Genetic Polymorphisms In Drug Metabolism Research Articles

Experience of Low Dose (25mg/Kg) of Cyclophosphamide (Chennai-Chezhian-Kishore PTCy Protocol) As Post Transplant Cyclophosphamide (PTCy) Dose in Haploidentical Bone Marrow Transplant

Introduction:-Haploidentical Bone marrow transplantation has become one of the most commonly employed alternative donor techniques, with many centers applying T-cell-replete strategies developed by the Baltimore group using high-dose post-transplant cyclophosphamide. The usefulness of this technique is to reduce graft acquisition cost, lesser grade of GVHD, and reduction in non-relapse mortality. One problem we face in a country like India is the worry of engraftment delay leading to refractory multi-drug resistant gram-negative sepsis increasing the risk of transplant-related mortality. We took up this pilot study to check for the feasibility of a low dose (50%) 25mg/kg of cyclophosphamide as PTCy and its impact on transplant outcomes especially GVHD.Methodology:-This study was done from January 2016 to June 2019. 41 Haploidentical bone marrow transplants were done for Acute Myeloid leukemia at this time under this protocol. 23 Cases had Busulfan / Fludarabine as conditioning and in 18 cases; we used Treosulfan / Fludarabine-based conditioning regimen. The study protocol PTCy dose was 25mg/kg on Day +3 and Day +4. Cyclosporine / Tacrolimus was used from day -1 in all patients as GVHD prophylaxis. The parameters analyzed are engraftment dynamics, rates of gram-negative sepsis, hemorrhagic cystitis, rates of acute and chronic GVHD, and 2-year Non-relapse mortality.Results:Parents were the haploidentical donors in 22 cases whereas siblings in the rest 19 cases. Peripheral blood stem cell collection was chosen in all cases. The average CD34 dose was 6.8 x 10 6/Kg of the recipient. The mean number of days to achieve engraftment was around day 11. Culture-proven gram-negative sepsis was seen in 11 cases (26.8%). Two patients died within Day +30. Both due to sepsis. The rates of acute GVHD of grade I/2 was 18 (43.9%) and grade 3/4 acute GVHD was seen only in 2 patients (5%). No mortality was due to GVHD. With a median follow-up of two years, chronic skin and liver grade 1/2 GVHD was noted in 29 patients (74.3%) but were manageable with oral and topical medications not needing admission. Three patients had hemorrhagic cystitis. CMV reactivation needing medications was seen in 5(12.2%) patients indicating a higher incidence of post-transplant viral reactivation with PTCy. At data cut-off, we had lost 12 patients due to relapse and there was no non-relapse mortality except for the two sepsis-related death.Conclusion:The results of this pilot study indicate the feasibility of using a low dose PTCy (25mg/kg) in Haploidentical transplant as a methodology for in vivo T cell depletion without increased incidence of GVHD and Non-relapse mortality in Indian patients. This is a small study and it needs further follow-up with drug metabolism analysis and a bigger cohort to make this Chennai-Chezhian-Kishore PTCy Protocol a validated standard in Haplo-identical transplants. This is a pilot study and we are planning to incorporate genetic polymorphism in drug metabolism to validate the proposed protocol more scientifically.Reference:1. Wang, Y et al. Low-dose post-transplant cyclophosphamide and anti-thymocyte globulin as an effective strategy for GVHD prevention in haploidentical patients. J Hematol Oncol 12, 88 (2019). https://doi.org/10.1186/s13045-019-0781-y2. Shannon R. McCurdy, Leo Luznik How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide Blood (2019) 134 (21): 1802-1810. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pharmacokinetic drug-drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy.

The extensive use of tyrosine kinase inhibitors (TKI's) in hematology and oncology has shown that these drugs have a significant potential for drug-drug interactions. Since these drugs have a rather low therapeutic window, some drug interactions are of particular clinical relevance either on drug toxicity or on patient's response. Significant interactions occur with concomitant use of acid-suppressive therapy leading to a decreased oral bioavailability. However, such interactions are drug dependent according to their solubility pattern and to the duration of action of acid-suppressive therapy, which is coprescribed. Significant interactions occur by inhibition or induction of CYP450 3A4 which is the main metabolic pathway of TKIs. However, minor metabolic pathways should also be paid attention to. Interactions involving efflux and influx transporters should also be considered occurring for some TKIs. Genetic polymorphism in drug metabolism as well as in drug transport is a factor of variability in drug exposure, which could modulate the magnitude of drug-drug interactions (DDIs). It should be noticed that TKIs can also be at the origin of drug interactions by altering the pharmacokinetics of coprescribed drugs. Since cancer patients are given many drugs either for supportive care or for the treatment of drug toxicity, and to the fact that the oldest patients are polymedicated, a clear understanding of DDIs with TKIs is of interest. The objectives of this review are to provide an overview of the mechanisms of DDIs with TKIs and to provide to physicians and pharmacists recommendations to manage these DDIs in their clinical practice.

