Imipramine demethylation and hydroxylation: Impact of the sparteine oxidation phenotype

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Abstract
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 .cntdot. 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 .cntdot. 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.