Lamotrigine-Valproic Acid Interaction Leading to Stevens-Johnson Syndrome.
Lamotrigine (LTG) is an important anticonvulsant with activity against both focal and generalized onset seizures . It is also effective in the treatment of bipolar disorder [2, 3] and neuropathic pain . However, its use is associated with a significant incidence of adverse cutaneous reactions, mainly when concomitant therapy is administered . Rash is the most common adverse reaction of this antiepileptic agent and the most common reason for treatment discontinuation as it can be life-threatening. Children under polytherapy have a higher risk of this adverse event . Such cutaneous reactions range from mild rashes to more serious conditions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis . SJS is thought to be a hypersensitivity reaction involving skin and mucous membranes.
LTG shows good absorption after oral administration, and 55% of LTG is bound to plasma proteins mostly to albumin. Its elimination half-life is 25-30 hours under monotherapy  and 60 hours approximately when combined with valproic acid (VPA) .
LTG is mainly eliminated by UDP-glucuronosyltransferases leading to the formation of two major metabolites: LTG-N-2 glucuronide and LTG-N-5 glucuronide. A minor metabolism pathway is the formation of the N-2 methyl and the N-2-oxide-LTG . The main route of LTG metabolism does not involve cytochrome P450 enzymes, so according to some authors, the possibility for drug interactions is generally low . However, LTG does have some clinically relevant interactions. As glucuronidation is the main pathway for LTG elimination, anything that inhibits UDP-glucuronosyltransferase enzymes will affect LTG levels, leading LTG metabolism to the minor elimination route in which cytochrome P450 enzymes are involved. So in the absence of the major pathway such as N-glucuronidation, LTG can be bioactivated to an arene oxide [12, 13]. Figure 1 schematizes LTG metabolic pathways.
Arene oxides are of significant toxicological concern because these intermediates are chemically reactive. Arene oxides can be mainly detoxified by rearrangement to arenols, but enzymatic hydration to trans-dihydrodiols and/or enzymatic conjugations with GSH also play very important roles. If not effectively detoxified by the aforementioned pathways, an increase in arene oxide will take place, and this reactive metabolite will bind covalently with nucleophilic groups of proteins, DNA, and RNA, leading to cellular damage [14, 15].
VPA is mainly metabolized by the liver, and it is a known inhibitor of UDP-glucuronosyltransferases ; according to some investigations , there was a significant increase in LTG serum concentrations from 4.67 [+ or -] 3.66 to 9.56 [+ or -] 5.27 [micro]g/mL by concomitant administration of VPA, indicating a decrease in LTG clearance when VPA was added to the therapy. In this case, the minor elimination pathway of LTG would play a more important role, and the formation of the arene oxide metabolite would be enhanced. As this epoxide appears to be detoxified mainly by enzymatic reactions, involving microsomal epoxide hydrolase (EPHX) and/or GSH-S-transferases and these enzymes are polymorphically expressed in humans , arene oxide toxicity is increased when EPHX or GSH S-transferases is either defective or inhibited or a depletion of intracellular glutathione levels is taking place. Inhibition of EPHX can occur when VPA is coadministered [19, 20]. High concentrations of VPA can deplete glutathione levels . These two facts could lead to the frequent adverse effects, mainly rash and other cutaneous reactions, reported in the literature [22-24].
Here, we present a case of SJS that occurred after addition of LTG to the VPA regimen.
2. Case Report
An 8-year-old boy with chronic encephalopathy secondary to hypoxic ischemic syndrome, with cerebral palsy and symptomatic epilepsy, was admitted to the emergency department of the children's hospital. He had been seizure-free for the past year with an enteric-coated delayed release formulation of VPA (375 mg every 8 hours). Thirty days prior to hospital admission, he was started on LTG 25 mg/day along with VPA, since his seizures were no longer under control with VPA. Two weeks later, the dose was increased (50mg/day). His morning trough plasma VPA level was measured before LTG was added to the therapy yielding a concentration of 85mg/L. On admission, he presented macular lesions on the front of the thorax that extend to the back, followed by bilateral eyelid edema and ulcerated lesions at the level of lips, jugal mucosa, and pharynx. He developed erythematosus conjunctivitis with ulcers. He presented skin rash with high fever (39[degrees]C) and respiratory failure type I. History revealed that no such lesions occurred earlier and that was the first time such rashes have occurred. Other personal and family history was not relevant. From a dermatologic point of view and based on the history and clinical presentation, a diagnosis of SJS was made. Since the presumptive cause was LTG, the drug was discontinued immediately. Soon after the patient admission, periofocal and ocular involvement worsened. Intravenous immunoglobulin was administered for 48 hours. Mouth care (oral washes with sodium borate) and eye care (tobramycin ophthalmic drops) were also indicated.
