Interindividual Variability In Drug Response Research Articles

Gene–Gene–Environment Interactions Between Drugs, Transporters, Receptors, and Metabolizing Enzymes: Statins, SLCO1B1, and CYP3A4 as an Example

Pharmacogenetic biomarker tests include mostly specific single gene-drug pairs, capable of accounting for a portion of interindividual variability in drug response and toxicity. However, multiple genes are likely to contribute, either acting independently or epistatically, with the CYP2C9-VKORC1-warfarin test panel, an example of a clinically used gene-gene-dug interaction. I discuss here further instances of gene-gene-drug interactions, including a proposed dynamic effect on statin therapy by genetic variants in both a transporter (SLCO1B1) and a metabolizing enzyme (CYP3A4) in liver cells, the main target site where statins block cholesterol synthesis. These examples set a conceptual framework for developing diagnostic panels involving multiple gene-drug combinations.

Frequencies of Single Nucleotide Polymorphisms in Cytochrome P450 Genes (CYP1A2, 2A6, 2B6, 3A4 and 3A5) in a Rwandan Population: Difference to Other African Populations

The cytochrome P450 (CYP450) enzymes play a key role for interindividual variability in drug response. No comprehensive pharmacogenetic data are yet available for the Rwandan population in regards to single nucleotide polymorphisms in CYP450s of major importance for personalized medicine. This study investigated the genotype and allele frequencies with respect to relevant SNPs for CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 genes in Rwandan subjects (n=80). Results were compared with data from South African and Cameroonian populations using Pearson’s Χ 2 and Fisher’s Exact statistical tests. Genetic variation was observed in 11 out of the 13 SNPs in the above CYP450 genes. There were significant differences in the distribution of the allelic variants when the Rwandan sample was compared to the Cameroonian and the South African groups, with respect to CYP2A6 1093G#62;A SNP (P=0.0033 and 0.019, respectively) and CYP3A4 -392A#62;G SNP (P=0.0001 and 0.0084, respectively). The distribution of the CYP1A2 -163C>A SNP differed between the Rwandans and the South Africans (P=0.0001), and CYP3A5 6986A#62;G SNP between the Rwandan and the Cameroonian subjects (P=0.017). The polymorphisms CYP2B6 516G>T and 785A>G did not show significant differences (P>0.05) between the Rwandans, Cameroonians and South Africans in the distribution of the 516T and the 785G variants. This is the first study evaluating the allele and genotype frequencies of these key CYP450 genes in Rwandan subjects. The results demonstrate the need to further characterize individual African populations with respect to genetic variations in order for personalized medicine to be realized among Africans. These data will also help illuminate the future planning of pharmacodynamic studies aimed at associations of these pharmacogenetic variants with drug safety and efficacy in Rwanda.

Quantitative assessment of the influence of cytochrome P450 2C19 gene polymorphisms and digestive tract cancer risk

Cytochrome P450 (CYP) 2C19 metabolizes many promutagens and procarcinogens to biologically active metabolites, which strongly promote proliferation of cancer cells in vitro and in vivo. The CYP2C19 gene exhibits several genetic polymorphisms that are thought to play a major role in inter-individual variability in drug response, drug-xenobiotic interactions, and in cancer susceptibility. Two polymorphisms of the CYP2C19 gene (CYP2C19*2, CYP2C19*3) which was associated with reduced enzyme activity have been investigated extensively digestive tract cancer; however, these studies have yielded contradictory results. To clarify this inconsistency, we performed this meta-analysis including 15 case-control studies with a total of 3,252 cases and 6,269 controls. Overall, we found significant association between CYP2C19*2 and digestive tract cancer (OR = 1.27, 95 % CI, 1.07-1.51, P = 0.007) while no significant results were found for CYP2C19*3. Potential sources of heterogeneity including cancer types, ethnicity, source of control, and sample size of study were assessed. In the subgroup analyses by cancer types, significant association was detected only in esophagus cancer for CYP2C19*2. When stratified by ethnicity, significantly increased risks were found for the CYP2C19*2 polymorphism among Asians. This meta-analysis demonstrated that the CYP2C19*2 polymorphism is a risk factor for developing digestive tract cancer. However, additional very large-scale studies are warranted to provide conclusive evidence on the effects of the CYP2C19 gene on risk of digestive tract cancer.

