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Orsini et al. J Transl Genet Genom 2018;2:16. I https://doi.org/10.20517/jtgg.2018.14 Page 3 of 18

Table 1. Genetic influences on AED metabolism
CYP Effects Reference
Reduced activity of CYP2C9(2-3) Higher serum phenytoin concentration [13,14]
Reduced activity of CYP2C9, CYP2A6, CYP2B6 and UGT/genes enzymes Valproato-related acid-induced liver damage [19-22]
Reduced activity of CYP2C19 Higher serum phenobarbital and clobazam concentrations [16-18]
Zonisamide in Japanese p
AED: antiepileptic drug; UGT: uridine diphosphate glucuronosyltransferase

[18]
metabolism of zonisamide (second generation AED) leading to a reduction of clearance up to 16%-30% .
The clinical relevance of these changes is still to be clarified. In addition, drug interactions can increase
zonisamide clearance, thus reducing the effects of the genetics variants.

Valproic acid (VPA) (first generation AED) is an AED that can cause severe adverse effects including severe
hyperammonemia and non-alcoholic fatty liver disease. Liver damage due to VPA has been associated
[19]
with the formation of the toxic 4-ene metabolite mediated by CYP2C9 . It has been shown that genetic
testing for CYP2C9 variant and subsequent different treatments significantly reduced VPA misdosing and
[20]
hyperammonemia in a controlled trial . A recent study showed that the content of 4-ene-VPA had no
direct correlation with the incidence of liver dysfunction. In addition, VPA metabolism is also influenced
by the polymorphism of ACSM2A, which can lead to higher levels of alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) compared with wild-type subjects, however, the mutations had no effect
[21]
on the VPA-related liver damage .
Finally, VPA metabolism is also influenced by genetically determined variation of uridine diphosphate
glucuronosyltransferase (UGT) enzymes. A study conducted on a pediatric cohort showed that -161C > T single
nucleotide polymorphism in UGT2B7 gene led to significant differences in plasma VPA concentrations.
Patients with the CC genotype had lower adjusted plasma VPA concentrations than those with CT
[22]
or TT genotype (P = 0.028) . Lamotrigine (second generation AED) is eliminated almost entirely by
glucuronidation. An old study conducted in a small number of patients with Gilbert syndrome found that
[23]
lamotrigine clearance was lower in these patients than in healthy control . The clinical impact of this
difference is still unknown. Other studies showed that UGT1A4 genetic polymorphisms also influence
lamotrigine clearance, such as -219C > T/-163G > A mutations in the 5’-upstream regions of the UGT1A4
gene, which significantly increases lamotrigine (LTG) serum concentrations. However, other factors may
play an important role in lamotrigine metabolism such as age, body weight and interaction with VPA [24,25] .

Another second-generation AED, retigabine, is also metabolized by N-glucuronidation and N-acetylation,
but its clearance has been found to be unaffected in Gilbert’s syndrome although arylamine N-acetyltrans-
[26]
ferase-2 acetylator status did influence the disposition of the weakly active metabolite N-acetyl-retigabine .
[27]
There is no evidence of any benefit of dose adjustments for genetic polymorphisms .

Pharmacoresistance
It is well established that at least one third of epileptic patients do not achieve complete seizure control
[28]
with currently available pharmacological treatments (AED) . The cause of pharmacoresistance, is still not
[29]
totally understood , but it has been shown that several ATP-dependent transport proteins are involved in
drug resistance. Drug transporters actively eliminate toxins from the cells, including many drugs. One of
[30]
the most studied transporters is P-glycoprotein (P-gp), encoded by the ABCB1 gene . In the brain, P-gp
is expressed in astrocytes, endothelial cells and neurons, and there is evidence that its overexpression in
epileptogenic tissue can be involved in pharmacoresistance to AEDs . Several studies have shown that
[31]
ABCB1 gene variants are involved in the response to treatment in epilepsy patients. A retrospective case-
control study of C3435T variants reported that patients with pharmacoresistant epilepsy were more likely to
have the CC genotype than the TT genotype (27.5% and 19.5%, respectively) compared with AED responders