Aripiprazole

Monopgraph

Therapeutic action

• Aripiprazole is an atypical antipsychotic drug indicated for the treatment of:
• Schizophrenia
• Type I Bipolar Disorder
• Major Depressive Disorder
• Irritability associated with autistic disorder

Metabolism

Aripiprazole is absorbed after its administration and reaches its maximum concentration after 3 to 5 hours. Its metabolism is mainly hepatic, catalized by the enzymes CYP3A4 and CYP2D6.

There are three main pathways in the metabolism of aripiprazole: deshydrogenation and hydroxilation happen thanks to the effects of both CYP3A4 and CYP2D6, while the remaining pathway, N-dealkylation, is done exclusively by CYP3A4. Dehydrogenation produces the only active metabolite generated by the elimination pathways of this drug, which is dehydroaripiprazole. Dehydroaripiprazole has a similar activity compared with the parent drug, and it is responsible for 40% of the exposure to the drug. It has been shown that when these pathways are inhibited or show a defective metabolism, the half-life of aripiprazole as well as the exposure to the drug and its active metabolite are increased; therefore the dose must be reduced under these circumstances.

Other factors to be considered

Given that aripiprazole is metabolized by CYP2D6 and CYP3A4, the concomitant use of inhibitors or inducers of these enzymes affects the concnetration and availability of aripiprazole. Strong inhibitors of either CYP2D6 or CYP3A4 reduce the clearance of aripiprazole and it is recommended to half the dose. Potent inducers of CYP3A4 increase the clearance and twice the ususal dose would be reduced.

Conclusions

People who are CYP2D6 PM show higher than usual aripiprazole concentrations, and toxic levels can be reached. The dose of aripiprazole should be adjusted to keep an adequate response level. The dose of aripiprazole should be reduced by about 40% in order to obtain blood concnetrations comparable with those desired forEM patients. It can be useful to monitor the aripiprazole and dehydroaripiprazole concentrations to confirm that the exposure to the drug does not exceed the safe values.

Bibliography

• Kirschbaum K. M. et al. (2008). Serum levels of aripiprazole and dehydroaripiprazole, clinical response and side effects. World J Biol Psychiatry; 9(3):212-8.
• Hendset M. et al. (2007). Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole. Eur J Clin Pharmacol. 63(12):1147-51.
• Oosterhuis M. et al. (2007). Safety of aripiprazole: high serum levels in a CYP2D6 mutated patient. Am J Psychiatry; 164(1):175

MarcBertranCendrósDegree inBiologyMasterinGenetic Counseling

Last modified: Sep 6, 2017 @ 09:59 am