Hepatic effects of duloxetine-I: non-clinical and clinical trial data.
OBJECTIVE
Review nonclinical and clinical trial data for hepatic effects of duloxetine.


METHODS
Review studies of toxicology, metabolism, mitochondrial effects, and clinical trials.


RESULTS
Nonclinical studies revealed no treatment-related transaminase elevations and no effects of duloxetine on mitochondrial beta-oxidation in rat hepatocytes. In patients with a normal baseline alanine transaminase (ALT), duloxetine was associated with elevated transaminases >3X ULN in about 1% of patients. ALT and aspartate transaminase values peaked at 8 weeks, alkaline phosphatase steadily increased to maximum value at Week 52 and mean total bilirubin values were not increased. Hepatic-related treatment-emergent adverse events were uncommon. Seven of 23,000 duloxetine- and 2/6000 placebo-treated patients met criteria for modified Hy's rule (significant elevation of both ALT and total bilirubin) but were complicated by contributing factors such as excessive alcohol consumption (n=3), gall stones, common bile duct calculus, hepatitis C, and liver adenocarcinoma (n=1 each).


CONCLUSIONS
Duloxetine has an effect on the liver, manifested by transient, self-limiting transaminase elevations. Rare events characterized as hepatocellular injury, cholestatic injury, or mixed type of hepatic injury have been reported. The pattern of liver effects was different from that in laboratory animals.
Wernicke
Joachim
J
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA. jfwernicke@lilly.com
Pangallo
Beth
B
Wang
Fujun
F
Murray
Isabelle
I
Henck
Judith W
JW
Knadler
Mary Pat
MP
D'Souza
Deborah N
DN
Uetrecht
Jack P
JP
D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects* / Q000633:toxicity; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D002986:Clinical Trials as Topic; D003257:Consumer Product Safety; D004353:Drug Evaluation, Preclinical; D000068736:Duloxetine Hydrochloride; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008107:Liver Diseases / Q000201:enzymology; D018570:Risk Assessment; D012307:Risk Factors; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects* / Q000633:toxicity; D013045:Species Specificity; D013876:Thiophenes / Q000009:adverse effects* / Q000633:toxicity
D018759:Adrenergic Uptake Inhibitors; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001219:Aspartate Aminotransferases; D001663:Bilirubin; D015415:Biomarkers; D000068736:Duloxetine Hydrochloride; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes