Non-response to maprotiline caused by ultra-rapid metabolism that is different from CYP2D6?
METHODS
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.


CONCLUSIONS
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.
Vormfelde
S V
SV
Department of Clinical Pharmacology, Robert-Koch-Strasse, Göttingen, Germany. SVVfelde@med.uni-goettingen.de
Bitsch
A
A
Meineke
I
I
Gundert-Remy
U M
UM
Gleiter
C H
CH
D000483:Alleles; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008297:Male; D008376:Maprotiline / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2
C000715087:ABCC2 protein, human; D000929:Antidepressive Agents, Tricyclic; D000089762:Multidrug Resistance-Associated Protein 2; D008376:Maprotiline; D019389:Cytochrome P-450 CYP2D6