Risk Factors for Subtherapeutic Tacrolimus Levels after Conversion from Continuous Intravenous Infusion to Oral in Children after Allogeneic Hematopoietic Cell Transplantation

Tacrolimus (FK506) is a calcineurin inhibitor and is an essential component of many immunosuppressive regimens. The oral bioavailability of tacrolimus may be affected by many factors, including patient age and gender, as well as by drug-drug interactions or genetic polymorphisms in drug metabolism. The dosing recommendations for pediatric allogeneic hematopoietic cell transplantation (alloHCT) recipients have been derived from tacrolimus use in adult solid-organ transplantation patients. Data describing the impact of conversion of i.v. tacrolimus to oral on the incidence of acute graft-versus-host disease (aGVHD) are limited in children after alloHCT. In this study, we describe the incidence of grades II to IV aGVHD after conversion from i.v. tacrolimus to oral tacrolimus and study the clinical factors associated with delayed achievement of therapeutic blood levels. In this retrospective analysis, 68 pediatric patients (median age, 6.7 years; range, .25 to 22 years), underwent alloHCT for malignant and nonmalignant diseases and received tacrolimus and mycophenolate mofetil for aGVHD prophylaxis. Among all patients, the median number of days to achieve therapeutic tacrolimus trough concentration (10 ng/mL to 20 ng/mL) was 7 days (range, 0 to 37 days). Twenty-two patients developed grades II to IV aGVHD and the cumulative incidence of grades II to IV aGVHD in all patients was 32.4% (standard error, .06). On multivariate analysis ethnicity (white versus others: odds ratio [OR], −4.5; 95% confidence interval [95% CI], 1.091 to 18.91; P = .038) and ≥ 10 days of subtherapeutic tacrolimus levels in first 30 days on i.v. (OR, −3.8; 95% CI, 1.276 to 11.43; P = .017) were significantly associated with delay in achieving therapeutic tacrolimus trough concentration. The impact of race/ethnicity on therapeutic tacrolimus trough concentration in pediatric alloHCT recipients should be further studied prospectively so that individualized dosing plans can be developed.

Pharmacogenetics of drug-metabolizing enzymes in Italian populations.

Drug-metabolizing enzymes play a major role in the biotransformation and subsequent elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Inter-individual differences in genes coding for drug-metabolizing enzymes are important for understanding variability in drug response and for individualization of drug prescription. The prevalence of genetic polymorphisms in drug metabolism varies widely with ethnicity, and marked differences in the distribution of allelic variants of genes encoding drug-metabolizing enzymes have been documented in populations of different racial origin. This review aimed to summarize the available studies on genetic polymorphisms associated with drug metabolism conducted in Italian populations and to compare the frequency of the various metabolizer phenotypes and most common variant alleles (and resulting genotypes) with corresponding values from other populations. Notably, published data are not extensive, and most studies were performed on relatively low numbers of individuals. In general, the frequency of polymorphisms in the cytochrome P450 (CYP) genes as well as in the investigated phase II enzymes in the Italian population was similar to values reported for other Caucasian populations. However, the prevalence of CYP2D6 gene duplication among Italians was found to be very high, confirming the higher frequency of CYP2D6 ultrarapid metabolizers in the Mediterranean area compared to Northern Europe. It is worth noting that a geographic gradient in the flavin-containing monooxygenase 3 polymorphism distribution was also seen, the Italian population showing higher similarity to other Mediterranean populations than to North Europeans.

Predictive potential of ABCB1, ABCC3, and GSTP1 gene polymorphisms on osteosarcoma survival after chemotherapy.

