title: Pharmacodynamics of norepinephrine reuptake inhibition: Modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4-dihydroxyphenylglycol in humans.
abstract: Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker.
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kielbasa
authors.affiliation: Former employee of Eli Lilly and Company; no current affiliation.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Lobo
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000097:blood / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000069445:Atomoxetine Hydrochloride / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; D015415:Biomarkers; D009025:Morpholines; C568831:alpha-((5-fluoro-2-methoxyphenyl)methyl)-alpha-(tetrahydro-2H-pyran-4-yl)-2-morpholinemethanol; D008734:Methoxyhydroxyphenylglycol; D000069445:Atomoxetine Hydrochloride; D000068736:Duloxetine Hydrochloride; D010626:Phenylethyl Alcohol; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine
keywords: 3,4-dihydroxyphenylglycol (DHPG); atomoxetine; duloxetine; edivoxetine; norepinephrine transporter (NET)