Abstract
The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the pharmacokinetics of atomoxetine hydrochloride [(−)-N-methyl-γ-(2-methylphenoxy)benzenepropanamine hydrochloride; LY139603] has been documented following both single and multiple doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the overall disposition and metabolism of a 20-mg dose of 14C-atomoxetine was evaluated in CYP2D6 extensive metabolizer (EM; n = 4) and poor metabolizer (PM;n = 3) subjects under steady-state conditions. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the preponderance of radioactivity being excreted into the urine. In EM subjects, the majority of the radioactive dose was excreted within 24 h, whereas in PM subjects the majority of the dose was excreted by 72 h. The biotransformation of atomoxetine was similar in all subjects undergoing aromatic ring hydroxylation, benzylic oxidation, andN-demethylation with no CYP2D6 phenotype-specific metabolites. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming 4-hydroxyatomoxetine-O-glucuronide. Due to the absence of CYP2D6 activity, the systemic exposure to radioactivity was prolonged in PM subjects (t1/2 = 62 h) compared with EM subjects (t1/2 = 18 h). In EM subjects, atomoxetine (t1/2 = 5 h) and 4-hydroxyatomoxetine-O-glucuronide (t1/2 = 7 h) were the principle circulating species, whereas atomoxetine (t1/2 = 20 h) andN-desmethylatomoxetine (t1/2 = 33 h) were the principle circulating species in PM subjects. Although differences were observed in the excretion and relative amounts of metabolites formed, the primary difference observed between EM and PM subjects was the rate at which atomoxetine was biotransformed to 4-hydroxyatomoxetine.
Footnotes
- Abbreviations used are::
- PM
- poor metabolizers
- EM
- extensive metabolizers
- HPLC
- high pressure liquid chromatography
- F
- absolute oral bioavailability
- AUC
- area under the time versus plasma concentration curve
- CL
- clearance
- Css,avg
- average plasma concentration at steady state
- LC/APCI/MS/MS
- liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry
- dpm
- disintegrations per minute
- LSC
- liquid scintillation counting
- MDA
- minimum detectable activity
- CLint
- intrinsic clearance
- Cmax
- maximal plasma concentration
- Css,max
- maximal plasma concentration at steady state
- Css,min
- minimal plasma concentration at steady state
- Tmax
- time to maximal plasma concentration
- Vz
- volume of distribution
- Received June 13, 2002.
- Accepted October 7, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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