Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics

BACKGROUND: Agomelatine is an agonist of the melatoninergic receptors used for the treatment of depression. Our aim was to evaluate the effect of genetic polymorphisms in metabolising enzymes and the P-glycoprotein transporter on agomelatine pharmacokinetics and pharmacodynamics. METHODS: Twenty-eight healthy volunteers receiving a single 25 mg oral dose of agomelatine, were genotyped for nine polymorphisms in cytochrome P450 enzymes ( CYP1A2, CYP2C9 and CYP2C19) and adenosine triphosphate-binding cassette subfamily B member 1 ( ABCB1), by real-time polymerase chain reaction . Agomelatine concentrations were measured by high performance liquid chromatography coupled to a tandem mass spectrometry detector. RESULTS: We calculated a CYP1A2 activity score that was directly correlated with agomelatine pharmacokinetics. Individuals with a decreased enzyme activity (*1C carriers) had a lower clearance and accumulated higher concentrations of agomelatine. In contrast, individuals with a high CYP1A2 inducibility (*1F or *1B carriers) showed an extensive clearance and lower agomelatine concentrations. The apparently marked differences between races were due to the different CYP1A2 genotype distribution. CYP2C9 intermediate/poor metabolisers showed a higher area under the concentration-time curve and maximum concentration. ABCB1 G2677T/A polymorphism affected the time to reach maximum concentration, as subjects carrying A/A+A/T genotypes showed higher values. No association was found for CYP2C19 phenotype. Agomelatine did not produce any change in blood pressure, heart rate or QT interval. CONCLUSIONS: CYP1A2 polymorphisms affect agomelatine pharmacokinetics. CYP1A2 phenotype inferred from the genotyping of CYP1A2*1C, *1F and *1B alleles might be a potential predictor of agomelatine exposure. ABCB1 G2677T/A could affect agomelatine absorption, as subjects with A/A+A/T genotypes had lower agomelatine concentration and they take more time to reach the maximum concentration.