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Lamotrigine-Valproic Acid Interaction Leading to Stevens-Johnson Syndrome
Marta Vázquez1, Cecilia Maldonado1, Natalia Guevara1
1Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, Avenida General Flores 2124, 11800 Montevideo, Uruguay.
Insights
Lamotrigine (LTG) can cause severe skin reactions like Stevens-Johnson syndrome (SJS), especially in children when combined with valproic acid (VPA). This case highlights how VPA increases LTG toxicity by affecting its metabolism and detoxification pathways.
Area of Science:
- Pharmacology
- Toxicology
- Dermatology
Background:
- Lamotrigine (LTG) is an anticonvulsant and mood stabilizer used for epilepsy and bipolar disorder.
- Skin rash is a known adverse effect of LTG, ranging from mild to life-threatening Stevens-Johnson syndrome (SJS).
- Concomitant use of valproic acid (VPA) with LTG increases the risk of severe cutaneous adverse reactions.
Observation:
- A case report of an 8-year-old boy who developed SJS and other complications.
- The patient was receiving adjunctive therapy with both LTG and VPA for seizure control.
- SJS occurred two weeks after the initiation of LTG treatment.
Findings:
- VPA reduces LTG clearance by inhibiting glucuronidation, leading to increased LTG levels.
- This interaction enhances the formation of a toxic arene oxide metabolite of LTG.
- VPA may also inhibit epoxide hydrolase and deplete glutathione, impairing the detoxification of the arene oxide metabolite, thus increasing toxicity.
Implications:
- The combination of LTG and VPA requires careful monitoring due to the increased risk of severe skin reactions.
- Understanding the metabolic pathways and genetic polymorphisms involved in LTG detoxification is crucial for predicting and preventing adverse drug reactions.
- This case underscores the importance of considering drug-drug interactions and individual metabolic variations in pediatric pharmacotherapy.
Abstract:
Lamotrigine (LTG) is currently indicated as adjunctive therapy for focal and generalized tonic-clonic seizures and for treatment of bipolar disorder and neuropathic pain. A common concern with LTG in children is the frequency of appearance of skin rash. The intensity of this adverse effect can vary from transient mild rash to Stevens-Johnson syndrome (SJS), which can be fatal mainly when LTG is coadministered with valproic acid (VPA). Hereby, we present the case of an 8-year-old boy who suffered from SJS and other complications two weeks after LTG was added to his VPA treatment in order to control his seizures. VPA is known to decrease LTG clearance via reduced glucuronidation. In this case, the minor elimination pathway of LTG would play a more important role, and the formation of an arene oxide metabolite would be enhanced. As this reactive metabolite is detoxified mainly by enzymatic reactions, involving microsomal epoxide hydrolase and/or GSH-S-transferases and these enzymes are polymorphically expressed in humans, arene oxide toxicity is increased when epoxide hydrolase or GSH-S-transferases is either defective or inhibited or a depletion of intracellular glutathione levels is taking place. VPA can cause inhibition of epoxide hydrolase enzymes and/or depletion of glutathione levels leading to adverse cutaneous reactions.
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