Lamotrigene Research Articles

Association between HLA‐B*1502 allele and aromatic antiepileptic drugs‐induced hypersensitivity syndrome reactions and the HLA‐B*15:02 pharmacogenetics screening in autistic spectrum disorder

Some autistic children also have symptoms of depression, anxiety or obsessive-compulsive disorder (OCD). Aromatic anti-epileptic drugs (AEDs) may be used as a mood-stabilizing medication to treat these symptoms, including carbamazepine (CBZ), oxcarbazepine (OX-CBZ), and lamotrigene (LMG). Moreover, one in every four autistic spectrum disorder children have seizures, the use of AED becomes imperative in managing symptoms. Previous studies found a strong association between HLA-B*1502 and carbamazepine (CBZ)-induced cutaneous adverse reactions in Thai epileptic patients. This study aimed to identify whether HLA-B*1502 is associated with AEDs-induced hypersensitivity syndrome (HSS) reactions and also determine the frequency of HLA-B*15:02 in autistic spectrum disorder (ASD) in Thailand. In this study, patients that developed fever and cutaneous eruptions in the presence or absence of organ involvement with exposure to carbamazepine (CBZ), phenytoin (PHY), or lamotrigine (LTG) were enrolled. HLA-B* 15:02 was then determined in 21 patients with AED-induced HSS (6 with CBZ-HSS, 4 PHY-HSS patients and 11 LTG-HSS patients and 292 children with ASD. HLA-B genotyping using PCR-SSOP methods was performed. HLA-B*15:02 was observed with HSS-induced by AEDs, which included carbamazepine (n=4; 66.7%), phenytoin (n=2; 50%), and lamotrigine (n=3; 27%). In addition, the allele frequencies of HLA-B*15:02 in ASD was 14.72% (43/292). HSS-induced by CBZ, PHY and LMG is strongly, moderately and slightly associated with HLA-B*15:02 in Thai patients, respectively. Our findings suggest that HLA-B*15:02 testing before AED therapy would be effective at risk of hypersensitivity and applicable to ASD populations providing hope for prevention in the future.

Bioactivation of Lamotrigine in Vivo in Rat and in Vitro in Human Liver Microsomes, Hepatocytes, and Epidermal Keratinocytes: Characterization of Thioether Conjugates by Liquid Chromatography/Mass Spectrometry and High Field Nuclear Magnetic Resonance Spectroscopy

Previous studies suggested that lamotrigene (LTG) underwent bioactivation to a reactive aryl epoxide intermediate in rats. Nevertheless, definitive structures of these thioether conjugates, which are often needed to substantiate the mechanism of bioactivation and identity of reactive intermediate(s), were not fully established. In the present study, GSH, cysteinylglycine, and N-acetyl cysteine conjugates of LTG were isolated from bile of rats orally dosed with LTG (100 mg/kg), and their structures were fully elucidated by LC/MS and NMR. The definitive structural characterization of these metabolites provided evidence for the existence of a reactive aryl epoxide that was trapped as a GSH adduct. In vitro studies using various hepatic cellular and subcellular fractions obtained from human and rat were performed to demonstrate that LTG underwent bioactivation to form a GSH conjugate that was identical to the one initially characterized from in vivo studies. Human P450 2A6 and rat P450 2C11 appeared to be the primary enzymes activating LTG in human and rat liver microsomes, respectively. Interindividual variation in the bioactivation of LTG was demonstrated with 20 individual human liver microsomes. Furthermore, it was shown that human epidermal keratinocytes were capable of forming the same GSH conjugate, suggesting that LTG could be bioactivated in skin cells. The results from these studies suggest that LTG has the potential to undergo hepatic and nonhepatic bioactivation, leading to a reactive aryl epoxide intermediate in human. The bioactivation of LTG in epidermal cells provides a possible explanation for the idiosyncratic cutaneous reactions associated with LTG therapy.