A CYP2D6 Phenotype-Genotype Mismatch in Japanese Psychiatric Patients

The aim of the present study was to seek a CYP2D6 genotypic-phenotypic discordance possibility in Japanese patients under psychotropic drug treatment where the CYP2D6 status and pharmacodynamic responses differ from those in Caucasian psychiatric patients. Ninety drug-free, healthy volunteers and 14 patients undergoing psychotropic drug treatment were phenotyped for their individual CYP2D6 activity using dextromethorphan as a probe, and then the metabolic ratio (MR) was calculated. For the genotyping, eight mutant alleles of the CYP2D6 genes were identified. Serum concentrations of two frequently co-medicated psychotropic drugs, biperiden and levomepromazine, were determined by GC/MS. Genotyping revealed no poor metabolizers (PMs) enrolled in our study. Healthy volunteers exhibited an identical phenotype-genotype concordance, whereas 7 of the 14 patients had significantly high (p < 0.05) MRs compared with genotype-matched volunteers. Three of the patients who had the extensive metabolizer (EM) genotype had extremely high MRs and were classified as phenotypic PMs. Five patients plus all of the seven high MR patients were treated with levomepromazine and/or biperiden, respectively. Their mean serum steady-state concentrations were 27.4 and 7.6 ng/ml, respectively. A CYP2D6 phenotype-genotype mismatch (phenocopying) can occur in Japanese psychiatric patients receiving clinical doses of some psychotropic drugs where the prevalence of PMs is low and the pharmacodynamic responses to those drugs are enhanced compared to Caucasian patients.

