Pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole in psychiatric patients.

Article Details

Citation

Molden E, Lunde H, Lunder N, Refsum H

Pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole in psychiatric patients.

Ther Drug Monit. 2006 Dec;28(6):744-9. doi: 10.1097/01.ftd.0000249944.42859.bf.

PubMed ID
17164689 [ View in PubMed
]
Abstract

Aripiprazole is a new atypical antipsychotic drug with a partial agonist activity at dopamine 2 and serotonin 1A receptors. The metabolism of aripiprazole involves both cytochrome P450 2D6 (CYP2D6) and CYP3A4. This study investigated the pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole on the basis of 155 drug monitoring samples from psychiatric patients treated with therapeutic doses of aripiprazole (10-30 mg/day). Serum concentrations of drug and metabolite were determined by liquid chromatographic and tandem mass spectrometric detection. Pharmacokinetic variability was expressed as the range in concentration/dose (C/D) ratios, and the effect of sex and occasionally coprescribed CYP2D6 or CYP3A4 inhibitors/inducers was studied. In addition, the dose-concentration relationship and combined interquartile range of concentrations obtained at low dose (10-15 mg/day) and high dose (20-30 mg/day) were described. Individual C/D ratios ranged 37-fold for aripiprazole, 78-fold for dehydroaripiprazole, and 27-fold for the active sum of aripiprazole + dehydroaripiprazole. Median C/D ratios in male and female patients differed by less than 15%, and none of the differences were significant (P > 0.14). Cases of concurrent CYP3A4 inducers/inhibitors were not found, but three patients were coprescribed the potent CYP2D6 inhibitors paroxetine or fluoxetine. No consistent difference in C/D ratio was observed in these three patients compared with the rest of the patients. There was a proportional dose-concentration relationship in the population, and the combined interquartile ranges were 230 to 960 nmol/L for aripiprazole and 330 to 1210 nmol/L for aripiprazole + dehydroaripiprazole. In conclusion, pharmacokinetic variability of aripiprazole is extensive in psychiatric patients but apparently not dependent on dose or sex. The variability of the pharmacologic active sum of aripiprazole + dehydroaripiprazole is 25% to 30% less than aripiprazole, suggesting that variability of aripiprazole is partly determined by metabolism to dehydroaripiprazole.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
AripiprazoleCytochrome P450 3A4ProteinHumans
No
Substrate
Details
Drug Interactions
DrugsInteraction
Aripiprazole
Chlorpromazine
The metabolism of Aripiprazole can be increased when combined with Chlorpromazine.
Aripiprazole
Lorlatinib
The metabolism of Aripiprazole can be increased when combined with Lorlatinib.
Aripiprazole
Pegvisomant
The metabolism of Aripiprazole can be increased when combined with Pegvisomant.
Aripiprazole
Calcitriol
The metabolism of Aripiprazole can be increased when combined with Calcitriol.
Aripiprazole
Flunisolide
The metabolism of Aripiprazole can be increased when combined with Flunisolide.