Genetic polymorphisms in drug metabolism and transport genes can influence the pharmacokinetics and pharmacodynamics of chemotherapy drugs. We investigated the role of genes involved in metabolic and transport pathways in response to chemotherapy and clinical outcome of osteosarcoma patients. The association between the eight polymorphisms with response to chemotherapy and clinical outcome of patients was carried out by unconditional logistic regression analysis and Cox proportional hazard models. Of 186 patients, 98 patients showed good response to chemotherapy, 64 died, and 97 showed progression at the end of the study. Patients carrying ABCB1 rs1128503 TT genotype and T allele were more likely to have a good response to chemotherapy. ABCC3 rs4148416 TT genotype and T allele and GSTP1 rs1695 GG genotype and G allele were associated with poor response to chemotherapy. In the Cox proportional hazards model, after adjusting for potential confounding factors, patients carrying ABCB1 rs1128503 TT genotype and T allele were associated with lower risk of progression-free survival (PFS) and overall survival (OS). ABCC3 rs4148416 TT genotype and T allele and GSTP1 rs1695 GG genotype and G allele were correlated with high risk of PFS and OS. The ABCB1 TT and GSTP1 GG genotypes were significantly associated with a shorter OS. In conclusion, variants of ABCB1 rs128503, ABCC3 rs4148416, and GSTP1 rs1695 are associated with response to chemotherapy and PFS and OS of osteosarcoma patients; these gene polymorphisms could help in the design of individualized therapy.

Personalisierte Pharmakotherapie

The broad clinical application of pharmacogenetic diagnostics for individualised drug treatment is still limited. With the exception of oncological therapies where molecular tumor makers are frequently used to decide upon individual drug therapies, pharmacogenetic testing is not generally offered in clinical laboratory diagnostics, because the costs are not covered by general health insurance and it is not evident what consequences the results of a genotyping test may have for the individual drug treatment. Especially in the context of pharmacokinetics, bioequivalence-based concepts have been developed that allow the individual drug dosage or therapy to be adjusted to genetic polymorphisms in drug metabolism, drug transport that affect drug absorption, metabolism and elimination. Pharmacogenetic aspects are increasingly included in the product information (e.g., on its website the FDA lists more than 60 drug labels that include pharmacogenetic information). However, most pharmacogenetic information on drug labels does not give recommendations for clinical decisions to be made based on individual genotypes. This gap is currently being closed by the development of international consortia aiming to base clinical recommendations on the best available evidence by systematic review of the existing data. The Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network (CPIC) is an international community-driven organisation that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). The aim of these guidelines is to give therapeutic recommendations such as dose adjustments or suggestions for the choice of an alternative drug in the case of specific genotypes (phenotypes) that predict slow metabolism or transport of drugs or safety risks or risks of therapeutic failure. These guidelines are not mandatory but serve to facilitate the translation of pharmacogenetic knowledge from bench to bedside.

Susceptibility of Human Lymphocytes to 2-Nitrofluorene-Induced Gene Mutation is Strongly Dependent on Metabolic Genotypes

Genetic polymorphisms in drug metabolism contribute largely to adverse drug reactions in susceptible individuals due to excess production of reactive metabolites and active oxygen species. We conducted an in vitro study that clearly demonstrates that functional impact of common polymorphisms in the metabolic genes, such as N-acetyltransferase 2 (NAT2), can be easily reflected in mutant induction in the gene coding for hypoxanthineguanine phosphoribosyl transferase (HPRT) in T-lymphocytes isolated from human peripheral blood. NAT2 is involved in the metabolic activation of 2-nitrofluorene (2-NF) to the known aromatic amide carcinogen N-acetyl- 2-aminofluorene. Subsequent deactivation through glutathione conjugation involves glutathione S-transferase M1 (GSTM1). We obtained a clear dose-related increase in the HPRT mutant frequency after treating mitogen-stimulated lymphocytes isolated from a normal blood donor with 2-NF (up to 5 fold at 400 μg/mL, 24h exposure), while no HPRT mutant induction was observed using cells from another blood donor. The susceptible cells turned out to have the NAT2 rapid and GSTM1 null genotype combination (capable of activation, with insufficient deactivation), while the resistant cells had the NAT2 slow and GSTM1 positive combination. Although the contribution of GSTM1 genotype is less clear, our finding suggests that functional polymorphisms in key metabolic genes do affect induction of gene mutations at the HPRT locus and at least the NAT2 genotype plays a critical role in determining the susceptibility of human cells to genotoxicity of 2-NF. Further, human peripheral T-lymphocytes and the in vitro HPRT gene mutation assay can be utilized to study the functional impact of common genetic polymorphisms in drug metabolism and to identify risk genotypes susceptible for drug toxicity and somatic mutations.

