Genetic Polymorphisms In Drug-metabolizing Enzymes Research Articles

Interethnic differences in drug response: projected impact of genetic variations in the Saudi population.

Ethnicity is known to have an impact on drug responses. This is particularly important for drugs that have a narrow therapeutic window, nonlinearity in pharmacokineticsand are metabolized by enzymes that demonstrate genetic polymorphisms. However, most clinical trials are conducted among Caucasians, which might limit the usefulness of thefindings of such studies for other ethnicities. The representation of participants from Saudi Arabia in global clinical trials is low. Therefore, there is a paucity of evidence to assess the impact of ethnic variability in the Saudi population on drug response. In this article, the authors assess the projected impact of genetic polymorphisms in drug-metabolizing enzymes and drug targets on drug response in the Saudi population.

Overview of Cardiac Arrhythmias and Treatment Strategies.

Maintenance of normal cardiac rhythm requires coordinated activity of ion channels and transporters that allow well-ordered propagation of electrical impulses across the myocardium. Disruptions in this orderly process provoke cardiac arrhythmias that may be lethal in some patients. Risk of common acquired arrhythmias is increased markedly when structural heart disease caused by myocardial infarction (due to fibrotic scar formation) or left ventricular dysfunction is present. Genetic polymorphisms influence structure or excitability of the myocardial substrate, which increases vulnerability or risk of arrhythmias in patients. Similarly, genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups within the population that affect specific drug biotransformation reactions. Nonetheless, identification of triggers involved in initiation or maintenance of cardiac arrhythmias remains a major challenge. Herein, we provide an overview of knowledge regarding physiopathology of inherited and acquired cardiac arrhythmias along with a summary of treatments (pharmacologic or non-pharmacologic) used to limit their effect on morbidity and potential mortality. Improved understanding of molecular and cellular aspects of arrhythmogenesis and more epidemiologic studies (for a more accurate portrait of incidence and prevalence) are crucial for development of novel treatments and for management of cardiac arrhythmias and their consequences in patients, as their incidence is increasing worldwide.

Opioid individualization by pharmacogenomics: the next wave of post-operative prescribing (065)

<b>Objectives:</b> Enhanced Recovery after Surgery and post-discharge prescribing guidelines significantly reduce opioid administration yet are limited by a lack of individualization, including genetic and metabolic factors. Pharmacogenomic (PGx) testing measures genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and drug targets, explaining inter-individual variation in drug efficacy and toxicity. This prospective study aimed to compare perioperative opioid use in women by the status of <i>CYP2D6,</i> a PGx mutation relevant to opioid metabolism. <b>Methods:</b> Patients with gynecologic pathology (96% malignant) undergoing laparotomy at a single institution were prospectively recruited and provided a one-time buccal scraping for the CLIA/CAP approved RightMed^TM PGx gene panel before surgery. Postoperative opioid usage and pain scores were evaluated via chart review, and a phone survey was planned for 21-35 days after discharge. Five pharmacogenes, including <i>CYP2D6</i>, were genotyped for all participants, and opioid metabolizing activity was defined by <i>CYP2D6</i> genotyping. Patient and procedural factors were compared by <i>CYP2D6</i> metabolizer status using Fisher's exact and Kruskal-Wallis tests. <b>Results:</b> The 96 enrolled patients were classified as ultra-rapid (3, 3%), normal (58, 60%), intermediate (27, 28%), and poor (8, 8%) opioid metabolizers. Over two-thirds (69%) of patients underwent complex cytoreductive surgery, and there was no difference in surgical complexity across <i>CYP2D6</i> categories (p=0.61). One-fifth of patients (20%) underwent a colon resection. Administration of nonopioid medications in the first 24 hours (p=1.00) or second 24 hours (p=1.00) after leaving the postoperative anesthesia care unit (PACU) or last 24 hours (p=0.47) of hospitalization were also not different across <i>CYP2D6</i> categories. There were significant differences between groups in consumed morphine milligram equivalents (MME) during the first 24 hours after exiting the PACU. Ultrarapid metabolizers had the highest median MME (75, IQR: 45-88) compared to the other three groups (median 22.5-47.5, p=0.03). The median pain scores also differed in the last 24 hours of hospitalization (p=0.04), with ultrarapid having higher median pain scores (4.9, IQR: 4.3-5.5) compared to the other three groups (median 2.3-2.9). There was no difference in length of stay (p=0.50), MME prescribed at discharge (p=0.23), or patient satisfaction with pain control (p=0.89) between groups. <b>Conclusions:</b> Genetically determined metabolism plays a role in opioid requirements after surgery. In this cohort of patients undergoing laparotomy, a positive association existed between increased <i>CYP2D6</i> activity and both in-hospital opioid requirements and higher pain scores. These results provide important information to help tailor opioid prescriptions to avoid overprescribing while adequately addressing postoperative pain.

Genetic polymorphism of NAT1 in local Pakistani population

The present research project was designed to determine the genetic polymorphism of N-acetyltransferase 1 (NAT1), the acetylation status in the local Pakistani population because of the genetic polymorphism of drug-metabolizing enzymes constitutes an individual's susceptibility and toxicity for drugs. The normal health status of enrolled volunteers was ensured by their baselines hematological and biochemical studies like CBC, blood cell morphology, LFTs, RFTs Lipid profile and plasma proteins. The acetylation capacity was determined genotypically by PCR-based allele-specific amplification assay and restriction fragment length polymorphism (RFLP) for wild-type and variant alleles. The mutual concordance between the phenotypic and genotypic analysis was determined. The target population showed bimodal distribution based on genotyping. Almost 69% Pakistani local population was found to have fast acetylator alleles/genotype and 30% population with slow acetylator allele/genotype. The interethnic distributions of NAT1 alleles show variability among various populations. Studies should be carried on all possible ethnic divisions to get an insight into varied drug responsiveness in different populations.

TPMT*3C as a Predictor of 6-Mercaptopurine-Induced Myelotoxicity in Thai Children with Acute Lymphoblastic Leukemia.

The response to 6-mercaptopurine (6-MP) can be altered by genetic polymorphisms in genes encoding drug-metabolizing enzymes and drug transporters. The purpose of this study was to investigate the association between genetic polymorphisms of drug-metabolizing enzymes (TPMT 719A > G (*3C), ITPA 94C > A and ITPA 123G > A) and drug transporters (MRP4 912C > A and MRP4 2269G > A) with 6-MP-related myelotoxicity and hepatotoxicity in Thai children with acute lymphoblastic leukemia (ALL). The prescribed dosage of 6-MP and its adverse effects were assessed from medical records during the first 8 weeks and 9–24 weeks of maintenance therapy. Children with the TPMT*1/*3C genotype had a higher risk of leukopenia with an odds ratio (OR) of 4.10 (95% confidence interval (CI) of 1.06–15.94; p = 0.033) compared to wild type (TPMT*1/*1) patients. Heterozygous TPMT*3C was significantly associated with severe neutropenia with an increased risk (OR, 4.17; 95% CI, 1.25–13.90); p = 0.014) during the first 8 weeks. No association was found among ITPA 94C > A, ITPA 123G > A, MRP4 912C > A, and MRP4 2269G > A with myelotoxicity and hepatotoxicity. The evidence that TPMT heterozygotes confer risks of 6-MP-induced myelotoxicity also supports the convincing need to genotype this pharmacogenetic marker before the initiation of 6-MP therapy.

Impact of Pharmacogenetic Determinants of Tacrolimus and Mycophenolate on Adverse Events in Renal Transplant Patients.

Graft acceptance against immunity is one of the major challenges in solid organ transplant. Immunosuppressive medications have effectively improved the post-transplantation outcome however, it has its own limitations. Genetic polymorphisms in drug-metabolizing enzymes have been identified as the potential targets in developing a pharmacogenetic strategy, to individualize drug dose and also in preventing the adverse events. The rationale of the study was to explore polymorphisms in tacrolimus and mycophenolate metabolic pathways that influence the adverse clinical outcomes in renal transplant recipients. A total of 255 renal transplant recipients were analyzed for the pharmacogenetic determinants of tacrolimus (CYP3A5*3 ABCB1 1236 T>C ABCB1 2677 G>A/T ABCB1 3435 T>C) and mycophenolate (UGT1A8*3 UGT1A9 IMPDH I IMPDH II c.787C>T ABCC2 -24 C>T and c.3972C>T) using Sanger sequencing. Acute rejection (AR) was observed in 5.88% of the transplant recipients whereas acute tubular necrosis (ATNs) was observed in 7.45% of the patients within early stage of the maintenance phase. Infections such as urinary tract infection (UTI) and cytomegalovirus (CMV) infection were observed in 11.37% and 12.16% of the patients. The AUC of mycophenolate was significantly higher in patients with increased risk for infections. ABCC2 -24 C>T c.3972C>T polymorphisms and ABCB1 3435 C-allele were associated with reduced risk for infections. ABCC2 rs3740066 was associated with 2.06-fold all-cause mortality risk. CYP3A5 AG- and UGT1A9-440 CC-genotypes showed increased risk and ABCC 3972C>T CC-genotype showed protection against adverse events. Genetic variants in tacrolimus and mycophenolate metabolic pathways were found to influence the morbidity and mortality in renal transplant recipients.

Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients.

Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 ( NUDT15 ) genes have been proposed as key determinants of 6-mercaptopurine (6-MP)-induced myelosuppression in pediatric acute lymphoblastic leukemia (ALL). In the present study, genotypes of TPMT and NUDT15 were investigated in 178 Thai pediatric patients with ALL by the TaqMan SNP genotyping assay and DNA sequencing. The frequency of TPMT*3C was 0.034. Among NUDT15 variants, NUDT15*3 is the most common variant with the allele frequency of 0.073, whereas those of NUDT15*2 , NUDT15*5 , and NUDT15*6 variants were 0.022, 0.011, and 0.039. These data suggest that a high proportion of Thai pediatric ALL patients may be at risk of thiopurine-induced myelosuppression.

Impact of genetic variants of selected cytochrome P450 isoenzymes on pharmacokinetics and pharmacodynamics of clopidogrel in patients co-treated with atorvastatin or rosuvastatin.

Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin. The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n= 25) or rosuvastatin (n= 25) for at least 6months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay. There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P< 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P< 0.01). The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.

Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole‐induced liver injury

Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug-induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug-metabolizing enzymes and drug transporters have been associated with drug-induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug-metabolizing enzymes and drug transporters to the MMI-DILI. A total of 44 GD patients with MMI-DILI and 118 GD patients without MMI-DILI development were included in the study. Thirty-three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI-DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI-DILI cases than that in the control group (OR=2.21, 95% CI=1.11-4.39, P=0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR=0.52, 95% CI=0.29-0.93, P=0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI-DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI-induced hepatotoxicity.

Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation.

Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation.

Pharmacogenomic Biomarkers for Improved Drug Therapy\u2014Recent Progress and Future Developments

Much of the inter-individual variability in drug efficacy and risk of adverse reactions is due to polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics or immunological responses. Pharmacogenetic research has identified a multitude of gene-drug response associations, which have resulted in genetically guided treatment and dosing decisions to yield a higher success rate of pharmacological treatment. The rapid technological developments for genetic analyses reveal that the number of genetic variants with importance for drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to millions of rare mutations. Here, we review the evolutionary background of genetic polymorphisms in drug-metabolizing enzymes, provide some important examples of current use of pharmacogenomic biomarkers, and give an update of germline and somatic genome biomarkers that are in use in drug development and clinical practice. We also discuss the current technology development with emphasis on complex genetic loci, review current initiatives for validation of pharmacogenomic biomarkers, and present scenarios for the future taking rare genetic variants into account for a true personalized genetically guided drug prescription. We conclude that pharmacogenomic information for patient stratification is of value to tailor optimized treatment regimens particularly in oncology. However, the routine use of pharmacogenomic biomarkers in clinical practice in other therapeutic areas is currently sparse and the prospects of its future implementation are being scrutinized by different international consortia.

Genetic Polymorphism of Drug-Metabolizing Enzymes CYP2C9 and CYP2C19 in Moroccan Population.

The polymorphic cytochrome P450 isoenzymes CYP2C9 and CYP2C19 are involved in the biotransformation of a wide variety of clinical drugs. Their major alleles occur with varying frequencies among different populations worldwide and have been associated with a varied capacity to degrade important therapeutic agents. This gives rise to important individual and interethnic variability in drug metabolism and may be the cause for different clinical responses regarding drug administration. In this study we aimed to analyze the distribution of the CYP2C9 and CYP2C19 major alleles associated with the impaired metabolism, and that account for the "poor metabolizer" phenotype in our study population. A sample of 290 healthy subjects living in South Morocco was genotyped using a restriction fragment length polymorphism-polymerase chain reaction genotyping method. The CYP2C9*3 and CYP2C19*3 mutations were not found in our population. The CYP2C9*2 and CYP2C19*2 were the most common alleles, respectively with frequencies of 8% and 11.4%. Regarding CYP2C9*2 and CYP2C19*2, approximately 16% and 22% of Moroccans are respectively deficient metabolizers, and thus largely lack this enzymatic activity. Our results suggest that only CYP2C9*2 and CYP2C19*2 are likely to substantially contribute to individual and interethnic variability of CY2C9-19 activity in our population. The distribution of clinically relevant alleles of the CYP2C19 and CYP2C9 genes among our population follows the patterns commonly found in other Mediterranean populations, and suggests a certain degree of African influence. This population study provides relevant information on polymorphisms within the CYP2C19 and CYP2C9 genes. In the future, these results could be used in prognosis and for predicting response to drug treatments as well as to help develop personalized medicine studies in the Moroccan population.

Molecular dynamics investigations of membrane-bound CYP2C19 polymorphisms reveal distinct mechanisms for peripheral variants by long-range effects on the enzymatic activity.

Increasing sophistication in methods used to account for human polymorphisms in susceptibility to drug metabolism has been one of the success stories in the prevention of adverse drug reactions. Genetic polymorphisms in drug-metabolizing enzymes can affect enzyme activity and cause differences in treatment response or drug toxicity. CYP2C19 is one of the most highly polymorphic CYP enzymes and acts on 10-15% of drugs in current clinical use. Despite the number of experimental analyses carried out for this system, the detailed structural basis for altered catalytic properties of polymorphic CYP2C19 variants remains unexplained at the atomic level. To this end, we have investigated the mutation effects on structural characteristics and tunnel geometry upon single point mutations to elucidate the underlying molecular mechanism for the enzymatic activity deficiencies by using the fully atomistic molecular dynamics (MD) simulations in their native, membrane-bound cellular environment. The obtained results demonstrate how significant sequence divergence causes heterogeneous variations, and further affects the shape and chemical properties of the substrate binding site. Principal component analysis (PCA) results combined with free energy calculations have revealed distinct mechanisms for different peripheral variants, implying a more complicated process for the decrease/loss of enzymatic activity upon the introduction of point mutations in CYP2C19 rather than simply structural changes of the region where the mutation is located. Overall, our present study provides important insights into the current pharmacogenetic knowledge of human drug-metabolizing CYP2C19 to understand the large inter-individual variability in drug clearance. The knowledge of heterogeneous variations in structural features could guide future experimental and computational work on efficient and safe drug treatment with better pharmacokinetic properties based on the common variant alleles of CYP genes, which varies among different ethnic populations.

