Influence of CYP2D6 genotype and medication on the sparteine metabolic ratio of psychiatric patients

Objective: To investigate the influence of CYP2D6 genotype and medication o n the reliability of phenotyping in a naturalistic setting of psychiatric i npatients. Methods: The phenotype of 160 psychiatric inpatients was estimated by takin g the urinary metabolic ratio (MR) of the concentrations of sparteine to 2- and 5-dehydrosparteine. Genotyping identified CYP2D6*1, *3, *4, *5 and *6 alleles as well as duplication of the CYP2D6 gene. All subjects underwent d etailed drug history including drug dose and therapeutic drug monitoring to control compliance and abuse of other psychotropic drugs. These data were compared with those of 195 unmedicated healthy Germans. Results: The cumulative distribution of the MR in patients showed a signifi cant shift to higher MR when compared with that of healthy subjects (P less than or equal to 0.001). Patients medicated either with selective serotoni n reuptake inhibitors (SSRIs, P less than or equal to 0.001), antipsychotic drugs (P = 0.002) or other drugs known to be substrates or inhibitors of C YP2D6 (P less than or equal to 0.001) showed a significantly higher mean MR than unmedicated patients. However, there was no significant effect of tri cyclic antidepressants on the MR. Healthy subjects with CYP2D6 deficiency w ere separated by a MR of greater than 20 from those who expressed functiona l CYP2D6. Seven patients carrying at least one functional CYP2D6 allele rev ealed a MR of greater than 20, indicating the occurrence of phenocopying. Conclusion: The results of phenotyping may be falsified by drugs known to b e substrates or inhibitors of CYP2D6; thus, this method is not sufficiently reliable. However, since we observed the phenomenon of phenocopying only i n patients treated with a SSRI such as fluoxetine, fluvoxamine or paroxetin e, we conclude that sparteine phenotyping of medicated patients detects CYP 2D6 deficiency correctly, provided that patients treated with these SSRIs a re excluded.