Pharmacokinetic–Pharmacodynamic Modeling of the Antihypertensive Effect of Eprosartan in Black and White Hypertensive Patients

It is well recognized that many antihypertensive drugs exhibit large interindividual variability in effect and that this wide range of patient response to antihypertensive drugs is a major problem in achieving blood pressure (BP) control. Variability in both drug concentration and drug effect may cause the heterogeneity in antihypertensive drug response. However, for most antihypertensive drugs, no clear relationship between drug concentration and its effect on BP has been reported. This study aimed to describe the relationship between eprosartan exposure and its effect on the systolic blood pressure (SBP) using population pharmacokinetic-pharmacodynamic modeling. Interindividual variability in pharmacokinetics and pharmacodynamics was quantified and the influence of covariates on this relationship was evaluated. Eprosartan plasma concentrations and SBP measurements were determined in 86 mildly hypertensive patients from the ROTATE study aged 48.1±7.6years with different ethnic backgrounds (33 White Dutch, 41 Creole Surinamese, 12 Hindustani Surinamese). In 12 of these patients, pharmacokinetics were densely sampled and 24-h ambulatory BP measurements were obtained. Data were analyzed using nonlinear mixed effects modeling. Eprosartan concentration-time profiles were adequately described with a two-compartment pharmacokinetic model with zero-order absorption. A log-linear relationship was used to describe the relationship between concentration and the decrease in SBP. A hypothetical effect compartment was used to describe hysteresis in the drug effect. Approximately 80% of the maximum decrease in SBP was observed after 24days. Interindividual variability in drug response was 65% and decreased to 14% when ethnicity was added as covariate. Creole Surinamese exhibited no drug response in contrast to White Dutch and Hindustani Surinamese [-2.6mmHg per (ng/ml)]. The developed pharmacokinetic-pharmacodynamic model allows the quantification and explanation of variability in SBP between individuals with ethnicity as a useful determinant of responsiveness to eprosartan.

Do MDR1 and SLCO1B1 Polymorphisms Influence the Therapeutic Response to Atorvastatin? A Study on a Cohort of Egyptian Patients with Hypercholesterolemia

Statins are among the most prescribed drugs worldwide to reduce the risk of cardiovascular events. Interindividual variability in drug response is a major clinical problem and is of concern during drug development. Statins, such as atorvastatin, are taken orally and access to their site of action in the liver is greatly facilitated by both intestinal and hepatic transporters. To examine the impact of polymorphisms of the multidrug resistance 1(MDR1) and solute carrier organic anion transporter 1B1 (SLCO1B1) genes on the therapeutic response to atorvastatin as well as the presence of gender-gene interaction. Serum lipid levels were determined at baseline and 4weeks following 40mg/day atorvastatin treatment in 50 Egyptian hypercholesterolemic patients (27 males and 23 females). Identification of MDR1 C3435T and SLCO1B1 A388G gene polymorphisms was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Treatment with atorvastatin resulted in a mean reduction of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) of 8.7%, 9.2%, and 4.1%, respectively, and a mean increase of high density lipoprotein cholesterol (HDL-C) of 1%. Baseline and post-treatment HDL-C levels were statistically significantly higher in the MDR 1 TT homozygotes when compared with the CC wild type. The percentage change in TC, LDL-C, TG, and HDL-C did not show any statistically significant difference when compared among the different MDR 1 C3435T or SLCO1B1 A388G genotypes. The SLCO1B1 GG homozygotes showed a decrease in TG, whereas there was an increase in TG following atorvastatin treatment in AA and AG carriers in females; however, males did not show any statistically significant difference. There was no statistically significant association between either the coronary artery disease (CAD) risk factors (family history of CAD, hypertension, diabetes mellitus, smoking) or concomitant medications with the percentage change in different lipid parameters. MDR1 C3435T was associated with baseline and post-treatment HDL-C variation. SLCO1B1 A388G showed gender-related effects on TG change following atorvastatin treatment. None of the comorbidities or the concomitant medications influenced the percentage change of lipid parameters following atorvastatin treatment. The results of this study may lead to an improved understanding of the genetic determinants of lipid response to atorvastatin treatment.

