Dextromethorphan and mephenytoin phenotyping of patients treated with thioridazine or amitriptyline.
The metabolism of most tricyclic antidepressants and some phenothiazine neuroleptics is under the genetic control of hepatic cytochrome P-450IID6, which also regulates the metabolism of dextromethorphan. This study investigated the effect of treatment with amitriptyline or thioridazine on testing for genetically regulated efficiency of the metabolism of dextromethorphan and mephenytoin. One group of 33 patients was treated with 150 mg amitriptyline a day (the AMI group); 25 other patients received a daily dose of thioridazine, either 200 mg (200-THD group; n = 7) or 400 mg (400-THD group; n = 18). Before and after 10 days of this treatment, all patients were tested with 25 mg dextromethorphan and 100 mg mephenytoin to determine their pharmacogenetic status with respect to their hepatic drug oxidizing systems (cytochrome P-450IID6 and P-450 MP). Two patients were poor metabolizers (PMs) of dextromethorphan and three of mephenytoin. Treatment with either psychotropic drug was without significant effect on the metabolism of mephenytoin, but both amitriptyline and thioridazine increased significantly the metabolic ratio of dextromethorphan/dextrorphan. Thioridazine had the effect of changing the pharmacogenetic status of 15 efficient metabolizers of dextromethorphan to poor metabolizers; amitriptyline did not have such an effect. There was no significant correlation between day-11 plasma levels of thioridazine, mesoridazine, or sulforidazine and the metabolism of dextromethorphan, but there was a correlation between the metabolism of dextromethorphan and plasma levels of amitriptyline and nortriptyline. Amitriptyline (p less than 0.05), but not thioridazine, decreases the ratio of conjugated/total dextrorphan in urine.(ABSTRACT TRUNCATED AT 250 WORDS)
Baumann
P
P
University Department of Adult Psychiatry, Hôpital de Cery, Prilly-Lausanne, Switzerland.
Meyer
J W
JW
Amey
M
M
Baettig
D
D
Bryois
C
C
Jonzier-Perey
M
M
Koeb
L
L
Monney
C
C
Woggon
B
B
D000328:Adult; D000639:Amitriptyline / Q000097:blood / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003915:Dextromethorphan / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D008617:Mephenytoin / Q000493:pharmacokinetics* / Q000652:urine; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010641:Phenotype; D013881:Thioridazine / Q000097:blood / Q000494:pharmacology*
D000639:Amitriptyline; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D013881:Thioridazine; D008617:Mephenytoin