and lower its plasma levels... 

Clearance of tiagabine may be reduced and thus plasma levels increased if taken with a non-enzyme inducing antiepileptic drug (e.g., valproate, gabapentin, lamotrigine), so tiagabine dose may need to be reduced... 

The effects of other antiepileptic drugs on the pharmacokinetics of lamotrigine have been studied in 62 patients with epilepsy (71). Carbamazepine, phenytoin, and phenobarbital, all enzjme inducers, increased the oral clearance of lamotrigine, individually by 58% and in combination by nearly 200%. 

Rifampicin induced the glucuronidation of lamotrigine, increasing total clearance about two-fold. 

Valproic acid is an enzyme inhibitor that can inhibit specific cytochrome P450 isozymes, epoxide hydrolase, and UGT isozymes. The addition of valproic acid to phenobarbital results in a 30% to 50% decrease in the clearance of phenobarbital and potential toxicity if the dose of phenobarbital is not reduced. Valproic acid may increase concentrations of 10,11-carbamazepine epoxide without affecting concentrations of the parent drug via inhibition of epoxide hydrolase. Valproic acid is also a potent inhibitor of lamotrigine, via inhibition of UGT enzymes, and can result in a doubling of the half-life of lamotrigine. ... 

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