From a hemodynamic point of view, four hours after admission, his condition deteriorated and he developed septic shock with peripheral circulatory failure. The patient was admitted to the intensive care unit with intravenous fluids and antibacterial therapy due to skin infection by Staphylococcus aureus. In addition to fluid resuscitation, dopamine was administered. Despite the inotropic treatment, the patient's condition did not improve, indicating a septic shock refractory to conventional vasopressor therapy but during treatment with milrinone and norepinephrine for six days (apart from the antibiotics), the septic shock was reversed.
His clinical state steadily improved over the following days. He made an excellent recovery under control seizure and was discharged after twelve days on admission with VPA (375 mg every 8 hours) and oral L-carnitine (2g/day).
2.1. Genotyping Procedure of EPHX. A blood sample (2 mL) of the patient was collected by venipuncture and was refrigerated (4-8[degrees]C) until analysis. The Wizard[R] genomic DNA purification kit was used to isolate the genomic DNA from whole blood. Then, it was quantified by spectrophotometry (260/280 nm) on a NanoQuant-Tecan instrument. EPHX genotype was determined by a real-time polymerase chain reaction using a TaqMan Drug Metabolism Genotyping Assay for rs1051740 and rs2234922.
Two polymorphisms, Tyr113His in exon 3 (SNP rs1051740 T > C) and His139Arg in exon 4 (SNP rs2234922 A > G), have been associated with a decrease or increase in enzyme activity, respectively [18, 25]. 113His/113His or 113His heterozygosity (mutated allele in exon 3) combined with His139/His139 (wild-type allele in exon 4) indicates a decrease in enzyme activity. An increase in activity occurs with 139Arg/139Arg or 139Arg heterozygosity (mutated allele in exon 4) combined with Tyr113/Tyr113 (wild-type allele in exon 3).
The genetic study revealed an increase in EPHX activity (wild-type allele in homozygosity for SNP rs1051740 and heterozygosity for SNP rs2234922).
This study was conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki and was approved by the Ethics Review Committee of the Faculty of Chemistry (Uruguay). Written informed consent of the mother was obtained for the purpose of reporting this case.
Several antiepileptic drugs (AEDs) are used in combination when seizures are poorly controlled. This fact leads to more potential pharmacokinetic and pharmacodynamic interactions in comparison with monotherapy.
When LTG was started, the patient was also receiving VPA for several years, and no adverse effects were recorded during this therapy. However, VPA even at low concentrations  is known to decrease LTG clearance leading to higher serum concentrations of LTG which in turn increases the risk of serious rash. This is due, as it was mentioned in Introduction, to VPA's inhibition of glucuronidation pathway [16, 17, 27]. Therefore, concomitant administration of these drugs needs a much slower titration, 25 mg of LTG for the first two weeks and an increase of 25 mg/day for the next two weeks. The starting dosage of LTG in our case was 25 mg/day, and dosage had been increased slowly to 50 mg/day.
Previous work has suggested that the predisposition to such skin reactions evidenced with the use of AEDs is based on a genetic abnormality in the detoxification of reactive metabolites of the drugs . Our research group has been working on this topic with phenytoin; in this case, EPHX is involved in arene oxide detoxification, so we started to investigate EPHX polymorphisms in patients with AED therapy [29, 30]. However, in the case of LTG, both Maggs et al.  and Chen et al.  research groups conclude that an arene oxide is formed and mainly an enzymatic conjugation with GSH takes place as the glutathione adduct was recovered in the bile. They also showed that human epidermal keratinocytes were capable of forming the GSH conjugate, evidencing that LTG could be bioactivated in skin cells giving a possible explanation for the cutaneous reactions observed with LTG therapy. So in view of their results, LTG can undergo hepatic and nonhepatic bioactivation. Genotyping of GSH S-transferases was not carried out in this patient, so a defective activity of this enzyme cannot be concluded. Nevertheless, VPA and its metabolites (i.e., 4-en-VPA) are likely to produce glutathione depletion or according to some authors, glutathione-S-transferases inhibition mainly at high VPA concentrations so detoxification of arene oxide could be impaired, as stated before [31, 32]. VPA is metabolized by three main routes: glucuronidation (50%), [beta]-oxidation in the mitochondria using L-carnitine (40%), and [omega]-oxidation (10%); the latter leads to formation of a toxic metabolite, 4-en-VPA . VPA chronic therapy or VPA overdose produces L-carnitine (LCAR) depletion, and this could impair [beta]-oxidation leading to the w-oxidation pathway and the formation of toxic metabolites. In our case, predose VPA level was high (85 mg/L). The enteric-coated preparation of VPA administered to our patient would yield important peak-trough fluctuations, so a predose of 85 mg/L could result in a much higher peak concentration. This could have resulted in [beta]-oxidation impairment and higher concentrations of toxic metabolites [34-36].
