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.

A frequent CYP2D6 variant promotes skipping of exon 3 and reduces CYP2D6 protein expression in human liver samples.

CYP2D6 is one of the most polymorphic drug-metabolizing enzymes in the liver. While genetic CYP2D6 variants serve as clinical biomarkers to predict CYP2D6 activity, large inter-person variability in CYP2D6 expression remains unaccounted for. Previous results suggest that there is variable expression of a CYP2D6 splice isoform with an in-frame deletion of exon 3 (CYP2D6ΔE3) encoding a protein lacking numerous active site residues. Here, using fragment analysis and RT-qPCR, we revealed that rs1058164G (MAF = 27%-43%) is associated with increased formation of CYP2D6∆E3 in human liver samples (1.4-2.5-fold) and transfected cells. Furthermore, western blots showed that rs1058164G was associated with a 50% decrease in full-length hepatic CYP2D6 protein expression. In addition, by studying a larger liver cohort, we confirmed our previous results that rs16947 (CYP2D6*2) reduces full-length CYP2D6 mRNA by increasing the production of an unstable splice isoform lacking exon 6 (CYP2D6ΔE6) and that the impact of CYP2D6ΔE6 is offset in carriers of the downstream enhancer variant rs5758550. The three frequent SNPs (rs1058164, rs16947, and rs5758550) form various 3-SNP-haplotypes, each with distinct CYP2D6 expression characteristics. Using an expression score (ES) system, we tested the impact of the 3-SNP-haplotype on improving the standard model to predict hepatic CYP2D6 protein expression based on genotype. A model that incorporates the 3-SNP-haplotype provided the best fit for CYP2D6 expression and also accounted for more variability in CYP2D6 protein levels (59%) than a model based on the accepted standard (36%) or one that only adds rs16947 and rs5758550 (42%). Clinical studies are needed to determine whether including the 3-SNP-haplotype alongside current standard CYP2D6 models improves the predictive value of CYP2D6 panels.

Pilot Study: Personalized Medicine in Endoscopy, Can Pharmacogenomics Predict Response to Conscious Sedation?

Adequate response to moderate (conscious) sedation varies significantly between individuals. Polymorphisms in genes encoding drug metabolizing enzymes can lead to inter-individual variability in drug efficacy, potentially influencing sedation requirements during endoscopic procedures. The aim of this study was to assess the potential role of inter-individual variation in inherited polymorphisms of drug-metabolizing enzymes, cytochrome P450 (CYP450), specifically CYP3A4 and CYP3A5, in sedation requirements for outpatient endoscopic procedures. A retrospective analysis of sedation requirements and pharmacogenomics data in 106 unique patients who received outpatient esophagogastroduodenoscopy (EGD), colonoscopy, or both between December 2011 and February 2019 was conducted. Patients were divided into two groups based on their sedation requirements during endoscopy (high vs. normal sedation). Patients with reduced a CYP2C19 metabolism (poor + intermediate metabolizers) (odds ratio [OR] = 0.38, 95% confidence interval [CI]: 0.16-0.91, p = 0.03), poor CYP3A5 metabolism (OR = 0.25, 95% CI: 0.095-0.65, p = 0.0046), and poor UGT1A1 (OR = 2.76, 95% CI: 1.07-7.13, p = 0.08) had higher odds of requiring normal sedation compared to those with CYP2C19 increased metabolism, CYP3A5 intermediate metabolism, and UGT1A1 intermediate metabolism. Information about inter-individual variation in (CYP450) genes may be useful for determining the sedation requirements for outpatient endoscopic procedures. We found that patients with reduced CYP2C19 metabolism, poor CYP3A5 metabolism, and poor UGT1A1 metabolism were more likely to require normal sedation requirements during outpatient endoscopic procedures.

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.

Role of Genetic Polymorphisms in Drug-Metabolizing Enzyme-Mediated Toxicity and Pharmacokinetic Resistance to Anti-Cancer Agents: A Review on the Pharmacogenomics Aspect.

