Disposition and metabolic fate of atomoxetine hydrochloride: pharmacokinetics, metabolism, and excretion in the Fischer 344 rat and beagle dog.
These studies were designed to characterize the disposition and metabolism of atomoxetine hydrochloride [(-)-N-methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride; formerly know as tomoxetine hydrochloride] in Fischer 344 rats and beagle dogs. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the majority of its metabolites being excreted into the urine, 66% of the total dose in the rat and 48% in the dog. Fecal excretion, 32% of the total dose in the rat and 42% in the dog, appears to be due to biliary elimination and not due to unabsorbed dose. Nearly the entire dose was excreted within 24 h in both species. In the rat, low oral bioavailability was observed (F = 4%) compared with the high oral bioavailability in dog (F = 74%). These differences appear to be almost purely mediated by the efficient first-pass hepatic clearance of atomoxetine in rat. The biotransformation of atomoxetine was similar in the rat and dog, undergoing aromatic ring hydroxylation, benzylic oxidation (rat only), and N-demethylation. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming O-glucuronide and O-sulfate (dog only) metabolites. Although subtle differences were observed in the excretion and biotransformation of atomoxetine in rats and dogs, the primary difference observed between these species was the extent of first-pass metabolism and the degree of systemic exposure to atomoxetine and its metabolites.
Mattiuz
Edward L
EL
Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Ponsler
G Douglas
GD
Barbuch
Robert J
RJ
Wood
Paul G
PG
Mullen
John H
JH
Shugert
Richard L
RL
Li
Qimin
Q
Wheeler
William J
WJ
Kuo
Fengjiun
F
Conrad
Preston C
PC
Sauer
John-Michael
JM
D000284:Administration, Oral; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001682:Biological Availability; D004285:Dogs; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011437:Propylamines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine*; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D011437:Propylamines; D000069445:Atomoxetine Hydrochloride