Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters

Abstract

Pharmacogenomics can identify polymorphisms in genes involved in drug pharmacokinetics and pharmacodynamics determining differences in efficacy and safety and causing inter-individual variability in drug response. Therefore, pharmacogenomics can help clinicians in optimizing therapy based on patient's genotype, also in psychiatric and neurological settings. However, pharmacogenetic screenings for psychotropic drugs are not routinely employed in diagnosis and monitoring of patients treated with mood stabilizers, such as carbamazepine and valproate, because their benefit in clinical practice is still controversial. In this review, we summarize the current knowledge on pharmacogenetic biomarkers of these anticonvulsant drugs.

Keywords: carbamazepine; mood stabilizers; pharmacogenomics; valproate.

Figure 1

Pharmacokinetics (PK) and pharmacogenomics of carbamazepine (CBZ). (A) Liver metabolism of CBZ by cytochrome P450 (CYP) enzymes, epoxide hydrolase 1 (EPXH1), and UDP-glucuronosyltransferase (UGT) and relative metabolites. (B) Genetic polymorphisms in genes involved in CBZ metabolism and their effects on PK of the drug. Abbreviations. (*) allele nomenclature; ADR, adverse drug reactions; SJS/TEN, Steven-Johnson syndrome/toxic epidermal necrolysis.

Figure 2

Pharmacokinetics (PK) and pharmacogenomics of valproate (VPA). (A) Liver metabolism of VPA by cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT) enzymes, and relative metabolites. (B) Genetic polymorphisms in genes involved in VPA metabolism and their effects on PK of the drug. Abbreviations. (*) allele nomenclature; ADR, adverse drug reactions.

Figure 3

Genetic polymorphisms of drug transporters and carbamazepine (CBZ) and valproate (VPA) response. ABCB1 (ATP Binding Cassette Subfamily B Member 1), ABCC2(ATP Binding Cassette Subfamily C Member 2), ADRs (Adverse Drug Reactions).