Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics.
The purpose of this study was to characterize the effect of potent CYP2D6 inhibition byparoxetine on atomoxetine disposition in extensive metabolizers. This was a single-blind, two-period, sequential studyin 22 healthy individuals. In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2, 20 mg paroxetine was administered qd for 17 days. On days 12 through 17, 20 mg atomoxetine bid were coadministered. Plasma pharmacokinetics of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine was determined at steady state in each treatment period. Plasma pharmacokinetics of paroxetine were determined after the 11th and 17th doses. Paroxetine increased C(ss,max), AUC0-12, and t1/2 of atomoxetine by approximately 3.5-, 6.5-, and 2.5-fold, respectively. After coadministration with paroxetine, increases in N-desmethylatomoxetine and decreases in 4-hydroxyatomoxetine concentrations were observed. No changes in paroxetine pharmacokinetics were observed after coadministration with atomoxetine. It was concluded that inhibition of CYP2D6 by paroxetine markedly affected atomoxetine disposition, resulting in pharmacokinetics similar to poor metabolizers of CYP2D6 substrates.
Belle
Donna J
DJ
Department of Clinical Pharmacology, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Ernest
C Steven
CS
Sauer
John-Michael
JM
Smith
Brian P
BP
Thomasson
Holly R
HR
Witcher
Jennifer W
JW
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D000069445:Atomoxetine Hydrochloride; D001794:Blood Pressure / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine / Q000494:pharmacology*; D010636:Phenols / Q000097:blood; D010647:Phenyl Ethers / Q000097:blood; D011437:Propylamines / Q000097:blood / Q000493:pharmacokinetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D016037:Single-Blind Method; D027981:Symporters / Q000037:antagonists & inhibitors*; D013997:Time Factors
D000069445:Atomoxetine Hydrochloride; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine; D010636:Phenols; D010647:Phenyl Ethers; D011437:Propylamines; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C493227:SLC6A2 protein, human; C454680:N-desmethylatomoxetine; C454679:4-hydroxyatomoxetine