Applications of CYP450 Testing in the Clinical Setting

Interindividual variability in drug response is a major clinical problem. Polymedication and genetic polymorphisms modulating drug-metabolising enzyme activities (cytochromes P450, CYP) are identified sources of variability in drug responses. We present here the relevant data on the clinical impact of the major CYP polymorphisms (CYP2D6, CYP2C19 and CYP2C9) on drug therapy where genotyping and phenotyping may be considered, and the guidelines developed when available. CYP2D6 is responsible for the oxidative metabolism of up to 25 % of commonly prescribed drugs such as antidepressants, antipsychotics, opioids, antiarrythmics and tamoxifen. The ultrarapid metaboliser (UM) phenotype is recognised as a cause of therapeutic inefficacy of antidepressant, whereas an increased risk of toxicity has been reported in poor metabolisers (PMs) with several psychotropics (desipramine, venlafaxine, amitriptyline, haloperidol). CYP2D6 polymorphism influences the analgesic response to prodrug opioids (codeine, tramadol and oxycodone). In PMs for CYP2D6, reduced analgesic effects have been observed, whereas in UMs cases of life-threatening toxicity have been reported with tramadol and codeine. CYP2D6 PM phenotype has been associated with an increased risk of toxicity of metoprolol, timolol, carvedilol and propafenone. Although conflicting results have been reported regarding the association between CYP2D6 genotype and tamoxifen effects, CYP2D6 genotyping may be useful in selecting adjuvant hormonal therapy in postmenopausal women. CYP2C19 is responsible for metabolising clopidogrel, proton pump inhibitors (PPIs) and some antidepressants. Carriers of CYP2C19 variant alleles exhibit a reduced capacity to produce the active metabolite of clopidogrel, and are at increased risk of adverse cardiovascular events. For PPIs, it has been shown that the mean intragastric pH values and the Helicobacter pylori eradication rates were higher in carriers of CYP2C19 variant alleles. CYP2C19 is involved in the metabolism of several antidepressants. As a result of an increased risk of adverse effects in CYP2C19 PMs, dose reductions are recommended for some agents (imipramine, sertraline). CYP2C9 is responsible for metabolising vitamin K antagonists (VKAs), non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas, angiotensin II receptor antagonists and phenytoin. For VKAs, CYP2C9 polymorphism has been associated with lower doses, longer time to reach treatment stability and higher frequencies of supratherapeutic international normalised ratios (INRs). Prescribing algorithms are available in order to adapt dosing to genotype. Although the existing data are controversial, some studies have suggested an increased risk of NSAID-associated gastrointestinal bleeding in carriers of CYP2C9 variant alleles. A relationship between CYP2C9 polymorphisms and the pharmacokinetics of sulfonylureas and angiotensin II receptor antagonists has also been observed. The clinical impact in terms of hypoglycaemia and blood pressure was, however, modest. Finally, homozygous and heterozygous carriers of CYP2C9 variant alleles require lower doses of phenytoin to reach therapeutic plasma concentrations, and are at increased risk of toxicity. New diagnostic techniques made safer and easier should allow quicker diagnosis of metabolic variations. Genotyping and phenotyping may therefore be considered where dosing guidelines according to CYP genotype have been published, and help identify the right molecule for the right patient.

