The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine

• Published in: European journal of clinical pharmacology Vol. 68; no. 1; pp. 29 - 37
• Main Authors: Azuma, Junichi, Hasunuma, Tomoko, Kubo, Masanori, Miyatake, Masaya, Koue, Toshiko, Higashi, Koushi, Fujiwara, Tsutomu, Kitahara, Sachiko, Katano, Tamiki, Hara, Sumiko
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.01.2012; Springer; Springer Nature B.V
• Subjects: Adult; Antipsychotic Agents - adverse effects; Antipsychotic Agents - blood; Antipsychotic Agents - pharmacokinetics; Aripiprazole; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotransformation; Clinical outcomes; Clinical Trial; Clinical trials; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacology; Fluvoxamine - adverse effects; Fluvoxamine - blood; Fluvoxamine - pharmacology; Genetic Association Studies; Genotype & phenotype; Half-Life; Humans; Japan; Male; Medical sciences; Metabolic Clearance Rate - drug effects; Paroxetine - adverse effects; Paroxetine - blood; Paroxetine - pharmacology; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Piperazines - adverse effects; Piperazines - blood; Piperazines - pharmacokinetics; Polymorphism; Polymorphism, Genetic; Prescription drugs; Quinolones - adverse effects; Quinolones - blood; Quinolones - pharmacokinetics; Serotonin 5-HT2 Receptor Antagonists - adverse effects; Serotonin 5-HT2 Receptor Antagonists - blood; Serotonin 5-HT2 Receptor Antagonists - pharmacokinetics; Serotonin Uptake Inhibitors - adverse effects; Serotonin Uptake Inhibitors - blood; Serotonin Uptake Inhibitors - pharmacology; Young Adult; Paroxetine; Drug interaction; Aripiprazole; Pharmacokinetics; CYP2D6 polymorphism; Fluvoxamine; Partial agonist; Atypical antipsychotic; Genetic variability; Isozyme; Neuroleptic; Psychotropic; Quinolinone derivatives; Reuptake inhibitor; Selective serotonin reuptake inhibitor; 5-HT1A Serotonine receptor; Piperidine derivatives; Antidepressant agent; Antagonist; 5-HT2A serotonin receptor; Human; Serotonin; Enzyme; Cytochrome P450; Genotype; D2 Dopamine receptor; Neurotransmitter; Pharmacokineties; Polymorphism
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-011-1094-4

Purpose To investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes. Methods Fourteen CYP2D6 extensive metabolizer (EM) and 14 CYP2D6 intermediate metabolizer (IM) subjects were coadministered a single oral dose of aripiprazole 3 mg after steady-state plasma concentrations of the SSRIs paroxetine (20 mg/day) or fluvoxamine (100 mg/day) were reached by repeated oral doses for 6–7 days. The pharmacokinetics of aripiprazole with and without coadministration of SSRIs were compared according to CYP2D6 genotypes. Results Coadministration of paroxetine, a potent CYP2D6 inhibitor, decreased systemic clearance (CL/F) of aripiprazole by 58 and 23% in CYP2D6 EMs and IMs, respectively, demonstrating that the percentage inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs. Coadministration of fluvoxamine, a less potent CYP3A4 inhibitor, decreased the CL/F of aripiprazole by 39% in CYP2D6 EMs and 40% in IMs, indicating the same inhibitory effect on CYP enzymes, regardless of the CYP2D6 genotype. Percent contribution of CYP2D6 to total CL/F (CYP2D6 plus CYP3A4) of aripiprazole estimated as a reduced percentage of CL/F by CYP enzyme inhibition was 62% for CYP2D6 EMs and 24% for IMs in paroxetine coadministration, and 40% for CYP2D6 EMs and 18% for IMs in fluvoxamine coadministration. Conclusions There were marked differences in the degree of influence of paroxetine coadministration on the pharmacokinetics of aripiprazole between CYP2D6 EMs and IMs, but no apparent differences were found between two CYP2D6 genotypes in fluvoxamine coadministration. Aripiprazole can be used safely in combination with SSRIs that have a CYP enzyme-inhibitory action.