Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady-state disposition of lamotrigine in adults with epilepsy

Br J Clin Pharmacol. 2018 Sep;84(9):2106-2119. doi: 10.1111/bcp.13646. Epub 2018 Jul 8.

Abstract

Aims: To investigate the impact of glucuronidation enzyme (UGT1A4*3 142T>G, UGT1A4*2 70C>A, UGT2B7 -161C>T) and transporter (MDR1/ABCB1 1236C>T, ABCG2 421C>A) polymorphisms on steady-state disposition of lamotrigine and on the lamotrigine-valproate interaction.

Methods: Adults with epilepsy on lamotrigine monotherapy (n = 131) or lamotrigine + valproate treatment (n = 74) were genotyped and steady-state lamotrigine and valproate morning troughs were determined as a part of routine therapeutic drug monitoring.

Results: No effect of UGT and MDR1/ABCB1 polymorphisms was observed. In the entire cohort, ABCG2 421A allele had no effect however an interaction between the variant allele and valproate was observed: (i) in lamotrigine-only patients, variant allele (vs. wild type homozygosity) was independently (adjustments: age, sex, body mass index, lamotrigine dose, other polymorphisms) associated with mildly lower lamotrigine troughs [geometric means ratio (GMR) = 0.76, 95% confidence interval (CI) 0.59-0.98], whereas in lamotrigine + valproate patients it was associated with higher troughs (GMR = 1.72, 95%CI 1.14-2.62); (ii) valproate cotreatment was overall associated with markedly higher troughs vs. lamotrigine monotherapy (GMR = 3.49, 95%CI 2.73-4.44), but more so in variant allele carriers (GMR = 5.24, 95%CI 3.38-8.15) than in wild type homozygotes (GMR = 2.32, 95%CI 1.89-2.83); (iii) variant allele effects in two treatment subsets and valproate effects in two genotype subsets differed by 2.36-fold (95%CI 1.39-3.67); (iv) increase in lamotrigine troughs associated with increasing valproate troughs was greater in variant allele carriers than in wild type homozygotes, i.e. variant allele effect increased with increasing valproate troughs.

Conclusion: This study is first to indicate a potentially relevant interaction between ABCG2 421C>A polymorphism and valproate in their effects on lamotrigine disposition.

Keywords: Clinical Pharmacology; Drug Interactions; Drug Transporter; Genetics And Pharmacogenetic; Pharmacogenomics; Pharmacokinetics.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Anticonvulsants / pharmacology*
  • Anticonvulsants / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Therapy, Combination / methods
  • Epilepsy / drug therapy*
  • Epilepsy / genetics
  • Female
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • Humans
  • Lamotrigine / pharmacology*
  • Lamotrigine / therapeutic use
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Valproic Acid / pharmacology*
  • Valproic Acid / therapeutic use
  • Young Adult

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Anticonvulsants
  • Neoplasm Proteins
  • bilirubin glucuronoside glucuronosyltransferase
  • Valproic Acid
  • UGT2B7 protein, human
  • Glucuronosyltransferase
  • Lamotrigine