Extremely slow metabolism of amitriptyline but normal metabolism of imipramine and desipramine in an extensive metabolizer of sparteine, debrisoquine, and mephenytoin

Abstract

A 34-year-old man with bipolar manic depressive illness suffered from severe adverse effects during treatment with amitriptyline, 50 mg/day. It was subsequently shown that the patient was a slow metabolizer of amitriptyline. However, he tolerated a dose of 200 mg of imipramine/day, which was necessary in order to reach a therapeutic level of about 900 nM for imipramine plus desipramine. Since both antidepressants are subject to the genetic sparteine/debrisoquine oxidation polymorphism, the patient was phenotyped with sparteine. The test performed during paroxetine treatment indicated that the patient was a poor metabolizer. Subsequent tests performed during a drug-free period, however, showed the patient to be an extensive metabolizer, with a sparteine metabolic ratio (MR) of 1.7 and 2.8 and debrisoquine MR of 2.3. It was subsequently shown that paroxetine is a potent, competitive inhibitor of 1'-hydroxybufuralol formation in a human liver microsome preparation (K1 approximately 800 nM). This patient thus illustrates two problems: (a) the erroneous phenotyping due to concurrent medication, and (b) the existence of a very slow amitriptyline elimination apparently not related to the sparteine/debrisoquine oxidation polymorphism.