The inter-individual differences in cancer susceptibility are somehow correlated with the genetic differences that are caused by the polymorphisms. These genetic variations in drug-metabolizing enzymes/drug-inactivating enzymes may negatively or positively affect the pharmacokinetic profile of chemotherapeutic agents that eventually lead to pharmacokinetic resistance and toxicity against anti-cancer drugs. For instance, the CYP1B1*3 allele is associated with CYP1B1 overexpression and consequent resistance to a variety of taxanes and platins, while 496T>G is associated with lower levels of dihydropyrimidine dehydrogenase, which results in severe toxicities related to 5-fluorouracil. In this context, a pharmacogenomics approach can be applied to ascertain the role of the genetic make-up in a person's response to any drug. This approach collectively utilizes pharmacology and genomics to develop effective and safe medications that are devoid of resistance problems. In addition, recently reported genomics studies revealed the impact of many single nucleotide polymorphisms in tumors. These studies emphasized the importance of single nucleotide polymorphisms in drug-metabolizing enzymes on the effect of anti-tumor drugs. In this review, we discuss the pharmacogenomics aspect of polymorphisms in detail to provide an insight into the genetic manipulations in drug-metabolizing enzymes that are responsible for pharmacokinetic resistance or toxicity against well-known anti-cancer drugs. Special emphasis is placed on different deleterious single nucleotide polymorphisms and their effect on pharmacokinetic resistance. The information provided in this report may be beneficial to researchers, especially those who are working in the field of biotechnology and human genetics, in rationally manipulating the genetic information of patients with cancer who are undergoing chemotherapy to avoid the problem of pharmacokinetic resistance/toxicity associated with drug-metabolizing enzymes.

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.

Molybdenum Cofactor Catabolism Unravels the Physiological Role of the Drug Metabolizing Enzyme Thiopurine S-Methyltransferase.

Therapy of molybdenum cofactor (Moco) deficiency has received US Food and Drug Administration (FDA) approval in 2021. Whereas urothione, the urinary excreted catabolite of Moco, is used as diagnostic biomarker for Moco-deficiency, its catabolic pathway remains unknown. Here, we identified the urothione-synthesizing methyltransferase using mouse liver tissue by anion exchange/size exclusion chromatography and peptide mass fingerprinting. We show that the catabolic Moco S-methylating enzyme corresponds to thiopurine S-methyltransferase (TPMT), a highly polymorphic drug-metabolizing enzyme associated with drug-related hematotoxicity but unknown physiological role. Urothione synthesis was investigated in vitro using recombinantly expressed human TPMT protein, liver lysates from Tpmt wild-type and knock-out (Tpmt-/- ) mice as well as human liver cytosol. Urothione levels were quantified by liquid-chromatography tandem mass spectrometry in the kidneys and urine of mice. TPMT-genotype/phenotype and excretion levels of urothione were investigated in human samples and validated in an independent population-based study. As Moco provides a physiological substrate (thiopterin) of TPMT, thiopterin-methylating activity was associated with TPMT activity determined with its drug substrate (6-thioguanin) in mice and humans. Urothione concentration was extremely low in the kidneys and urine of Tpmt-/- mice. Urinary urothione concentration in TPMT-deficient patients depends on common TPMT polymorphisms, with extremely low levels in homozygous variant carriers (TPMT*3A/*3A) but normal levels in compound heterozygous carriers (TPMT*3A/*3C) as validated in the population-based study. Our work newly identified an endogenous substrate for TPMT and shows an unprecedented link between Moco catabolism and drug metabolism. Moreover, the TPMT example indicates that phenotypic consequences of genetic polymorphisms may differ between drug- and endogenous substrates.

Chronic Myeloid Leukemia Following Exposure to Radioactive Iodine (I 131): A Systematic Review

IntroductionTherapy-related leukemia or secondary leukemia are the terms that describe the occurrence of leukemias following exposure to hematotoxins and radiation to emphasize the difference from leukemia that arises de novo . Many leukemogenic agents have been described, including radiation, alkylating agents, among others . Certain host factors contribute to this predisposition, such as polymorphisms in drug-metabolizing enzymes and inherited cancer predisposition syndrome . These rising leukemias have no specific biologic features that set them apart from de novo malignancies .Therapy-related acute myeloid leukemia (t-AML) has extensive literature to support it. In contrast, therapy-related chronic myeloid leukemia (t-CML) possibly because it originates from a more potent premature progenitor cell .Radioactive iodine (RAI) with I 131 has an established role in managing differentiated thyroid carcinoma, namely papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma. However, concerns have been raised about its possible carcinogenic effects. Papers of t-CML following I 131 are increasingly reported, and thus this review is dedicated to highlighting it.Designs and methodsAll reports from the 1960s to date related to CML following RAI therapy were searched on Google Scholar and PubMed. Different search terms with Boolean function to search for the relevant articles. All articles were in English.ResultsWe identified ten articles reporting 12 cases, as presented in table 1. We found that most of the reports were for men (8/12) under the age of 60 years (10/12), and the primary tumor was of PTC characteristics (5/12 were PTC, and 3/12 were mixed papillary-follicular carcinoma). The dose of I 131 ranged between 30 millicuries (mCi) to 850 mCi; the mean dose was 331 mCi. Also, t-CML developed within the first ten years (9/12), mainly between 4-7 years post-exposure.DiscussionA few reports found a statistically significant increased risk of leukemia following RAI therapy; some suggested a relative risk of 2.5 for I 131 vs. no I 131 . Observed findings from these studies include a linear relationship between the cumulative dose of I 131 and the risk of leukemia, doses higher than 100 mCi were associated with a greater risk of developing secondary leukemia, and most of the leukemias developed within the initial ten years of exposure .The precise mechanism through which RAI provokes leukemia is largely unclear. Possibly, by inducing oxidative stress, reactive oxygen species production results in damage to the cellular membrane, DNA strand breakage, DNA base alterations, and eventually cancer in the instances of poor repair of damage .Many questions remain open. For example, most of the subjects had PTC histopathology in our review. Is there a relationship between PTC and the emergence of leukemia? This question is relevant because some reported that PTC has a mutation of the RET protooncogene, which has been linked to leukemia, prostate and breast cancers.ConclusionAlthough the risk of t-CML appears to be low based on current reports, it should not be disregarded. Further studies are needed to establish or refute a causal relationship. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Different Effects of Polymorphic Flavin-Containing Monooxygenase 3 and Cytochrome P450 2A6 Activities on an Index of Arteriosclerosis as a Lifestyle-Related Disease in a General Population in Japan.