Our patient was discharged with the same dose initially administered of VPA, and LCAR was added. LCAR supplementation restores VPA metabolism to normal routes, increasing [beta]-oxidation and thus decreasing [omega]-oxidation and therefore 4-en-VPA formation. Moreover, [beta]-oxidation impairment produced perhaps by the initial high concentrations of VPA could have been the cause of hyperammonemia [36, 37], and thus of the occurrence of seizures. That was the reason why LTG was added to the therapy, not taking into consideration that perhaps seizures were the consequence of high levels of ammonia. The introduction of LCAR to VPA therapy would reverse such condition.
Even though there is no current evidence of microsomal EPHX involvement in arene oxide detoxification in the case of LTG and no formation of dihydrodiol was reported in the literature, EPHX participation is chemically possible and cannot be disregarded. Only EPHX polymorphism was studied in this patient, and genetic study yielded an increased activity of the EPHX. On the one hand, the higher catalytic efficiency of EPHX increases the formation of trans-dihydrodiol, but on the other hand, VPA, as it was stated in Introduction, inhibits the EPHX so perhaps an increase of arene oxide intermediate could have also occurred due to VPA inhibition.
Several studies [38, 39] have determined the association of increased risk of LTG-induced cutaneous reactions with human leukocyte antigen (HLA) genotypes. However, the researchers concluded that further investigation was needed to confirm this association. No HLA genotyping was carried out in this patient in order to infer its implication.
The main limitation of this study is that LCAR, ammonia, and LTG levels were not measured prior admission, and even though no seizures were recorded in the follow-up, once again no VPA, ammonia, and LCAR levels were monitored.
In conclusion, the present case report supports the clinical evidence that a combination of LTG and VPA increases the frequency and severity of skin reactions. VPA not only decreases LTG clearance by competing with the glucuronidation pathway leading LTG metabolism to arene oxide formation, but also inhibits either epoxide hydrolase or GSH-S-transferases or depletes glutathione avoiding arene oxide detoxification regardless the polymorphisms of these enzymes. This case also supports the recommendation that antiepileptic levels as well as ammonia levels in patients undergoing chronic VPA treatment should be monitored.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
 A. Warshavsky, A. Eilam, and R. Gilad, "Lamotrigine as monotherapy in clinical practice: efficacy of various dosages in epilepsy," Brain and Behaviour, vol. 6, no. 3, article e00419, 2016.
 J. G. Reid, M. J. Gitlin, and L. L. Altshuler, "Lamotrigine in psychiatric disorders," Journal of Clinical Psychiatry, vol. 74, no. 7, pp. 675-684, 2013.
 C. T. Clark, A. M. Klein, J. M. Perel, J. Helsel, and K. L. Wisner, "Lamotrigine dosing for pregnant patients with bipolar disorder," American Journal of Psychiatry, vol. 170, no. 11, pp. 1240-1247, 2013.
 N. B. Finnerup, S. H. Sindrup, and T. S. Jensen, "Management of painful neuropathies," Handbook of Clinical Neurology, vol. 115, pp. 279-290, 2013.
 J. R. Calabrese, J. R. Sullivan, C. L. Bowden et al., "Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management," Journal of Clinical Psychiatry, vol. 63, no. 11, pp. 1012-1019, 2002.
 O. Egunsola, I. Choonara, and H. M. Sammons, "Safety of lamotrigine in paediatrics: a systematic review," BMJ Open, vol. 5, no. 6, article e007711, 2015.
 I. Fricke-Galindo, H. Jung-Cook, A. LLerena, and M. Lopez-Lopez, "Pharmacogenetics of adverse reactions to antiepileptic drugs," Neurologia, vol. 33, no. 3, pp. 165-176, 2018.