Expanding Role of Pharmacogenomics in the Management of Cardiovascular Disorders

Cardiovascular disease is a leading cause of death worldwide. Many pharmacologic therapies are available that aim to reduce the risk of cardiovascular disease but there is significant inter-individual variation in drug response, including both efficacy and toxicity. Pharmacogenetics aims to personalize medication choice and dosage to ensure that maximum clinical benefit is achieved whilst side effects are minimized. Over the past decade, our knowledge of pharmacogenetics in cardiovascular therapies has increased significantly. The anticoagulant warfarin represents the most advanced application of pharmacogenetics in cardiovascular medicine. Prospective randomized clinical trials are currently underway utilizing dosing algorithms that incorporate genetic polymorphisms in cytochrome P450 (CYP)2C9 and vitamin k epoxide reductase (VKORC1) to determine warfarin dosages. Polymorphisms in CYP2C9 and VKORC1 account for approximately 40% of the variance in warfarin dose. There is currently significant controversy with regards to pharmacogenetic testing in anti-platelet therapy. Inhibition of platelet aggregation by aspirin in vitro has been associated with polymorphisms in the cyclo-oxygenase (COX)-1 gene. However, COX-1 polymorphisms did not affect clinical outcomes in patients prescribed aspirin therapy. Similarly, CYP2C19 polymorphisms have been associated with clopidogrel resistance in vitro, and have shown an association with stent thrombosis, but not with other cardiovascular outcomes in a consistent manner. Response to statins has been associated with polymorphisms in the cholesterol ester transfer protein (CETP), apolipoprotein E (APOE), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, calmin (CLMN) and apolipoprotein-CI (APOC1) genes. Although these genes contribute to the variation in lipid levels during statin therapy, their effects on cardiovascular outcomes requires further investigation. Polymorphisms in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene is associated with increased statin exposure and simvastatin-induced myopathy. Angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists (β-blockers) are medications that are important in the management of hypertension and heart failure. Insertion and deletion polymorphisms in the ACE gene are associated with elevated and reduced serum levels of ACE, respectively. No significant association was reported between the polymorphism and blood pressure reduction in patients treated with perindopril. However, a pharmacogenetic score incorporating single nucleotide polymorphisms (SNPs) in the bradykinin type 1 receptor gene and angiotensin-II type I receptor gene predicted those most likely to benefit and suffer harm from perindopril therapy. Pharmacogenetic studies into β-blocker therapy have focused on variations in the β1-adrenoceptor gene and CYP2D6, but results have been inconsistent. Pharmacogenetic testing for ACE inhibitor and β-blocker therapy is not currently used in clinical practice. Despite extensive research, no pharmacogenetic tests are currently in clinical practice for cardiovascular medicines. Much of the research remains in the discovery phase, with researchers struggling to demonstrate clinical utility and validity. This is a problem seen in many areas of therapeutics and is because of many factors, including poor study design, inadequate sample sizes, lack of replication, and heterogeneity amongst patient populations and phenotypes. In order to progress pharmacogenetics in cardiovascular therapies, researchers need to utilize next-generation sequencing technologies, develop clear phenotype definitions and engage in multi-center collaborations, not only to obtain larger sample sizes but to replicate associations and confirm results across different ethnic groups.

Highlights of This Issue

The cytidine analogues 5-azacytidine and decitabine have a powerful molecular epigenetic effect: depletion of DNA-methyltransferase. This is an S-phase, DNA-replication dependent action, so treatment exposure time is likely a crucial determinant of efficacy, and genetic factors that influence cytidine analogue metabolism could potentially affect treatment outcomes. The ubiquitously expressed enzyme cytidine deaminase (CDA) rapidly inactivates 5-azacytidine/decitabine. Mahfouz and colleagues evaluated here for the first time the impact of pharmacogenetic factors that affect CDA enzyme activity/expression on 5-azacytidine/decitabine treatment outcomes. Interestingly and significantly, they found that gender had a substantially greater influence on CDA enzyme activity/expression than the well-known CDA SNP A79C, with a corresponding impact on overall survival in 5-azacytidine/decitabine-treated MDS patients. The identification of this pharmacogenetic factor and the mechanism by which it affects outcomes suggest rational methods for optimizing the clinical application of these unique oncotherapeutics.KRAS hyperactivation can occur through mutation or genomic amplification and defines a subset of lung tumors with poor prognosis and fewer therapeutic options. McCleland and colleagues utilize both functional and genomic techniques to identify genes that functionally cooperate with KRAS. These integrative approaches identify lactate dehydrogenase B (LDHB) as overexpressed and necessary for cell growth in the context of KRAS-hyperactive lung cancers. Consistent with a role for LDHB in glycolysis and tumor growth, lung cancers with high LDHB show an increased dependence on glycolysis and a worse patient outcome. These findings warrant further investigation of LDHB as a metabolic driver in KRAS-dependent lung cancer.Cancer chemotherapy is complicated by interindividual variation in drug response and toxicity and drug–drug interactions. Given their tissue distribution and broad substrate specificity, drug uptake transporters of the organic anion transporting polypeptide (OATP) family may play a marked role in these processes. Using humanized OATP1B1, OATP1B3, and OATP1A2 transgenic mice, van de Steeg and colleagues found that all 3 OATPs transport the anticancer drug methotrexate in vivo, whereas OATP1B3 and OATP1A2 transport paclitaxel. Variation in OATP1A/1B activity due to genetic variation or drug–drug interactions, and tumor-specific expression of OATPs, might therefore codetermine treatment efficacy and/or toxicity of these, and likely many other, anticancer drugs.There has been significant interest in fully understanding the ability of plasma VEGF-A to predict for patients who may respond favorably to bevacizumab, an antiangiogenesis agent approved for metastatic cancers including colorectal cancer (CRC), non–small cell lung cancer (NSCLC), and renal cell cancer (RCC). Previous studies have examined small cohorts or single clinical trials that are underpowered for retrospective subset analyses. To provide a more definitive answer, Hegde and colleagues evaluated VEGF-A levels in plasma from 1,816 patients from 5 randomized controlled trials in indications including CRC, NSCLC, and RCC. Using an assay that recognizes major isoforms of VEGF-A with equivalent sensitivities, this study provides robust data on prevalence of plasma VEGF-A in these indications. This study shows for the first time in a rigorous manner that plasma levels of total VEGF do not predict benefit from bevacizumab therapy in these indications.

