Christoph Sachse

The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment

The genetically polymorphic enzyme cytochrome P450 (CYP) 2D6 contributes to the biotransformation of the antipsychotic drug haloperidol. The impact of the polymorphism on haloperidol pharmacokinetics, adverse events, and efficacy was prospectively evaluated under naturalistic conditions in 172 unselected psychiatric inpatients with acute psychotic symptoms.

Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population

The genetically polymorphic cytochrome P450 enzymes 2C19 (CYP2C19) and 2D6 (CYP2D6) contribute to the metabolism of about 30% of all drugs. For analysis of the ethnic‐related differences in drug disposition and as a preparation for routine genotyping, we examined CYP2C19 and CYP2D6 mutations in a large Turkish population.

CYP2D6 Genotyping as an alternative to phenotyping for determination of metabolic status in a clinical trial setting

The emerging application of pharmacogenomics in the clinical trial setting requires careful comparison with more traditional phenotyping methodologies, particularly in the drug metabolism area where phenotyping is used extensively. The research objectives of this study were 1) to assess the utility of cytochrome P450 2D6 (CYP2D6) genotyping as an alternative to traditional phenotyping as a predictor of poor metabolizer status; 2) to identify issues for consideration when implementing CYP2D6 genotyping in clinical trials; and 3) to outline the advantages and disadvantages of CYP2D6 genotyping compared with phenotyping. DNA samples obtained from 558 previously phenotyped individuals were blindly genotyped at the CYP2D6 locus, and the genotype-phenotype correlation was then determined. The CYP2D6 genotyping methodology successfully predicted all but 1 of the 46 poor metabolizer subjects, and it was determined that this 1 individual had a novel (presumably inactive) mutation within the coding region. In addition, we identified 2 subjects with CYP2D6 genotypes indicative of poor metabolizers who had extensive metabolizer phenotypes as determined by dextromethorphan/dextrorphan ratios. This finding suggests that traditional phenotyping methods do not always offer 100% specificity. Our results suggest that CYP2D6 genotyping is a valid alternative to traditional phenotyping in a clinical trial setting, and in some cases may be better. We also discuss some of the issues and considerations related to the use of genotyping in clinical trials and medical practice.

Polymorphisms in xenobiotic conjugation and disease predisposition

Low activity of arylamine N-acetyltransferase 2 (slow NAT2) was consistently associated with urinary bladder cancer risk. The increased cancer risk attributable to slow NAT2 was more significant when taking gene-environment interactions and gene-gene interactions into account. In urinary bladder, slow NAT2 was no risk factor in subjects who never smoked but became increasingly relevant with increasing lifetime dose of tobacco smoke expressed by an odds ratio of 2.7 for slow NAT2 in extensive smokers. The functional impact of some arylamine N-acetyltransferase 1 variants is controversial. It was published that the NAT1 allele 10 was associated with high enzyme activity and that there was an overrepresentation of carriers of NAT1*10 in bladder and colon cancer, but we could only detect a moderately elevated activity of NAT1*10 and an underrepresentation of fast NAT1 alleles in bladder cancer. Recently, a C/A-polymorphism in intron 1 of cytochrome P450 1A2 was associated with high inducibility and persons with this high inducibility variant were overrepresented in bladder cancer, but only if they were smokers or if they had slow NAT2 genotypes. Numerous studies have shown that glutathione S-transferase M1 deficiency (GSTM1*0/0) increases the risk for lung and bladder cancer but the overall risk attributable to GSTM1*0/0 was only around 1.3 according to meta-analyses. The GSTM1*0/0 genotype appears to be the best established metabolic susceptibility factor. Several independent experimental approaches showed that GSTM1 decreases mutagenicity of reactive epoxides and it was shown that carriers of GSTM1*0/0 were at increased risk for several types of cancer and other diseases. There are also studies which showed no effects of GSTM1, a result which is compatible with the assumption that GSTM1*0/0 is a susceptibility factor of moderate strength. GSTM1*0/0 may, however, become a dominant risk factor in certain gene-gene combinations such as the combination with highly active CYP1A1 gene variants or in combination with specific types of exposure. Specific precautions have to be taken in the design of molecular epidemiological studies on risk factors with moderate strength; some requirements for high quality molecular epidemiological studies will be discussed in this article. Molecular epidemiology is an increasingly powerful approach to understand carcinogenesis and may be used in the future to individualize cancer prevention strategies.

Flavin monooxygenase 3 (FMO3) polymorphism in a white population: Allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism

The flavin‐containing monooxygenase 3 (FMO3) has been shown to be genetically polymorphic. In vitro, the enzyme contributes to the N‐oxidation of clozapine, caffeine, and several other drugs. We therefore wanted to analyze population frequencies and allelic linkage of FMO3 mutations and their functional effect on the metabolism of clozapine and caffeine.

Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients

Abstract. Rationale: Clozapine is a unique antipsychotic drug, outstanding for its lack of extrapyramidal side-effects and its superior efficacy in refractory schizophrenia. However, an unambiguous concentration-response relationship has not yet been established. Objective: We investigated serum concentrations of clozapine, norclozapine and clozapine-N-oxide in psychiatric in- and outpatients to identify particular metabolic patterns in clozapine responders and non-responders and putative threshold levels for clozapine response. Methods: Psychiatric assessments, CYP2D6 genotype, and weekly serum concentrations of clozapine, norclozapine and clozapine-N-oxide were obtained in 34 adult schizophrenic in-and outpatients (18 men, 16 women) during 10 weeks of clozapine treatment with a naturalistic dose design. Results: Responders (n=21) displayed significantly lower serum concentrations of clozapine corrected for dose compared to non-responders (n=13; P<0.05), while none of the other parameters (absolute clozapine concentration, metabolite ratios, gender) were different. Smokers had significantly lower dose-corrected clozapine concentrations. A positive correlation was observed between age and average steady state clozapine concentrations. Conclusions: These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.