Effects of aripiprazole on circadian prolactin secretion related to pharmacogenetics in healthy volunteers

Abstract

Aripiprazole treatment in schizophrenic patients was previously associated with lower or normalized prolactin levels. Genetic variants in cytochrome P450 (CYP) (CYP2D6), dopamine receptor (DRD2, DRD3) and serotonin receptor (HTR2A, HTR2C) genes were previously associated with antipsychotic‐induced hyperprolactinaemia. Our aim was to evaluate whether aripiprazole affects prolactin secretion and its relationship with pharmacogenetics. Thirty‐one healthy volunteers receiving a 10‐mg single oral dose of aripiprazole were genotyped for 12 polymorphisms in CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by qPCR. Aripiprazole and dehydro‐aripiprazole plasma concentrations were measured by HPLC‐MS/MS. Prolactin concentrations of the 31 volunteers taking aripiprazole and 12 volunteers receiving ibuprofen were determined by ELISA. Prolactin concentrations after ibuprofen intake were considered as control, since it is known to cause no effect. Prolactin concentrations were slightly higher in the aripiprazole group compared to the ibuprofen group. All prolactin pharmacokinetic parameters were higher in females than in males. CYP2D6 poor and intermediate metabolizers had notably higher prolactin Cmax and AUC0‐12 than normal and ultrarapid metabolizers. The DRD3 rs6280 polymorphism affected prolactin levels: volunteers carrying Ser/Ser genotype had significantly lower prolactin levels than volunteers carrying the Gly allele. Furthermore, HTR2C rs3813929 C/C homozygotes had significantly lower prolactin levels than T allele carriers. Nevertheless, aripiprazole did increase prolactin levels compared to ibuprofen.

Metabolic Effects of Aripiprazole and Olanzapine Multiple-Dose Treatment in a Randomised Crossover Clinical Trial in Healthy Volunteers: Association with Pharmacogenetics

“…Prolactin levels decreased after changing the therapy from other SGAs-including OLA-to ARI [32]. Our previous study showed that a single dose of ARI mildly increases prolactin levels compared to the controls [13]. However, compared to OLA, no change was observed in prolactin levels after administration in the present study.…”

“…Nevertheless, prolactin concentrations were not affected by DRD2 polymorphisms and CYP2D6 phenotype after ARI administration in patients with schizophrenia [12]. On the contrary, an association was found between prolactin levels and CYP2D6 phenotype and HTR2C polymorphisms in healthy volunteers [13].…”

Metabolic effects of aripiprazole and olanzapine multiple-dose treatment in healthy volunteers. Association with pharmacogenetics

“…Nevertheless, prolactin concentrations were not affected by DRD2 polymorphisms and CYP2D6 phenotype after ARI administration in schizophrenic patients 12 . On the contrary, an association was found between prolactin levels and CYP2D6 phenotype and HTR2C polymorphisms in healthy volunteers 13 .…”

“…Prolactin levels decreased after changing the therapy from other atypical antipsychoticsincluding OLA -to ARI 23 . Our previous study showed that a single dose of ARI mildly increases prolactin levels compared to the controls 13 . However, compared to OLA, no change was observed in prolactin levels after administration in the present study.…”

“…HTR2C rs17326429 and rs3813929, COMT rs4680, DRD2 rs1800497, DRD3 rs6280 and ABCB1 rs1045642, rs1128503, rs2032582 and rs2235048 polymorphisms and CYP2D6 phenotypes were previously associated to prolactin levels after risperidone, quetiapine, clozapine, ARI or OLA treatment 10,13,26,27 . We expected similar results as ARI is a partial agonist at DRD2 and at 5HT1A receptors and an antagonist at 5HT2A receptors while OLA is an antagonist at DRD2 and at 5HT2A and 2C receptors 28,29 .…”