Atomoxetine

Monopgraph

Therapeutic action

Atomoxetine is a selective inhibitor of norepinephrine reuptake transporters at presynaptic neurons. Atomoxetina.ClH is the isomer R (-) according to analysis of X-ray diffraction. The chemical name is (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride. Molecular formula is C17H21NO, which corresponds to molecular weight of 255.36.

It is used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children, adolescents, and adults.

More information

Atomoxetina is included in the list from the FDA of drugs with a validated genetic biomarker. Speciffically it says:

“Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs).”

Metabolism

Atomoxetine is metabolized in thePhase Iof the hepatic detoxification byCYP2D6. The oral bioavailability of patients with an EM genotype (extensive metabolizers)is 65%, while it is 94% for PM (poor metabolizers), therefore the conventional doses in these patients could trigger adverse effects, mainly tremors, tachycardia and weight loss.

CYP2D6 transforms atomoxetine into 4-OH-atomoxetine, which has as much therapeutic activity as atomoxetine, but its levels are about 1% because it is conjugated in thePhase IIwith glucuronic acidglucuronic acid forming an inactive compound easy to clear in urine, clearance in feces being lower than 2%. 24 hours after the dose  about 90% of the drug has been eliminated in EMs but only 25-30% in PMs.

Atomoxetine is demethylated to N-desmethyl-atomoxetine by CYP2C19 in the Phase I. This pathway is secondary and the metabolite that is formed does not have pharmacologic activity. It is not worthwile to determine the polymorphisms of CYP2C19 to assess the possible clinical effects for the particular case of atomoxetine.

Other factors to be considered

Farmacokinetics: plasma levels When an absorption curve is drawn, with the plasma levels of atomoxetine in the ordinates and time in the abscisses, patients with a CYP2D6 PM phenotype show higher levels than EMs. The area under the curve (AUC) is about 8-10 times higher at the steady state in PMs compared with EMs and the plasma concentration is 5 times higher. In patients with the IM phenotype (intemediate metabolizers, with a functional an a non-functional allele) have intermediate values. Therefore the interest in knowing the CYP2D6 polymorphisms is confirmed in order to adjust the dose in a personalyzed way according to the genotype of the patient.

NOTE:CYP2D6 is just 3% of the total liver CYP content and metabolizes 26% of the must used drugs, and therefore this can lead to many competitive inhibition mechanisms in polymedicated patients that can contribute to increased plasma levels. This should be checked in case of polymedication with other drugs.

Conclusions

Knowing the genetic polymorphisms of CYP2D6 carried by the patient and adjusting the dose according to the genotype allows for a personalized therapeutic that can prevent a lot of adverse effects that due to their nature contribute to complicate the clinical presentation.

Bibliography

• Belle, DJ et al. (2002) Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine kinetics” L. Clin. Pharmacol; 42: 1219-27.
• Ring, Bj. Et al (2002) Identification of the human cytochrome P450 responsible for atomoxetine metabolism. Drug Metab Dispos; 30: 319-23.
• Sauer JM et al (2003) Disposition and metabolic fate of atomoxetine hycrochloride: the role of CYP2D6 in human disposition and metabolism. Drug Metab Dispos; 31:  98-107.

Juan Sabater TobellaDoctor en FarmaciaEurpean Specialist in Clinical Chemistryand Laboratory Medicine (EC4)

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