Pharmacogenetics of Taxanes: Impact of Gene Polymorphisms of Drug Transporters on Pharmacokinetics and Toxicity

Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

Epigenomics and Interindividual Differences in Drug Response

Epigenomics is a rapidly growing field. New developments in epigenetics, such as the recently described modified cytosine variants (e.g., 5-hydroxymethylcytosine, 5hmC) and an arsenal of novel noncoding forms of RNA, can be applied in the area of drug pharmacokinetics and pharmacodynamics. Epigenetic aberrations can affect drug treatment by modulating the expressions of key genes involved in the metabolism and distribution of drugs as well as drug targets, thereby contributing to interindividual variation in drug response. These epigenetic alterations, along with the epigenetic profiles of circulating nucleic acids, have great potential to be used as biomarkers for personalized therapy, particularly in the treatment of cancer. In this review we present an update of pharmacoepigenetics with respect to epigenetic regulation of ADME genes (genes related to drug absorption, distribution, metabolism, and excretion) and drug targets, and we illustrate how this information can be used for predicting interindividual variations in drug response.

Drug treatment developments in schizophrenia and bipolar mania: latest evidence and clinical usefulness

Schizophrenia and bipolar disorder are often highly debilitating with chronic courses, and psychotropic drugs represent cornerstones in the treatment. The primary aim of the review was to summarize the latest evidence with regards to the efficacy and effectiveness of drug treatment of schizophrenia and the manic phases of bipolar disorder. Schizophrenia systematic reviews conclude that antipsychotic drugs are effective in treating overall symptoms of psychosis and in preventing relapse. Some of the newer agents, the second-generation antipsychotics (SGAs), have demonstrated superiority compared with the older first-generation drugs and other SGAs but side-effect differences among the drugs are of a greater magnitude than effect differences. The pragmatic randomized trials of effectiveness have shown a longer time until treatment discontinuation for olanzapine compared with other antipsychotics. Cohort studies have found superiority for the long-acting injection formulations compared with the oral formulations of the drugs, and lower total mortality risk in users of antipsychotics compared with non-users. In bipolar mania SGAs have shown superior antimanic efficacy compared with other mood-stabilizing drugs. In conclusion antipsychotics, in particular some of the SGAs, seem to be drugs of first choice for both schizophrenia and bipolar mania. This perspective review focused on mean effects but the group means may not always be particularly useful as schizophrenia and bipolar mania are biologically heterogeneous disorders with large inter-individual variations in drug response and tolerance. In patients with a prior drug history the different pharmacological and clinical profiles may be exploited in subsequent choices of drugs.

