Tabla I. Estudios que han investigado la relación del polimorfismo C3435T (rs1045642) del gen ABCB1 en la respuesta a fármacos antiepilépticos. |
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Población |
Resistentes |
Respondedores |
Resultado |
|
Siddiqui et al [27] |
Reino Unido |
200 |
115 |
CC>TT (OR = 2,66) |
Soranzo et al [50] |
Reino Unido |
280 |
136 |
CC>TT (OR = 4,50) |
Zimprich et al [51] |
Austria |
123 |
87 |
C>T (OR = 4,67) |
Tan et al [52] |
Australia |
401 |
208 |
NS |
Seo et al [28] |
Japón |
126 |
84 |
TT>CC (OR = 3,64) |
Hung et al [53] |
China |
114 |
213 |
CC>TT (OR = 3,62) |
Kwan et al [29] |
China |
221 |
297 |
TT>CC (OR = 2,50) |
Shahwan et al [54] |
Irlanda |
122 |
233 |
NS |
Dericioglu et al [55] |
Turquía |
89 |
100 |
NS |
Ozgon et al [56] |
Turquía |
44 |
53 |
NS |
Szoeke et al [57] |
Australia |
63 |
148 |
NS |
Szoeke et al [57] |
Escocia |
133 |
152 |
NS |
Szoeke et al [57] |
China |
11 |
34 |
NS |
Ufer et al [33] |
Alemania |
188 |
103 |
NS |
Lakhan et al [58] |
India |
94 |
231 |
NS |
Vahab et al [59] |
India |
113 |
54 |
NS |
Kim et al [60] |
Corea |
198 |
193 |
NS |
Alpman et al [61] |
Turquía |
39 |
92 |
NS |
Grover et al [62] |
India |
87 |
125 |
NS |
Sánchez et al [63] |
España |
111 |
178 |
NS |
Haerian et al [64] |
Asiática |
323 |
362 |
NS |
Dong et al [65] |
China |
157 |
193 |
NS |
Kumari et al [66] |
India |
125 |
260 |
NS |
Sayyah et al [67] |
Irán |
132 |
200 |
CC>TT (OR = 2,17) |
Emich-Widera et al [68] |
Polonia |
60 |
25 |
NS |
Emich-Widera et al [69] |
Polonia |
193 |
135 |
NS |
Saygi et al [70] |
Turquía |
59 |
60 |
NS |
Seven et al [71] |
Turquía |
69 |
83 |
NS |
NS: no significativo; OR: odds ratio. |
Tabla II. Estudios que han investigado la relación del polimorfismo –24C>T (rs717620) del gen ABCC2 en la respuesta a fármacos antiepilépticos. |
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Población |
Resistentes |
Respondedores |
Resultado |
|
Seo et al [32] |
Japón |
133 |
146 |
NS |
Kim et al [60] |
Corea |
198 |
193 |
NS |
Ufer et al [33] |
Alemania |
118 |
103 |
OR = 2,15 |
Ufer et al [72] |
Alemania |
176 |
32 |
NS |
Kwan et al [73] |
China |
262 |
328 |
NS |
Qu et al [74] |
China |
217 |
320 |
OR = 4,06 |
Sha’ari et al [34] |
China, Malasia, India, Japón |
987 |
1.069 |
OR = 1,50 |
Ma et al [75] |
China |
246 |
207 |
OR = 1,88 |
Zhou et al [76] |
China |
156 |
235 |
NS |
NS: no significativo; OR: odds ratio. |
Tabla III. Fármacos antiepilépticos sustratos de los transportadores ABCB1 y ABCB2. |
|||||
ABCB1 |
ABCB2 |
||||
In vitro |
In vivo |
In vitro |
In vivo |
||
Cultivo celular no humano |
Cultivo celular |
Microdiálisis |
Cultivo celular |
Microdiálisis |
|
Fenitoína |
Sí [81] |
– |
|||
Carbamacepina |
No [79,82,83] |
No [79] |
Sí [84] |
Sí [84] |
|
Ácido valproico |
No [83] |
No [83] |
No [83] |
No [88] |
|
Fenobarbital |
Sí [79] |
No [87] |
– |
||
Lamotrigina |
Sí [77] |
Sí [79] |
No [87] |
– |
|
Levetiracetam |
Sí [79] |
No [85] |
No [85] |
||
Topiramato |
Sí [86] |
Sí [86] |
– |
No [86] |
– |
ABC transporters and drug resistance in epilepsy: biological plausibility, pharmacogenetics and precision medicine Introduction. A plausible mechanism that may contribute to drug resistance in epilepsy is the failure of drugs to reach the brain tissue, caused by changes in the activity of ABC transporters. The main argument in favour of this hypothesis is that resistance occurs against a wide variety of antiepileptic drugs with different mechanisms of action, suggesting a non-specific underlying phenomenon that limits the effectiveness of drug treatments. Development. A review of the literature on ABC transporters, their role in the normal physiology of the blood-brain barrier and drug resistance in epilepsy, both in human studies and in animal models, is conducted. Studies of genetic variants in the ABCB1 and ABCC2 genes, which code for these transporters, and recent genomic studies in epilepsy and related pathologies are also reviewed, followed by a discussion of their scope and limitations. Conclusions. To date, the association of genetic variants of ABC transporters with resistance to anticonvulsant drugs remains a matter of debate. The increasingly widespread use and accessibility of modern sequencing technologies is expected to allow the establishment of genetic markers that provide a precision medicine based approach to the treatment of epilepsy. Key words. ABC transporters. Epilepsy. P-glycoprotein. Pharmacogenetics. Refractory. Resistance. |