 V. Ramesh Yasam, S. L. Jakki, V. Senthil et al., "A pharmacological overview of lamotrigine for the treatment of epilepsy," Expert Review of Clinical Pharmacology, vol. 9, no. 12, pp. 1533-1546, 2016.
 G. Zaccara and E. Perucca, "Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs," Epileptic Disorders, vol. 16, no. 4, pp. 409-432, 2014.
 M. V. Doig and R. A. Clare, "Use of thermospray liquid chromatography-mass spectrometry to aid in the identification of urinary metabolites of a novel antiepileptic drug, lamotrigine," Journal of Chromatography, vol. 554, no. 1-2, pp. 181-189, 1991.
 D. Italiano and E. Perucca, "Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update," Clinical Pharmacokinetics, vol. 52, no. 8, pp. 627-645, 2013.
 J. L. Maggs, D. J. Naisbitt, J. N. A. Tettey, M. Pirmohamed, and B. K. Park, "Metabolism of lamotrigine to a reactive arene oxide intermediate," Chemical Research in Toxicology, vol. 13, no. 11, pp. 1075-1081, 2000.
 H. Chen, S. Grover, L. Yu, G. Walker, and A. Mutlib, "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," Chemical Research in Toxicology, vol. 23, no. 1, pp. 159-170, 2010.
 D. J. Naisbitt, "Drug hypersensitivity reactions in skin: understanding mechanisms and the development of diagnostic and predictive tests," Toxicology, vol. 194, no. 3, pp. 179-196, 2004.
 D. M. Jerina and J. W. Daly, "Arene oxides: a new aspect of drug metabolism," Science, vol. 185, no. 4151, pp. 573-582, 1974.
 W. Lu and J. P. Uetrecht, "Possible bioactivation pathways of lamotrigine," Drug Metabolism and Disposition, vol. 35, no. 7, pp. 1050-1056, 2007.
 M. Lalic, J. Cvejic, J. Popovic et al., "Lamotrigine and valproate pharmacokinetics interactions in epileptic patients," European Journal of Drug Metabolism and Pharmacokinetics, vol. 34, no. 2, pp. 93-99, 2009.
 L. W. Wormhoudt, J. N. Commandeur, and N. P. Vermeulen, "Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity," Critical Reviews in Toxicology, vol. 29, no. 1, pp. 59-124, 1999.
 O. Spiegelstein, D. L. Kroetz, R. H. Levy et al., "Structure activity relationship of human microsomal epoxide hydrolase inhibition by amide and acid analogues of valproic acid," Pharmaceutical Research, vol. 17, no. 2, pp. 216-221, 2000.
 M. Rosa, P. Bonnaillie, and H. Chanteux, "Prediction of drug-drug interactions with carbamazepine-10,11-epoxide using a new in vitro assay for epoxide hydrolase inhibition," Xenobiotica, vol. 46, no. 12, pp. 1076-1084, 2016.
 D. Dikio, D. Jutric, and K. Dominko, "The dual nature of the antiepileptic drug valproic acid, with possible beneficial effects in Alzheimer's disease," SEEMEDJ, vol. 1, no. 1, pp. 74-89, 2017.
 X. Wang, B. Iv, H. Wang et al., "Lamotrigine-induced severe cutaneous adverse reaction: update data from 1999-2014," Journal of Clinical Neuroscience, vol. 22, no. 6, pp. 1005-1011, 2015.
 B. Yalcin and A. Karaduman, "Stevens-Johnson syndrome associated with concomitant use of lamotrigine and valproic acid," Journal of the American Academy of Dermatology, vol. 43, no. 5, pp. 703-706, 2012.
 K. Maduemem, A. Vatca, T. O'Neill, and D. Buckley, "Stevens- Johnson syndrome induced by combination of lamotrigine and valproic acid in a 9-year-old boy," Irish Medical Journal, vol. 110, no. 6, p. 586, 2017.
 H. Pinarbasi, Y. Silig, and E. Pinarbasi, "Microsomal epoxide hydrolase polymorphisms," Molecular Medicine Reports, vol. 3, no. 4, pp. 723-727, 2010.
 A. M. Kanner, "When thinking of lamotrigine and valproic acid, think "pharmacokinetically"!," Epilepsy Currents, vol. 4, no. 5, pp. 206-207, 2004.
 A. Rowland, D. J. Elliot, J. A. Williams, P. I. Mackenzie, R. G. Dickinson, and J. O. Miners, "In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction," Drug Metabolism and Disposition, vol. 34, no. 6, pp. 1055-1062, 2006.