A huge number of mixtures and substances: How to deal with them?

It is of great importance that the effects of any potentially interacting factors, such as food supplements, nutraceuticals, and dietary products, folk herbal and medicinal plants with general chemotherapy are identified and assessed. A survey of the main molecules from such products available need to be assessed to help in the understanding of the possible risk involved.Nevertheless in all these products a huge number of mixtures and substances are present, the more suggested situations in literature which cause herbal–drug interactions, are regarding both phases of the metabolizing process. Phase-I (functionalization, mainly involving CYP450 iso-enzymes as 2C6 and 3A4) and Phase-II (conjugation, mainly sulpho- and glucuron-) reactions are the more important.Variable factors such as age-dependent variations and changes caused by physiological conditions and diseases, as well as on drug–drug, food–drug or herbal–drug interactions may lead to variations in drug metabolism. Diversity in the genome is the main source for differences in drug metabolism between animal species including humans and leads to variations between individuals of a particular species. A broad range of relevant polymorphic enzymes and examples of affected drugs are published. A profound knowledge on frequent variations in drug metabolizing enzymes and their consequences is indispensable for personalized pharmacotherapy (Kramer and Testa, 2008). In a near future approaches for therapy optimization with regard to genetic polymorphisms in drug metabolism will be available.In mean time it is important to have the most reports possible in this issue that will help us to understand this complex mechanism and create easy ways to help the patients and the knowledge to educate the population in general with the warnings that need to be proven for future advice.

AmpliChip for Cytochrome P-450 Genotyping: The Epoch of Personalized Prescriptions

The clinical importance of genetic polymorphisms in drug metabolism is well-known in clinical pharmacotherapy. The first widely available pharmacogenomic microarray technology approved by the Food and Drug Administration as a medical device to clinically genotype genetic polymorphisms in drug metabolism is now available with the launch of AmpliChip technology. This readily accessible clinical microarray test allows the genotyping of cytochrome (CYP) P-450 2D6 and 2C19 and marks a milestone in the epoch of evidence based personalized medicine. Many commonly used drugs are substrates for CYP2D6 and CYP 2C19 and hence may potentially demonstrate phenotypic differences as poor, intermediate, extensive, and ultrarapid metabolizers. These phenotypic variations could lead to expressed differences in pharmacotherapeutic patient outcomes. AmpliChip currently allows for testing of multiple alleles (31) in a single assay. Other technologies for pharmacogenomics are on the horizon. This article reviews the importance of polymorphic enzymes and genotyping as to how genetic polymorphisms alter pharmacotherapy and the emergence of a plethora of technologies that may become routinely available for clinical pharmacogenomic testing in the near future.

Global systems biology, personalized medicine and molecular epidemiology

Mol Syst Biol. 2: 52 One of the great challenges for 21st century medicine is to deliver effective therapies that are tailored to the exact biology or biological state of an individual to enable so‐called ‘personalized healthcare solutions’. Ideally, this would involve a system of patient evaluation that would tell clinicians the correct drug, dose or intervention for any individual before the start of therapy. A practical approach to this evaluation is the concept of patient stratification in which individuals are biologically subclassified (classically according to some genetic features) and biofeatures modelled in relation to outcome. In principle, such stratification for personalized therapy can be applied to drug safety and efficacy modelling and to more general healthcare paradigms involving optimized nutrition and lifestyle management. Of course, truly personalized treatments, even if they can be developed and applied widely, will lamentably always be a luxury of the worlds' richest citizens and nations. So in some respects, personalized healthcare might appear to be at the opposite end of the medical spectrum to the subject of epidemiology in which disease risk factors and disease incidence are studied in populations rich and poor alike. Systems biology provides us with a common language for both describing and modelling the integrated action of regulatory networks at many levels of biological organization from the subcellular through cell, tissue and organ right up to the whole organism. The relatively new science of molecular epidemiology concerns the measurement of the fundamental biochemical factors that underlie population disease demography and understanding ‘the health of nations’ and this subject naturally lends it to systems biology approaches. Hence, systems biology is certain to have in future a major role in both the development of personalized medicine and in molecular epidemiological studies. Populations are, of course, made up of individuals and, in …

Ethnic differences in responses to disease modifying drugs.

