Abstract
Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.
| Original language | English |
|---|---|
| Pages (from-to) | 102-109 |
| Number of pages | 8 |
| Journal | Epilepsia Open |
| Volume | 4 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Mar 2019 |
| Externally published | Yes |
Keywords
- adverse effects
- antiepileptic drugs
- EpiPGX Consortium
- GWAS
- hyponatremia
Cite this
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A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine. / Berghuis, Bianca; Stapleton, Caragh; Sonsma, Anja C.M.; Hulst, Janic; de Haan, Gerrit Jan; Lindhout, Dick; Demurtas, Rita; the EpiPGX Consortium; Krause, Roland; Depondt, Chantal; Kunz, Wolfram S.; Zara, Federico; Striano, Pasquale; Craig, John; Auce, Pauls; Marson, Anthony G.; Stefansson, Hreinn; O'Brien, Terence J.; Johnson, Michael R.; Sills, Graeme J.; Wolking, Stefan; Lerche, Holger; Sisodiya, Sanjay M.; Sander, Josemir W.; Cavalleri, Gianpiero L.; Koeleman, Bobby P.C.; McCormack, Mark.
In: Epilepsia Open, Vol. 4, No. 1, 01.03.2019, p. 102-109.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine
AU - Berghuis, Bianca
AU - Stapleton, Caragh
AU - Sonsma, Anja C.M.
AU - Hulst, Janic
AU - de Haan, Gerrit Jan
AU - Lindhout, Dick
AU - Demurtas, Rita
AU - the EpiPGX Consortium
AU - Krause, Roland
AU - Depondt, Chantal
AU - Kunz, Wolfram S.
AU - Zara, Federico
AU - Striano, Pasquale
AU - Craig, John
AU - Auce, Pauls
AU - Marson, Anthony G.
AU - Stefansson, Hreinn
AU - O'Brien, Terence J.
AU - Johnson, Michael R.
AU - Sills, Graeme J.
AU - Wolking, Stefan
AU - Lerche, Holger
AU - Sisodiya, Sanjay M.
AU - Sander, Josemir W.
AU - Cavalleri, Gianpiero L.
AU - Koeleman, Bobby P.C.
AU - McCormack, Mark
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.
AB - Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.
KW - adverse effects
KW - antiepileptic drugs
KW - EpiPGX Consortium
KW - GWAS
KW - hyponatremia
UR - http://www.scopus.com/inward/record.url?scp=85062408600&partnerID=8YFLogxK
U2 - 10.1002/epi4.12297
DO - 10.1002/epi4.12297
M3 - Article
VL - 4
SP - 102
EP - 109
JO - Epilepsia Open
JF - Epilepsia Open
SN - 2470-9239
IS - 1
ER -