Imipramine disposition in alcoholics

The disposition of orally administered imipramine (IMI) was studied in 11 depressed alcoholic and 12 depressed nonalcoholic male inpatients. Subjects received 50 mg three times daily for at least 10 days to ensure steady state. Following a temporary discontinuation of therapy, several blood samples were drawn over a 40-hour period. Imipramine, desipramine, and their 2-hydroxylated metabolites were measured in plasma using a high performance liquid chromatography assay. Eight hours following the last dose, alcoholics has significantly lower IMI (50 +/- 41 versus 106 +/- 46 ng/ml; p less than 0.005) and 2-hydroxyimipramine (12.8 +/- 7.5 versus 22.6 +/- 9.8 ng/ml; p less than 0.01) levels than controls. The mean terminal half-lives in the two groups were nearly identical (16.3 +/- 6.7 hours in alcoholics versus 17.1 +/- 5.4 hours in controls). Beck Depression Inventory scores were significantly reduced during IMI therapy (p less than 0.001) in the non-alcoholic controls, whereas no change was observed in the alcoholic group. These results are consistent with either a decrease in oral bioavailability of IMI in alcoholics or, assuming complete absorption, an increase in intrinsic clearance of 2.5 fold (2444 +/- 1151 versus 986 +/- 438 ml/min; p less than 0.005) over the clearance found in control subjects. The latter seems a more likely result of chronic ethanol intake. The fact that lower levels of IMI in the alcoholic group were accompanied by a lack of efficacy in relieving depressive symptomatology suggests that whether through an effect on bioavailability or intrinsic clearance, ethanol consumption is an important consideration when recommending tricyclic therapy.