Lamotrigine enzymes

Lamotrigine Modulate sodium channels Loading dose Not recommended due to increased risk of rash Maintenance dose 1 50-800 mg/day in 2-3 divided doses. Doses should be initiated and titrated according to the manufacturer s recommendations to reduce the risk of rash Half-life Not established Monotherapy 24 hours Concurrent enzyme inducers 12-15 hours Concurrent enzyme inhibitors 55-60 hours Apparent volume of distribution 1.1 L/kg Protein binding 55% Primary elimination route Hepatic Ataxia, drowsiness, headache, insomnia, sedation Rash... 

Valproic acid is an enzyme inhibitor that increases serum concentrations of concurrently administered phenobarbital and may increase concentrations of carbamazepine 10,11-epoxide without affecting concentrations of the parent drug. It also inhibits the metabolism of lamotrigine. 

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. 

Dosage regimen for bipolar disorder The target dose of lamotrigine is 200 mg/day (100 mg/day in combination with valproate and 400 mg/day in combination with carbamazepine or other enzyme-inducing drugs). Doses above 200 mg/day are not recommended. 

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. 

Also, if concomitant enzyme-inducing antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin, and primidone are discontinued after lamotrigine dose is stabilized, then the lamotrigine dose should be maintained for 1 week following discontinuation of the other drug and then reduced by half over 2 weeks in equal decrements each week... 

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... 

Sodium valproate is extensively metabolised in the liver and has a t / of 13 h. It is 90% bound to plasma albumin. Sodium valproate is a nonspecific inhibitor of metabolism, and indeed inhibits its own metabolism, and that of lamotrigine, phenobarbitone, phenytoin and carbamazepine. Sodium valproate does not induce drug metabolising enzymes but its metabolism is enhanced by induction due to other drugs, including antiepileptics. 

A 49-year-old man with bipolar disorder inadvertently took four daily doses of lamotrigine 2700 mg each. He developed a low-grade fever, a skin rash, and periorbital edema. He had a leukocytosis, raised liver enzymes, and acute renal insufficiency. He recovered fully after lamotrigine withdrawal and steroid therapy. 

Plasma concentrations of lamotrigine were reduced in seven women taking an oral contraceptive (mean reduction 49%, range 41-64%), probably through induction of glucuronide conjugating enzymes (77). 

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 enzyme inducers, increased the oral clearance of lamotrigine, individually by 58% and in combination by nearly 200%. 

Both patients were taking a non-enzyme-inducing agent (valproate and lamotrigine respectively), which probably resulted in higher serum tiagabine concentrations than those seen in enzyme-induced patients. 

Decreased levels with enzyme inducers DPH, CB PB. CYP450 en e inhibitors (iA, antidepressant) expected to have little effect Incr sed levels of ediosuximide, lamotrigine, PB. 

A recent study prospectively genotyped all patients for the CYP2D6 gene and excluded poor metabolizers to enhance patient safety (129). The study was a randomized, double-blinded comparison of lamotrigine with desipramine in patients with unipolar depression. Desipramine is a substrate for CYP2D6 and poor me-tabolizers of this enzyme have serum desipra-... 

Drug Interactions. Lamotrigine does not inhibit or induce liver enzymes and has a low potential for pharmacokinetic interactions with other drugs. Lamotrigine does not interfere with oral contraceptives. 

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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