Should Race-Genotype Interactions Be Considered in the Global Development of CYP2C19 Substrates? A Proposed Framework Using Physiologically Based Pharmacokinetic Modeling.

Should Race-Genotype Interactions Be Considered in the Global Development of CYP2C19 Substrates? A Proposed Framework Using Physiologically Based Pharmacokinetic Modeling.

ABCB1 and ABCC2 and the risk of distant metastasis in Thai breast cancer patients treated with tamoxifen

BackgroundGenetic polymorphisms of drug-metabolizing enzymes and transporters have been extensively studied with regard to tamoxifen treatment outcomes. However, the results are inconclusive. Analysis of organ-specific metastasis may reveal the association of these pharmacogenetic factors. The aim of this study is to investigate the impact of CYP3A5, CYP2D6, ABCB1, and ABCC2 polymorphisms on the risk of all distant and organ-specific metastases in Thai patients who received tamoxifen adjuvant therapy.MethodsGenomic DNA was extracted from blood samples of 73 patients with breast cancer who received tamoxifen adjuvant therapy. CYP3A5 (6986A>G), CYP2D6 (100C>T), ABCB1 (3435C>T), and ABCC2 (−24C>T) were genotyped using allelic discrimination real-time polymerase chain reaction assays. The impacts of prognostic clinical factors and genetic variants on disease-free survival were analyzed using the Kaplan–Meier method and Cox regression analysis.ResultsIn the univariate analysis, primary tumor size >5 cm was significantly associated with increased risk of distant metastasis (P=0.004; hazard ratio [HR] =3.05; 95% confidence interval [CI], 1.44–6.47). In the multivariate analysis, tumor size >5 cm remained predictive of distant metastasis (P<0.001; HR=5.49; 95% CI, 2.30–13.10). ABCC2 −24CC were shown to be associated with increased risk of distant metastasis (P=0.040; adjusted HR=2.34; 95% CI, 1.04–5.27). The combined genotype of ABCC2 −24CC − ABCB1 3435 CT+TT was associated with increased risk of distant and bone metastasis (P=0.020; adjusted HR=2.46; 95% CI, 1.15–5.26 and P=0.040; adjusted HR=3.70; 95% CI, 1.06–12.89, respectively).ConclusionThis study indicates that polymorphisms of ABCC2 and ABCB1 are independently associated with bone metastasis. Further prospective studies with larger sample sizes are needed to verify this finding.

Highlights from the latest articles in pharmacogenomics of solid organ transplantation.