References

• 1 Balant-Gorgia A E, Gex-Fabry M, Balant I P. Clinical pharmacogenetics of clomipramine.  Clin Pharmacokinet. 1991;  20 447-462
• 2 Baumann P, Meyer J W, Amey M, Baettig D, Bryois C, Jonzier-Perey M, Koeb L, Monney C, Woggon B. Dextromethorphan and mephenytoin phenotyping of paients treated with thioridazine or amitriptyline.  Ther Drug Monit. 1992;  14 1-8
• 3 Broly F, Marez D, Sabbagh N, Legrand M, Millecamps S, Guidice J ML, Boone P, Meyer U A. An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis.  Pharmacogenetics. 1995;  5 373-384
• 4 Brosen K, Gram L F, Haghfelt T, Bertilsson L. Extensive metabolizers of debrisoquine become poor metabolizers during quinidine treatment.  Pharmacol Toxicol. 1987;  60 312-314
• 5 Brosen K. Drug metabolizing enzymes and therapeutic drug monitoring in psychiatry.  Ther Drug Monit. 1996;  18 393-396
• 6 Chen S, Chou W -H, Blouin R A, Mao Z, Humphries L L, Meek Q C, Neill J R, Martin W L, Hays L R, Wedlund P J. The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: Screening costs and influence on clinical outcomes in psychiatry.  Clin Pharmacol Ther. 1996;  60 522-534
• 7 Chida M, Yokoi T, Nemoto N, Inaba M, Kinoshita M, Kamataki T. A new variant CYP2D6 allele (CYP2D6*21) with a single base insertion in exon 5 in a Japanese population associated with a poor metabolizer phenotype.  Pharmacogenetics. 1999;  9 287-293
• 8 Dahl M L, Yue Q y, Roh H K, Johansson I, Sawe J, Sjoqvist F, Ingelman-Sundberg M. Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects.  Pharmacogenetics. 1995;  5 159-164
• 9 Derenne F, Joanne C, Vandel S, Bertschy G, Volmat R, Bechtel P. Debrisoquine oxidative phenotyping and psychiatric drug treatment.  Eur J Clin Pharmacol. 1989;  36 53-58
• 10 Eap C B, Bertel-Laubscher R, Zullino D, Amey M, Baumann P. Marked increase of venlafaxine enantiomer concentrations as a consequence of metabolic interactions: a case report.  Pharmacopsychiatry. 2000;  33 112-115
• 11 Frackiewicz E J, Sramek J J, Herrera J M, Kurtz N M, Cutler N R. Ethnicity and antipsychotic responses.  Ann Pharmacother. 1997;  31 1360-1369
• 12 Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer U A. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism.  Am J Hum Genet. 1991;  48 943-950
• 13 Gram L F, Debruyne D, Caillard V, Boulenger J P, Lacotte J, Moulin M, Zarifian E. Substantial rise in sparteine metabolic ratio during haloperidol treatment.  Br J Clin Pharmacol. 1989;  27 272-275
• 14 Gram L F, Hansen M GJ, Sindrup S H, Brosen K, Poulsen J H, Aaes-Jorgensen T, Overo K F. Citalopram: Interaction studies with levomepromazine, imipramine, and lithium.  Ther Drug Monit. 1993;  15 18-24
• 15 Haffen E, Vandel P, Broly F, Vandel S, Sechter D, Bizouard P, Bechtel P R. Citalopram: an interaction study with clomipramine in a patient heterozygous for CYP2D6 genotype.  Pharmacopsychiatry. 1999;  32 232-234
• 16 Horai Y, Nakano M, Ishizaki T, Ishikawa K, Zhou H H, Zhou B I, Liao C L, Zhang L M. Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese.  Clin Pharmacol Ther. 1989;  46 198-207
• 17 Jerling M, Bertilsson L, Sjoqvist F. The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline.  Ther Drug Monit. 1994;  16 1-12
• 18 Johansson I, Lundqvist E, Bertilsson L, Dahl M L, Sjoqvist F, Ingelman-Sundberg M. Inherited amplification of an active gene in the cytochrome P450 2D-locus as a cause of ultrarapid metabolism of debrisoquine.  Proc Natl Acad Sci USA. 1993;  90 11 825-11 829
• 19 Johansson I, Oscarson M, Yue Q Y, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation.  Mol Pharmacol. 1994;  46 452-459
• 20 Kudo S, Uchida M, Odomi M. Metabolism of carteolol by cDNA-expressed human cytochrome P450.  Eur J Clin Pharmacol. 1997;  52 479-485
• 21 Lin K M, Poland R E, Nuccio I, Matsuda K, Hathuc N, Su T P, Fu P. A longitudinal assessment of haloperidol doses and serum concentrations in Asian and Caucasian schizophrenic patients.  Am J Psychiatry. 1989;  146 1307-1311
• 22 Lin K M, Poland R E, Lau J K, Rubin R T. Haloperidol and prolactin concentrations in Asians and Caucasians.  J Clin Psychopharmacol. 1988;  8 195-201
• 23 Llerena A, Herraiz A G, Cobaleda J, Johansson I, Dahl M L. Debrisoquin and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents.  Clin Pharmacol Ther. 1993;  54 606-611
• 24 Marshall P S, Straka R J, Johnson K. Determination of dextromethorphan and its O-demethylated metabolite from urine.  Ther Drug Monit. 1992;  14 402-407
• 25 Mihara K, Suzuki A, Kondo T, Yasui N, Furukori H, Nagashima U, Otani K, Kaneko S, Inoue Y. Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia.  Clin Pharmacol Ther. 1999;  65 291-294
• 26 Nakamura K, Goto F, Ray W A, McAllister C B, Jacqz E, Wilkinson G R, Branch R A. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations.  Clin Pharmacol Ther. 1985;  38 402-408
• 27 Potkin S G, Shen Y, Pardes H, Phelps B H, Zhou D, Shu L, Korpi E, Wyatt J. Haloperidol concentrations elevated in Chinese patients.  Psychiatry Res. 1984;  12 167-172
• 28 Roh H K, Dahl M L, Johansson I, Ingelman-Sundberg M, Cha Y N, Bertilsson L. Debrisoquine and S-mephenytoin hydroxylation phenotypes and genotypes in a Korean population.  Pharmacogenetics. 1996;  6 441-447
• 29 Schmid B, Bircher J, Preisig R, Kupfer A. Polymorphic dextromethorphan metabolism: Cosegregation of oxidative O-demethylation with debrisoquine hydroxylation.  Clin Pharmacol Ther. 1985;  38 618-624
• 30 Sindrup S H, Brosen K, Hansen M G, Aaes-Jorgensen T, Overo K F, Gram L F. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphism.  Ther Drug Monit. 1993;  15 11-17
• 31 Sohn D R, Shin S G, Park C W, Kusaka M, Chiba K, Ishizaki T. Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations.  Br J Clin Pharmacol. 1991;  32 504-50
• 32 Spina E, Martines C, Caputi A P, Cobaleda J, Pinas B, Carrillo J A, Benitez J. Debrisoquine oxidation phenotype during neuroleptic monotherapy.  Eur J Clin Pharmacol. 1991;  41 467-470
• 33 Sramek J J, Sayles M A, Simpson G M. Neuroleptic dosage for Asians: a failure to replicate.  Am J Psychiatry. 1986;  143 535-536
• 34 Syvalahti E KG, Lindberg R, Kallio J, De Vocht M. Inhibitory effects of neuroleptics on debrisoquine oxidation in man.  Br J Clin Pharmacol. 1986;  22 89-92
• 35 Tateishi T, Chida M, Ariyoshi N, Mizorogi Y, Kamataki T, Kobayashi S. Analysis of the CYP2D6 gene in relation to dextromethorphan O-demethylation capacity in a Japanese population.  Clin Pharmacol Ther. 1999;  65 570-575
• 36 Tucker G T. Clinical implications of genetic polymorphism in drug metabolism.  J Pharm Pharmacol. 1994;  1 417-424
• 37 von Bahr C, Spina E, Birgersson C, Ericsson O, Goransson M, Henthorn T, Sjoqvist F. Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes.  Biochem Pharmacol. 1985;  34 2501-2505
• 38 Yokoi T, Kosaka Y, Chida M, Chiba K, Nakamura H, Ishizaki T, Kinoshita M, Sato K, Gonzalez F J, Kamataki T. A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype.  Pharmacogenetics. 1996;  6 395-401
• 39 Yokota H, Tamura S, Furuya H, Kimura S, Watanabe M, Kanazawa I, Kondo I, Gonzalez F J. Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism.  Pharmacogenetics. 1993;  3 256-263