The UK has a growing South Asian population. In the South Asian population of Bradford people appear to be less tolerant of disease-modifying anti-rheumatic drugs (DMARDs). One reason for this may be poor communication during patient education, which is generally designed for white North European people. Our objective was to obtain information on DMARDs that were used, the duration of their use and reasons for their discontinuation between ethnic groups. Retrospective data were obtained from the inception of a clinical database in August 1993 to July 2001 using 'DMARD' as the main search item; a total of 5479 DMARD prescriptions were represented in the data. A subset of the data so obtained was cross-checked against the patient records. Inaccuracies in start and stop dates prior to January 1997, together with other reasons (such as incomplete data), resulted in a final data set of 2356 drugs. The drugs had been given to 1391 patients. Overwhelmingly, the two main ethnic groups were North European (1191 patients) and South Asian (193 patients). The final data set was based on the following drugs: azathioprine (179); antimalarials (chloroquine and hydroxychloroquine) (407); corticosteroids (648); D-penicillamine (61); methotrexate (459); sulphasalazine (493); and sodium aurothiomalate (96). Survival analysis showed that age and drug type were important variables influencing the duration of time spent on a drug before discontinuation. For age, drug survival was better for the older age group [log rank test, chi2(3) = 29.1, P < 0.0001]. For drug, survival was best for steroids, followed in decreasing order by sulphasalazine, methotrexate, sodium aurothiomalate, azathioprine, antimalarials and D-penicillamine [chi2(6) = 99.3, P < 0.00001). For all drugs, the main ethnic groups differed, with a 12-month survival rate of drugs in the North European group of 0.742 (95% confidence interval 0.693-0.791) and the South Asian group of 0.665 (95% confidence interval 0.645-0.684) [log rank test, chi2(1) = 18.19, P < 0.00001]. As the two main ethnic groups differed with respect to age and drug type, further survival analysis adjusting for these variables confirmed a significant difference between the two ethnic groups. The main reasons for terminating the DMARD differed between the groups: people of South Asian origin were more likely to discontinue the drug because of rashes, lack of efficacy and worry about the potential side-effects of the drug. People of South Asian ethnic status terminate DMARD therapy sooner than North Europeans. The reasons for this difference are not clear but may concern problems with effective communication, cultural differences in attitudes to chronic illness or genetic polymorphisms in drug metabolism.

Gene-environmental interactions: Lessons from porphyria

The porphyrias are uncommon, complex, and fascinating metabolic conditions, caused by deficiencies in the activities of the enzymes of the heme biosynthetic pathway. Two cardinal symptoms of the porphyrias are cutaneous photosensitivity and neurologic disturbances. Molecular analysis of gene defects has shown that there are multiple and heterogeneous mutations in each porphyria. Patients with symptomatic porphyria can suffer greatly, and, in rare cases, may die. While congenital porphyrias are inherited, other forms of porphyria occur as acquired diseases. In addition, not all gene carriers of inherited porphyrias develop clinical disease and there is a significant interplay between the gene defect and acquired or environmental factors. The variable response of porphyrias to acquired factors may, likely reflect genetic polymorphisms in drug metabolism. The lessons from acute hepatic porphyria, such as acute intermittent porphyria, are very useful in clarifying the complex nature of the clinical expression of metabolic disorders.

Research agenda for pediatric gastroenterology, hepatology and nutrition: molecular basis of gastrointestinal diseases. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Research agenda for pediatric gastroenterology, hepatology and nutrition: molecular basis of gastrointestinal diseases. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Pharmacogenetics and adverse drug reactions

Polymorphisms in the genes that code for drug-metabolising enzymes, drug transporters, drug receptors, and ion channels can affect an individual's risk of having an adverse drug reaction, or can alter the efficacy of drug treatment in that individual. Mutant alleles at a single gene locus are the best studied individual risk factors for adverse drug reactions, and include many genes coding for drug-metabolising enzymes. These genetic polymorphisms of drug metabolism produce the phenotypes of "poor metabolisers" or "ultrarapid metabolisers" of numerous drugs. Together, such phenotypes make up a substantial proportion of the population. Pharmacogenomic techniques allow efficient analysis of these risk factors, and genotyping tests have the potential to optimise drug therapy in the future.

Antiepileptic drug pharmacogenetics.