 W. H. Chung, W. C. Chang, Y. S. Lee et al., "Genetic variants associated with phenytoin-related severe cutaneous adverse reactions," JAMA, vol. 312, no. 5, pp. 525-534, 2014.
 M. Vozquez, P. Fagiolino, S. Alvariza et al., "Skin reactions associated to phenytoin administration: multifactorial cause," Clinical Pharmacology & Biopharmaceutics, vol. 3, no. 2, 2014.
 N. Guevara, C. Maldonado, M. Uria et al., "Role of CYP2C9, CYP2C19 and EPHX polymorphism in the pharmacokinetic of phenytoin: a study on Uruguayan Caucasian subject," Pharmaceuticals, vol. 10, no. 4, p. 73, 2017.
 R. M. Nanau and M. G. Neuman, "Adverse drug reactions induced by valproic acid," Clinical Biochemistry, vol. 46, no. 15, pp. 1323-1338, 2013.
 Y. Fukushima, T. Seo, N. Hashimoto, Y. Higa, T. Ishitsu, and K. Nakagawa, "Glutathione-S-transferase (GST) M1 null genotype and combined GSTM1 and GSTT1 null genotypes are risk factors for increased serum gammaglutamyltransferase in valproic acid-treated patients," Clinica Chimica Acta, vol. 389, no. 1-2, pp. 98-102, 2008.
 S. Klee, S. Johanssen, and F. R. Ungemach, "Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity," Pharmacology and Toxicology, vol. 87, no. 2, pp. 89-95, 2000.
 C. Maldonado, N. Guevara, C. Queijo, R. Gonzalez, P. Fagiolino, and M. Vazquez, "Carnitine and/or acetylcarnitine deficiency as a cause of higher levels of ammonia," BioMed Research International, vol. 2016, Article ID 2920108, 8 pages, 2016.
 J. Perrott, N. G. Murphy, and P. J. Zed, "L-carnitine for acute valproic acid overdose: a systematic review of published cases," Annals of Pharmacotherapy, vol. 44, no. 7-8, pp. 1287-1293, 2010.
 M. Vazquez, P. Fagiolino, C. Maldonado et al., "Hyperammonemia associated with valproic acid concentrations," BioMed Research International, vol. 2014, Article ID 217269, 7 pages, 2014.
 C. Maldonado, N. Guevara, A. Silveira, P. Fagiolino, and M. Vaazquez, "L-carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: a case report," Journal of International Medical Research, vol. 45, no. 3, pp. 1268-1272, 2017.
 E. Y. Kim, K. H. Ji, H. J. Kim, H. E. Jung, E. Y. Cha, and J. G. Shin, "HLA-A*24:02/B* 51:01 haplotype and lamotrigine-induced cutaneous adverse drug reactions in Koreans," Translational and Clinical Pharmacology, vol. 24, no. 3, pp. 143-146, 2016.
 N. Koomdee, J. Pratoomwun, T. Jantararoungtong et al., "Association of HLA-A and HLA-B alleles with lamotrigineinduced cutaneous adverse drug reactions in the Thai population," Frontiers in Pharmacology, vol. 8, p. 879, 2017.
Marta Vazquez, (1) Cecilia Maldonado, (1) Natalia Guevara, (1) Andrea Rey, (2) Pietro Fagiolino, (1) Antonella Carozzi, (3) and Carlos Azambuja (3)
(1) Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la Republica, Avenida General Flores 2124, 11800 Montevideo, Uruguay
(2) Department of Neuropediatrics, Faculty of Medicine, Universidad de la Republica, Avenida General Flores 2125, 11800 Montevideo, Uruguay
(3) Genia-Genetics Molecular Laboratory, Bulevar General Artigas 922, 11300 Montevideo, Uruguay Correspondence should be addressed to Marta Vazquez; firstname.lastname@example.org Received 28 May 2018; Accepted 5 August 2018; Published 29 August 2018 Academic Editor: Bruno Megarbane
Caption: Figure 1: Metabolism pathways of lamotrigine. UDPGT: uridine diphosphate glucuronosyltransferase; EPHX: epoxide hydrolase; GSH: glutathione.
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|Title Annotation:||Case Report|
|Author:||Vazquez, Marta; Maldonado, Cecilia; Guevara, Natalia; Rey, Andrea; Fagiolino, Pietro; Carozzi, Anton|
|Publication:||Case Reports in Medicine|
|Date:||Jan 1, 2018|
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