title: Phenobarbital induces the 2-hydroxylation of desipramine.
abstract: The kinetics of a single oral dose of desipramine (DMI; 100 mg) were studied in eight epileptic patients chronically treated with phenobarbital (PB) and in eight drug-free healthy controls. All subjects were extensive metabolizers with respect to the genetically determined CYP2D6-related metabolic polymorphism. Compared with controls, epileptic patients exhibited lower peak plasma DMI concentrations (74 +/- 24 vs. 107 +/- 32 nmol/L; means +/- SD, p < 0.05), smaller DMI area-under-the-curve 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-hydroxydesipramine (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 kinetics, 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 information on the specific P450 isoenzyme(s) being induced.
authors.affiliation: Institute of Pharmacology, University of Messina, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Spina
authors.forename: A
authors.initials: A
authors.lastname: Avenoso
authors.forename: G M
authors.initials: GM
authors.lastname: Campo
authors.forename: A P
authors.initials: AP
authors.lastname: Caputi
authors.forename: E
authors.initials: E
authors.lastname: Perucca
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D003647:Debrisoquin; D003891:Desipramine / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000652:urine; D004790:Enzyme Induction / Q000187:drug effects; D004827:Epilepsy / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000502:physiology
chemical_list: D000927:Anticonvulsants; D000929:Antidepressive Agents, Tricyclic; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D003891:Desipramine; C028653:2-hydroxydesipramine; D003647:Debrisoquin; D010634:Phenobarbital