PHENOBARBITAL INDUCES THE 2-HYDROXYLATION OF DESIPRAMINE

The kinetics of a single oral dose of desipramine (DMI; 100 mg) were s tudied in eight epileptic patients chronically treated with phenobarbi tal (PB) and in eight drug-free healthy controls. All subjects were ex tensive metabolizers with respect to the genetically determined CYP2D6 -related metabolic polymorphism. Compared with controls, epileptic pat ients exhibited lower peak plasma DMI concentrations (74 +/- 24 vs. 10 7 +/- 32 nmol/L; means +/- SD, p < 0.05), smaller DMI area-under-the-c urve values (1,943 +/- 461 vs. 3,234 +/- 1,145 nmol L(-1) h; p < 0.01) , and shorter DMI elimination half-lives (15.1 +/- 2.1 vs. 20.6 +/- 3. 4 h; p < 0.01). The proportion of the dose excreted as 2-hydroxydesipr amine (2-OH-DMI) was significantly higher in the patients (54 +/- 8 vs . 40 +/- 9%; p < 0.05). In one single poor metabolizer volunteer, a 3- week treatment with PB was associated with no major changes in DMI kin etics, but the urinary excretion of 2-OH-DMI tended to increase. These results suggest that PB is an inducer of the 2-hydroxylation of DMI, a reaction primarily catalyzed by CYP2D6, but do not provide further i nformation on the specific P450 isoenzyme(s) being induced.