Association Between Lamotrigine Concentrations and ABCB1 Polymorphisms in Patients With Epilepsy

Epilepsy is treated with a variety of anticonvulsants that are often used concomitantly. Therefore, therapeutic drug monitoring is often necessary. Along with clinical and environmental factors, genetic predisposition has been recognized to be relevant for interindividual variability in drug response. Polymorphic transporter proteins such as P-glycoprotein significantly influence pharmacokinetics and bioavailability of many structurally unrelated drugs. The aim of the study was to evaluate the impact of polymorphisms in the P-glycoprotein-encoding gene ABCB1 (C1236T, G2677T/A, C3435T) on antiepileptic drug disposition. We recruited 222 patients with epilepsy who were prescribed lamotrigine in monotherapy or polytherapy. Lamotrigine plasma concentrations were analyzed and compared with ABCB1 gene variants. The ABCB1 genotyping was performed by real-time polymerase chain reaction methods. The therapeutic drug monitoring was performed by high-performance liquid chromatography-diode array detector (DAD) and immunoassay. A significant correlation was confirmed between lamotrigine concentration and additional drugs (P < 0.001). In the whole group, statistical analysis showed correlations between lamotrigine concentrations and ABCB1 C1236T variants: 10.1 and 6.5 μmol/L for CC versus CT + TT, respectively (P = 0.021), and for dose corrected lamotrigine 0.068 and 0.053 μmol·L·mg, for CC versus CT + TT, respectively (P = 0.017). Analysis of a specific haplotype showed that 1236C-2677G-3435C carriers had higher lamotrigine concentrations than 1236T-2677G-3435T carriers (P < 0.001), followed by 1236T-2677T-3435C carriers (P < 0.001). ABCB1 C1236T, G2677T/A, C3435T polymorphisms have an influence on lamotrigine serum concentrations.

Ontogeny and drug metabolism in newborns

In pediatric age and particularly in newborn infants the drug efficacy and safety are influenced by the growth and development on drug Absorption, Distribution, Metabolism and Excretion (ADME). Thanks to the fast development of pharmacogenomics and pharmacogenetics, the drug therapy promises to be adapted to the genetic profile of the individual, reducing considerably the side effects of drugs and increasing their efficacy. Interindividual variability in drug response is well known in both adults and children. Such a variability is multifactorial considering both intrinsic and extrinsic factors. Drug distribution in the neonate is influenced by a variety of age-dependent factors as a total body water content and distribution variations, role of drug transporters, blood/tissue protein binding, blood and tissue pH and perfusion. The development of enzymes involved in human metabolism were classified in 3 categories: 1) those expressed during the whole or part of the fetal period, but silenced or expressed at low levels within 1–2 years after birth; 2) those expressed at relatively constant levels throughout fetal development, but increased to some extent postnatally; and 3) those whose onset of expression can occur in the third trimester, but substantial increase is noted in the first 1–2 years after birth. Besides this intrinsic aspects influencing pharmacokinetics during the neonatal period there are other important events such as inborn or acquired diseases, environment and finally pharmacogenetics and pharmacogenomics. Thousands of deaths every years are caused by fatal drug reactions; among the potential causes there are not only the severity of the disease being treated, drug interactions, nutritional status, renal and liver functions, but also the inherited differences in drug metabolism and genetic polymorphism. Adverse drug reactions (ADRs) among pediatric patients have been shown to be three times more frequent than in adults. On August 2010 The National Institute of Child Health and Human Development (NICHD) addressed patient safety issues in the NICU, recognizing that to understand and prevent adverse events, systematic research and education in safety issues needed. From all these concepts in terms of ADME, pharmacogenetics (relative to a single gene) and pharmacogenomics (relative to many genes) it is becoming more evident the perspective of the new concept of individualized medicine. The goal of this should be to identify which group of patients responds positively, which patients are nonresponders and who experiences adverse reaction for the same drug and dose. The interindividual variability in response to any drug is mostly dependent on DNA sequence variations across the human genome, the haplotype map (HAPMAP). At present there is still a big distance beween the knowledge in genetic and the practical application to model the drug profile to the genetic/genomic profile of the single patient. In the neonatal period the effects of growth in the pharmacodynamic, processes can help optimizing the dosage of neonatal frequently used medicines, thereby, minimizing their toxicity and increasing their efficacy. It should be useful to create accurate dosage adjustments according to the week of development.

Epigenetic-Dependent Regulation of Drug Transport and Metabolism: An Update

The pharmacokinetics of a drug are subject to large interindividual variability, which can result in lack of response or adverse drug reactions. In addition to genetic polymorphisms and drug interactions, key genes involved in the metabolism and transport of drugs are demonstrated to have epigenetic influences that can potentially affect interindividual variability in drug response. Emerging studies have focused on the importance of DNA methylation for ADME gene expression and for drug action and resistance, particularly in cancer. However, the epigenetic and ncRNA-dependent regulation of these genes, as well as the pharmacological consequences, is in need of greater attention. In the current review we provide an update of epigenetic and ncRNA-dependent regulation of ADME genes.