2014 Understanding the pharmacogenetics of tacrolimus may help in adequate immunosuppression Evaluation of: Li CJ, Li L, Lin L et al. Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients. PLoS ONE 9(1), e86206 (2014). Solid organ transplantation is the treatment of choice for patients with end-stage organ failure. Recent studies have shown a significant improvement in graft survival. This improvement results from the introduction of new immunosuppressive drugs that prevent rejection episodes. The susceptibility to developing adverse events or therapeutic failure varies between patients. An important part of this variability in drug response is thought to be the consequence of interindividual differences in drug metabolism. Some individuals have relatively fast drug clearance, while others exhibit a slower drug elimination rate. Because there is no reliable monitoring of the immunological status of patients receiving immunosuppressive drugs, many attempts have been made to optimize therapeutic drug monitoring by determining the blood concentrations of these drugs. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters has led to the hypothesis that genetic factors may be implicated in the interindividual variability of pharmaco kinetics and pharmacodynamics of immunosuppressive drugs [1]. The role of pharmacogenetics and specific genetic polymorphisms in the choice of treatment is of growing interest. Tacrolimus is a macrolide antibiotic that is widely used to prevent acute rejection after solid organ transplantation. This drug is indicated for the prevention of organ rejection in patients receiving a liver, kidney or heart transplant [2]. Because tacrolimus is metabolized extensively by CYP3A4 and CYP3A5 isoenzymes, polymorphisms in CYP3A4 and CYP3A5 genes have been reported that affect tacrolimus dosing and serum concentrations, and may be helpful in dosing of tacrolimus in kidney transplant recipients [3,4]. Li and colleagues designed a study in the search for genetic determinants of tacrolimus metabolism in Chinese renal transplant recipients [5]. In the retrospective study, the authors evaluated the influence of CYP3A4, CYP3A5, COMT, IL-10 and POR SNPs on concentration/dose ratio (C0/D) and the time required to reach the target blood concentration range during the early phase after transplantation. They found that CYP3A5*3, CYP3A4*1G and CYP3A4 rs4646437 T>C polymorphisms presented a significant association with tacrolimus C0/D at different time points after transplantation. Moreover, the CYP3A5*3 allele and CYP3A4 rs4646437 T>C were strongly associated with tacrolimus pharmacokinetics. IL-10 rs1800871 polymorphism was associated with tacrolimus blood concentration at week 3 after transplantation. None of the COMT and POR variants had a significant association with C0/D. This study confirmed the results of previous investigators indicating an association between CYP3A4 and CYP3A5 polymorphisms and tacrolimus pharmacokinetics. Understanding the pharmacogenetics of tacrolimus may enable individualized therapy, resulting in adequate Highlights from the latest articles in pharmacogenomics of solid organ transplantation

PBPK Model Describes the Effects of Comedication and Genetic Polymorphism on Systemic Exposure of Drugs That Undergo Multiple Clearance Pathways

An important goal in drug development is to understand the effects of intrinsic and/or extrinsic factors (IEFs) on drug pharmacokinetics. Although clinical studies investigating a given IEF can accomplish this goal, they may not be feasible for all IEFs or for situations when multiple IEFs exist concurrently. Physiologically based pharmacokinetic (PBPK) models may serve as a complementary tool for forecasting the effects of IEFs. We developed PBPK models for four drugs that are eliminated by both cytochrome P450 (CYP)3A4 and CYP2D6, and evaluated model prediction of the effects of comedications and/or genetic polymorphism on drug exposure. PBPK models predicted 100 and ≥70% of the observed results when the conventional "twofold rule" and the more conservative 25% deviation cut point were applied, respectively. These findings suggest that PBPK models can be used to infer effects of individual or combined IEFs and should be considered to optimize studies that evaluate these factors, specifically drug interactions and genetic polymorphism of drug-metabolizing enzymes.

Toxicogenetic Profile and Cancer Risk in Lebanese

An increasing number of genetic polymorphisms in drug-metabolizing enzymes (DME) were identified among different ethnic groups. Some of these polymorphisms are associated with an increased cancer risk, while others remain equivocal. However, there is sufficient evidence that these associations become significant in populations overexposed to environmental carcinogens. Hence, genetic differences in expression activity of both Phase I and Phase II enzymes may affect cancer risk in exposed populations. In Lebanon, there has been a marked rise in reported cancer incidence since the 1990s. There are also indicators of exposure to unusually high levels of environmental pollutants and carcinogens in the country. This review considers this high cancer incidence by exploring a potential gene–environment model based on available DME polymorphism prevalence, and their impact on bladder, colorectal, prostate, breast, and lung cancer in the Lebanese population. The examined DME include glutathione S-transferases (GST), N-acetyltransferases (NAT), and cytochromes P-450 (CYP). Data suggest that these DME influence bladder cancer risk in the Lebanese population. Evidence indicates that identification of a gene–environment interaction model may help in defining future research priorities and preventive cancer control strategies in this country, particularly for breast and lung cancer.

