Duloxetine increases serotonin and norepinephrine availability in healthy subjects: a double-blind, controlled study.

Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine (NE) transporters. The ability of duloxetine to alter 5-HT and NE reuptake was tested in 12 healthy male subjects. Placebo, desipramine 50 mg b.i.d., and duloxetine (80 mg q.d. or 60 mg b.i.d.) were compared in a randomized, double-blind, three-period crossover study in 12 healthy male subjects. Whole-blood 5-HT, urinary excretion of NE and major metabolites, and TYR PD30 (IV tyramine pressor dose needed to increase systolic blood pressure by 30 mmHg) were measured at steady state. Vital signs were measured periodically. Duloxetine affected 5-HT reuptake, with whole-blood 5-HT depletion vs placebo (80 mg q.d.: p=0.07; 60 mg b.i.d.: p=0.02; combined regimens: p=0.01). Cardiovascular changes reflecting increased sympathetic tone were observed with both duloxetine and desipramine, and both treatments significantly decreased whole body NE turnover (p<0.01). Duloxetine and desipramine were associated with similar mean increases in fractional extraneuronal NE concentration, although these changes did not reach statistical significance. TYR PD30 increased significantly with desipramine dosing (p<0.01). In conclusion, whole-blood measurements confirm that duloxetine inhibits platelet 5-HT uptake in vivo. Urinary and cardiovascular measurements suggest that duloxetine has an effect on NE synthesis and turnover, indicative of NE reuptake inhibition. The lack of a detectable impact of duloxetine on TYR PD30 suggests that this may not be the most sensitive indirect measure of NE reuptake when assessing dual reuptake inhibitors.

Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites.

BACKGROUND AND OBJECTIVES: Atomoxetine is a treatment for attention-deficit/hyperactivity disorder and is primarily eliminated via cytochrome P4502D6 (CYP2D6). The pharmacokinetics of atomoxetine and its primary metabolites were investigated in 10 adults with hepatic impairment (6 moderate, 4 severe) and 10 age- and sex-matched control subjects, all being genotyped as CYP2D6 extensive metabolizers. METHODS: A single oral 20-mg dose of atomoxetine was given. Multiple blood samples were collected for 48 hours in healthy subjects and for 120 hours in patients. Urine was collected up to 24 hours. Before atomoxetine administration (10-20 days), sorbitol clearance and debrisoquin (INN, debrisoquine) metabolic ratio were determined as markers of hepatic blood flow and CYP2D6 activity, respectively. RESULTS: The systemic clearance of atomoxetine was significantly reduced in those with hepatic impairment compared with controls, thereby resulting in increased exposure (area under the concentration-time curve from time 0 to infinity, 1.58 versus 0.85 microg. h(-1). mL(-1); P =.035) but no change in maximum concentration. Mean 4-hydroxyatomoxetine area under the concentration-time curve from time 0 to time t and maximum concentration were increased approximately 7-fold and 2-fold, respectively (P =.0001 and P =.0056, respectively). For the glucuronide conjugate of 4-hydroxyatomoxetine, the mean half-life was longer and the mean area under the concentration-time curve from time 0 to infinity and the maximum concentration were lower (P =.0028, P =.003, and P =.0001, respectively). The sorbitol clearance was lower and the debrisoquin metabolic ratio was higher, reflecting reduced hepatic blood flow and decreased CYP2D6 activity, respectively. Decreased atomoxetine clearance in patients with hepatic impairment was clearly correlated with decreased CYP2D6 activity and decreased hepatic blood flow. Mean atomoxetine plasma protein binding was lower in patients with hepatic impairment compared with controls (96.5% versus 98.7%, P =.0008). Atomoxetine was well tolerated in the 2 populations. CONCLUSION: For patients with attention-deficit/hyperactivity disorder who have hepatic impairment, dosage adjustment is recommended. Initial target doses should be reduced to 25% and 50% of the normal dose for patients with severe and moderate hepatic impairment, respectively.