Until recently, the drug treatment of epilepsy has been empirical. However, in recent years as a result of improved understanding of seizure neurochemistry and mechanisms of action of antiepileptic drugs (AEDs), drug treatment has become somewhat more rational. Nevertheless, it is currently impossible to predict which patient will respond to a particular AED, and which patient will experience adverse drug effects. The only practical way to determine whether a patient will find a drug useful is to try it. The discovery of genetic polymorphism in drug metabolism has contributed significantly to understanding of the variability in dose-concentration relationships, susceptibility to adverse effects, and susceptibility to seizure intractability. The discovery that predisposition to seizure intractability and expression of brain neuromolecules consequent to seizures is under genetic control may allow a more rational approach to AED choice. In the future, treatment may be guided by a series of pharmacogenetic tests, which would serve not only to choose the most appropriate AED (in terms of efficacy and adverse effects) but also to monitor the antiepileptogenic and the evolution status of the disease.

Pharmacogenetics of Cancer Therapy: Getting Personal

The term “pharmacogenetics” was coined in the 1950s to describe inherited differences in the disposition and effects of medications and other xenobiotics. Pharmacogenetic studies have focused largely on inherited variations in drug metabolism and polymorphisms of the genes encoding drug-metabolizing enzymes, to elucidate the molecular basis of these variations (Nebert 1997). Although genetic polymorphism in drug metabolism remains a primary focus, inherited differences in drug targets (e.g., receptors, genetic subsets of diseases, etc.) represent another facet of pharmacogenetics that can be of equal importance in determining the effects of some medications.

S16-1 - Genetic polymorphism of drug metabolism: elucidation of novel mutations in CYP2D6 and CYP2A6 genes in Japanese

S16-1 - Genetic polymorphism of drug metabolism: elucidation of novel mutations in CYP2D6 and CYP2A6 genes in Japanese

39-68 - Genetic polymorphisms of drug metabolism (Cyp 2D6) and tardive dyskinesia in schizophrenia

39-68 - Genetic polymorphisms of drug metabolism (Cyp 2D6) and tardive dyskinesia in schizophrenia

High-performance liquid chromatographic determination of urinary 4'-hydroxymephenytoin, a metabolic marker for the hepatic enzyme CYP2C19, in humans.

The preferential hydroxylation of (S)-mephenytoin to 4'-hydroxymephenytoin (4'-OH-M) displays a genetic polymorphism of drug metabolism in humans. Thus the excreted 4'-OH-M is considered to be an important marker for the hepatic (S)-mephenytoin 4'-hydroxylase. Accordingly, a mixture of urine containing total 4'-OH-M after enzymatic deconjugation and phenobarbital as internal standard (I.S.) was extracted with absolute diethyl ether. The residue remaining after evaporation was dissolved in 50 microliters of eluate and 20 microliters were injected into the chromatographic system. All components were separated isocratically on a reversed-phase column using acetonitrile-water (24:76, v/v) as the mobile phase at a flow-rate of 1.2 ml/min. The effluent was monitored at 204 nm. The retention times for 4'-OH-M and the I.S. were within 6 min. The absolute recovery was in the range 84-89% for 4'-OH-M and that of the I.S. was 75.9 +/- 4.2%. Quantification was performed by measuring the peak-height ratio compared with the ratio of the amount of 4'-OH-M divided by that of the I.S. The intra- and inter-day variations were less than 8% and 10%, respectively. The proposed method is simpler and more convenient than those reported previously. Its practical applicability was assessed by phenotyping the efficient and deficient hydroxylators among the Chinese minorities and Han Chinese populations.

Relevance and limits of pharmacogenetics to detect patients at risk of adverse drug reactions

AbstractFor more than 15 years genetic polymorphism of drug metabolism has been extensively studied. Poor Metabolizer (PM) and Extensive Metabolizer (EM) Slow Acetylators (SA) Rapid Acetylators (RA) phenotype and genotype can be defined for CYP2D6 (Debrisoquine) and N‐AT (acetylation). Lists of drugs whose metabolism is CYP2D6 or N‐AT dependent have been published. So it is theoretically possible to forecast an adverse drug reaction (ADR) for a specific patient who is given a drug affected by a polymorphism. However, not only PM are at risk of ADRs. When an active or reactive metabolite is produced, EM might be at risk whatever the enzyme involved. Drug interactions must also be taken into account. Competitive inhibition of the metabolism of a drug CYP2D6 dependent provokes not only a blurring effect on phenotyping, leading to a misclassification, but also increases the risk of ADRs. New drug metabolic polymorphism is under scrutiny. Determination of phenotypes and genotypes when possible, development of investigations of drug metabolic capacity at large, in patients exhibiting ADR's, might improve the efficiency of pharmacovigilance to forecast at‐risk subjects.