Genetic polymorphisms of CYP2E1, GST, and NAT2 enzymes are not associated with risk of breast cancer in a sample of Lebanese women

Changes in the activity of drug metabolizing enzymes (DMEs) are potentially associated with cancer risk. This relationship is attributed to their involvement in the bioactivation of multiple procarcinogens or the metabolism of multiple substrates including an array of xenobiotics and environmental carcinogens.326 Lebanese women of whom 99 were cancer free (controls) and 227 were diagnosed with breast cancer (cases) were included. Blood for DNA was collected and medical charts were reviewed. Three genotyping methods were employed including: (1) restriction fragment length polymorphism (RFLP) for CYP2E1*5B, CYP2E1*6, NAT2*5 and NAT2*6; (2) gel electrophoresis for GSTM1 and GSTT1; and (3) real-time PCR for GSTP1 Ile/Val polymorphism. We analyzed the relationship between genetic susceptibilities in selected xenobiotic metabolizing genes and breast cancer risk.Allele frequencies were fairly similar to previously reported values from neighboring populations with relevant migration routes. There were no statistically significant differences in the distribution of variant carcinogen metabolizing genes between cases and controls even after adjusting for age at diagnosis, menopausal status, smoking, and alcohol intake.Despite its limitations, this is the first study that assesses the role of genetic polymorphisms in DMEs with breast cancer in a sample of Lebanese women. Further studies are needed to determine the genetic predisposition and gene–environment interactions of breast cancer in this population.

Genetic Interaction between NAT2, GSTM1, GSTT1, CYP2E1, and Environmental Factors Is Associated with Adverse Reactions to Anti-Tuberculosis Drugs

Adverse drug reactions (ADRs) associated with anti-tuberculosis (anti-TB) drug regimens have considerable impact on anti-TB treatment, potentially leading to unsuccessful outcomes. Nevertheless, the risk factors that play a role in anti-TB drug-induced ADRs are not well established. It is well documented that genetic polymorphisms in drug-metabolizing enzymes (DMEs) result in considerably complex variability in anti-TB drug disposition. In addition, the impact of pharmacogenetic variation on the metabolism of anti-TB drugs may be modifiable by environmental exposure. Thus, an assessment of pharmacogenetic variability combined with biomarkers of environmental exposure may be helpful for demonstrating the effect of the gene-environment interaction on susceptibility to ADRs induced by anti-TB drug therapy. The aim of the study was to investigate the impact of the interaction between environmental risk factors and pharmacogenetic polymorphisms in four common DMEs--N-acetyltransferase 2 (arylamine N-acetyltransferase) [NAT2], glutathione S-transferase theta 1 [GSTT1], glutathione S-transferase mu 1 [GSTM1], and cytochrome P450 2E1 [CYP2E1]--on commonly reported ADRs to first-line anti-TB drugs in 129 patients receiving homogeneous TB treatment. TB patients monitored during drug treatment were divided into subgroups according to the presence or absence of ADRs. Additionally, the patients' clinical and demographic characteristics were collected in order to identify the environmental factors that are potential triggers for ADRs induced by anti-TB drug treatment. Pharmacogenetic variability was determined by gene sequencing, TaqMan® assays, or polymerase chain reaction. The findings of this study suggest that the NAT2 slow acetylator haplotype, female sex, and smoking are important determinants of susceptibility to ADRs induced by anti-TB drugs. Patients carrying multiple, but not single, polymorphisms in the NAT2, GSTM1, GSTT1, and CYP2E1 genes were found to have an increased risk of ADRs, as revealed by gene-gene interaction analysis. Moreover, we also identified meaningful gene-environment interaction models that resulted in the highest levels of ADR risk. The study findings provide evidence of the clinical impact of the interaction between pharmacogenetic variability and environmental factors on ADRs induced by anti-TB drug therapy. Predictive pharmacogenetic testing and a comprehensive clinical history would therefore be helpful for identification and careful monitoring of patients at high risk of this complication.