Drug/xenobiotic metabolizing enzyme polymorphisms in a Turkish population

Genetic polymorphisms of drug/xenobiotic metabolizing enzymes can have great impact on the inter-individual variation in drug response or susceptibility to toxicities of xenobiotics. The frequencies of the polymorphic enzymes not also differ from ethnicity, but also differ from country to country in the same ethnic group. In this study, CYP2E1*5B, GSTM1, GSTT1,GSTP1 exon 5 and GSTP1 exon 6 genetic polymorphisms were determined in 302 unrelated healthy individuals in a Turkish population and the results were compared with previous reports. The frequencies of CYP2E1*5B c1/c1, c1/c2 and c2/c2 genotypes were 94.7, 5.3 and 0%, respectively. The frequencies of the deleted GSTM1 and GSTT1 genotypes were 54.6 and 22.2%, respectively. The GSTP1 exon 5 genotype frequencies were Ile/Ile: 56.0%, Ile/Val: 34.8% and Val/Val: 9.3%; GSTP1 exon 6 genotype frequencies were Ala/Ala: 84.8%, Ala/Val: 14.2% and Val/Val: 1.0%. These results revealed that the frequencies of CYP2E1*5B,GSTM1, GSTT1, GSTP1 exon 5 and GSTP1 exon 6 genetic polymorphisms in a Turkish population are similar to European Caucasian populations. Key words: Drug metabolism, CYP2E1 polymorphism, GST polymorphism, Turkish population.

Sex Differences in Human Lymphoblastoid Cells Sensitivities to Antipsychotic Drugs

Adverse drug reactions (ADRs) are a major concern in pharmacotherapy and are more common among women. Immortalized human lymphoblastoid cell lines (LCLs) are emerging as a novel tool for studying interindividual variability in drug response, including ADRs. In the present study, we compared sensitivities of LCLs from unrelated healthy male and female donors to growth inhibition by a panel of common drugs. We observed large interindividual drug sensitivity variations with similar mean sensitivities recorded for LCLs from male and female donors for most tested drugs. A notable exception was observed for the typical antipsychotic haloperidol and the atypical antipsychotic risperidone, which exhibited, on average, more robust in vitro growth inhibition in male as compared with female LCLs. An opposite finding was observed for the antidepressant paroxetine, which was more potent for inhibiting the growth of female as compared with male LCLs. These observations are discussed in the context of the higher incidence of dystonia reported for male schizophrenia patients treated with haloperidol and the higher efficacy of paroxetine in female major depression patients.

Genome-Wide Approaches in Pharmacogenomics: Heritability Estimation and Pharmacoethnicity as Primary challenges

The ultimate aim of pharmacogenomics is the identification of genetic variants that underlie interindividual variation in drug response. The furious pace of technological advances [1], such as DNA sequencing and genotyping technologies [2], has begun to enhance our understanding of human diversity in pharmacologic traits. Meanwhile, methodological advances, such as the genome-wide association study (GWAS) approach, have facilitated the discovery of genetic variation with considerable clinical relevance [3]. The sine qua non of the rapidly developing field of pharmacogenomics is the translation of genomic information from these convergent developments into individualized patient care. Exciting promises of the new science abound, including the possibilities of optimized drug therapy, adverse-effect risk prediction, and improved drug discovery and development. The purpose of this article is to explore two of the major challenges to pharmacogenomic progress despite the substantial advances in genome-wide approaches that have already been made.

