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Non-response to maprotiline caused by ultra-rapid metabolism that is different from CYP2D6?
S V Vormfelde1, A Bitsch, I Meineke
1Department of Clinical Pharmacology, Robert-Koch-Strasse, Göttingen, Germany. SVVfelde@med.uni-goettingen.de
Case:
We are reporting about a patient with major depression who failed to respond to pharmacotherapy due to ultra-rapid metabolism of maprotiline. Under daily oral doses of 175 mg maprotiline, the patient's metabolic ratio (MR) for maprotiline in plasma was 9.2 (expected MRp: 2.4) and the clearance of maprotiline (CLM) was 4190 ml.min-1 (expected CLM = 1220 in extensive metabolisers of CYP2D6).
Results:
The patient's MRurine for sparteine was 0.5, which is within the range for extensive metabolisers of CYP2D6. Genotyping did not show a duplication of the CYP2D6L allele. The patient's caffeine half-life was 10 h, thus, precluding ultra-rapid metabolism for CYP1A2. The therapeutic regiment was changed to co-administration of 200 mg maprotiline and 20 mg fluoxetine once per day in order to inhibit metabolism via CYP2D6. Subsequently, MRP of maprotiline (4.9) and CLM were reduced (1900 ml.min-1; expected CLM in poor metabolisers: of CYP2D6 364). This regimen improved the clinical outcome of the underlying disease.
Conclusion:
We conclude that for the non-response seen with maprotiline, P450 isozymes other than CYP2D6 or CYP1A2 are responsible. As CYP2C19 is involved in the metabolism of a number of tricyclic antidepressants it may be a candidate for ultra-rapid metabolism in this patient.