Fluoxetine disposition and elimination in cirrhosis

Fluoxetine is a specific and potent inhibitor of presynaptic serotonin reuptake and has been shown to be a clinically effective antidepressant. Elimination of the drug depends primarily on hepatic metabolism, with formation of a pharmacologically active demethylated product, norfluoxetine. The present study assesses for the first time the effect of chronic liver disease on these processes. Our data show that in stable alcoholic cirrhosis, the elimination of fluoxetine is significantly reduced. The mean t1/2 was 6.6 vs. 2.2 days and plasma clearance was 4.2 vs. 9.6 ml/min/kg for patients with cirrhosis vs. normal volunteers, respectively. In addition, the formation of norfluoxetine was decreased and its clearance was also reduced. Thus, at steady state both fluoxetine and norfluoxetine concentrations will be higher in patients with cirrhosis, unless the dosage is reduced. Conventional liver tests and indocyanine green clearance in cirrhosis did not correlate in a predictive manner with individual patients' elimination of fluoxetine.