Pharmacogenetics and Anesthetic Drugs

The incidence and potential for serious adverse drug reactions (SADRs) in anesthesia are high due to the narrow therapeutic indices of anesthetic and analgesic drugs and high interindividual variability in drug responses. Genetic factors contribute to a majority of these SADRs. Pharmacogenetics (PG), the study of genetic effects on drug action, is strongly related to the field of anesthesia; historically, succinylcholine apnea and malignant hyperthermia were among the first PG disorders reported. Recent years have strengthened this affiliation with an emerging wide base of knowledge of the effects of genetic variations on the pharmacodynamics and pharmacokinetics of anesthetic drugs. Here, we review the history of anesthetic PG, the important genes influencing enzymes involved in anesthetic drug metabolism, the influence of genotypic expression and the potential ramifications of recent discoveries on the practice of clinical anesthesia. Epigenetics and functional genomics are also discussed. The article also addresses various critical deficits in our current knowledge of PG related to anesthesia that account for the minimal clinical translation of the findings in this area in the present time. The review concludes that in addition to enhanced data generation facilitated by rapidly evolving genetic techniques, robust clinical study designs in a large sample and sound statistical analyses are essential prerequisites for the successful clinical implementation of research findings to individual perioperative care for every patient.

The role of ABC transporters in progression and clinical outcome of colorectal cancer

Worldwide, colorectal cancer (CRC) is the third most common cancer, with the highest mortality rates occurring in Central Europe. The use of chemotherapy to treat CRC is limited by the inter-individual variability in drug response and the development of cancer cell resistance. ATP-binding cassette (ABC) transporters play a crucial role in the development of resistance by the efflux of anticancer agents outside of cancer cells. The aim of this study was to explore transcript levels of all human ABCs in tumours and non-neoplastic control tissues from CRC patients collected before the first line of treatment by 5-fluorouracil (5-FU)-containing regimen. The prognostic potential of ABCs was evaluated by the correlation of transcript levels with clinical factors. Relations between transcript levels of ABCs in tumours and chemotherapy efficacy were also addressed. The transcript profile of all known human ABCs was assessed using real-time polymerase chain reaction with a relative standard curve. The majority of the studied ABCs were down-regulated or unchanged between tumours and control tissues. ABCA12, ABCA13, ABCB6, ABCC1, ABCC2 and ABCE1 were up-regulated in tumours versus control tissues. Transcript levels of ABCA12, ABCC7 and ABCC8 increased in direction from colon to rectum. Additionally, transcript levels of ABCB9, ABCB11, ABCG5 and ABCG8 followed the reverse significant trend, i.e. a decrease in direction from colon to rectum. The transcript level of ABCC10 in tumours correlated with the grade (P = 0.01). Transcript levels of ABCC6, ABCC11, ABCF1 and ABCF2 were significantly lower in non-responders to palliative chemotherapy in comparison with responders. The disease-free interval of patients treated by adjuvant chemotherapy was significantly shorter in patients with low transcript levels of ABCA7, ABCA13, ABCB4, ABCC11 and ABCD4. In conclusion, ABCC11 may be a promising candidate marker for a validation study on 5-FU therapy outcome.

Simultaneous quantitative analysis of letrozole, its carbinol metabolite, and carbinol glucuronide in human plasma by LC-MS/MS

Letrozole is an efficient endocrine treatment of postmenopausal breast cancer, however, not all patients benefit from this treatment, and moreover, severe side-effects like arthralgia frequently lead to discontinuation. To better understand inter-individual variability in drug response and side-effects, plasma analysis of steady-state concentrations of letrozole and its major metabolites is crucial. We developed a rapid, sensitive, and specific method for the simultaneous quantification of letrozole and its metabolites 4,4'-(hydroxymethylene)dibenzonitrile (carbinol) and bis(4-cyanophenyl)methyl hexopyranosiduronic acid (carbinol-gluc) by UHPLC-ESI-MS/MS using in-house synthesized, stable isotope-labeled internal standards. Following solid-phase extraction in BondElut C18 96-well plates, the analytes were separated on a ZORBAX Eclipse XDB-C18 column (1.8 μm, 4.6 × 50 mm) with a gradient of acetonitrile in 0.1% acetic acid in water and detected on a triple quadrupole mass spectrometer with electrospray ionization in the multiple reaction monitoring mode. Lower limits of quantification were 20, 0.2, and 2 nM for letrozole, carbinol, and carbinol-gluc, respectively. The assay has been validated according to FDA guidance and applied to the analysis of 20 plasma samples of postmenopausal breast cancer patients treated with 2.5 mg of letrozole per day. Mean plasma levels (±SD) were 366 ± 173, 0.38 ± 0.09, and 34 ± 12 nM for letrozole, carbinol, and carbinol-gluc, respectively. Our rapid and sensitive mass spectrometry based method enables future pharmacokinetic investigations of letrozole outcome.