Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype.

Eighteen healthy volunteers, selected according to their ability to oxidize sparteine, took single oral doses of 100 mg imipramine and desipramine. For imipramine the following clearances (L X min-1) were found in six rapid extensive metabolizers (EM), six slow EM, and six poor metabolizers (PM), respectively (mean and range): apparent oral clearance: 2.55 (1.39 to 3.47), 2.28 (1.18 to 4.26), and 1.35 (0.96 to 1.64). Clearance via demethylation was: 1.42 (0.61 to 2.01), 1.60 (0.78 to 3.81), and 1.09 (0.76 to 1.64); clearance via other pathways was: 1.13 (0.74 to 1.75), 0.69 (0.40 to 1.59), and 0.26 (0 to 0.46). For desipramine the apparent oral clearance (L X min-1) was 0.19 (0.12 to 0.24) in PM compared with 1.64 (1.46 to 1.80) and 1.03 (0.77 to 1.13) in rapid EM and slow EM. Extremely long elimination t1/2s of desipramine were seen in PM: 81 to 131 hours compared with 13 to 23 hours in EM. 2-OH-imipramine and 2-OH-desipramine were detectable in plasma of only the 12 EM, where the ratio-to-parent compound was higher in rapid EM than in slow EM. This study confirms that 2-hydroxylation of imipramine and desipramine depends almost exclusively on the sparteine oxygenase, whereas the demethylation of imipramine depends mainly on a different isozyme.