The relationships between lifestyle-related diseases and polymorphic drug-metabolizing enzyme activities in the general population in Japan remain unclear. In this study, the relationships between an index of arteriosclerosis and the phenotypic activities of flavin-containing monooxygenase 3 (FMO3) and cytochrome P450 (P450) 2A6 were analysed. Subjects in a general population in Japan (age range 35-97 years, 640 men and 795 women, 12% were current smokers) who took part in a health check program were recruited. Subjects were divided into two groups using the median ankle-brachial pressure index (ABI) score. Subjects harbouring P450 2A6 wild-type allele had a significant age-adjusted odds ratio of 1.3 (95% CI, 1.0-1.6) of having a lower than median ABI score compared with subjects for mutant P450 2A6. For subjects with wild-type FMO3, the odds ratio of 0.89 was not significant. The proportions of P450 2A6 extensive metabolizers varied significantly across the inter-quartile ranges of the ABI scores (p = 0.008). Furthermore, the proportion of subjects with low ABI scores was also dependent on the phenotypic P450 2A6 activity (p = 0.025) as estimated from the P450 2A6 genotype. These results suggest that in a general population in Japan, the ABI score, as a risk index for arteriosclerosis, is associated with the predicted P450 2A6 phenotype but is not associated with FMO3 function. The P450 2A6 wild-type allele may be a possible candidate biomarker for arteriosclerosis in a general population in Japan with a variety of dietary habits.

Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data, while N = 415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

Impact of gene polymorphisms in drug-metabolizing enzymes and transporters on trough concentrations of rivaroxaban in patients with atrial fibrillation.

Rivaroxaban is excreted from the body via multiple pathways involving glomerular filtration, drug-metabolizing enzymes and transporters. In this study, we aimed to examine the impact of single nucleotide polymorphisms in P-glycoprotein, breast cancer resistance protein, cytochrome P450 (CYP) 3A5 and CYP2J2 on the pharmacokinetics of rivaroxaban. Eighty-six patients with non-valvular atrial fibrillation (NVAF) undergoing AF catheter ablation were enrolled in this study. In these analyses, the dose-adjusted plasma trough concentration ratio (C0h /D) of rivaroxaban was used as the pharmacokinetic index. The median (quartile range) rivaroxaban C0h /D was 3.39 (2.08-5.21)ng/mL/mg (coefficient of variation: 80.5%). The C0h /D did not differ significantly among ABCB1 c.3435C>T, c.2677G>A/T, c.1236C>T, ABCG2 c.421C>A, CYP3A5*3 and CYP2J2*7 genotypes. Stepwise selection multiple linear regression analysis showed that the estimated glomerular filtration rate was the only independent factor influencing the C0h /D of rivaroxaban (R2 = 0.152, P< 0.001). There was a significant correlation between the C0h of rivaroxaban and prothrombin time (PT) (rho=0.357, P= 0.001). In patients with NVAF, pharmacokinetic genotype tests are unlikely to be useful for prediction of the C0h of rivaroxaban.

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.

Polymorphisms of Drug-Metabolizing Enzymes and Transporters Contribute to the Individual Variations of Erlotinib Steady State Trough Concentration, Treatment Outcomes, and Adverse Reactions in Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Patients.

BackgroundErlotinib is presently the first line treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) active mutation. An increasing number of evidences show that the treatment efficacy and toxicities are considerably heterogeneous among individuals. Hence, it is necessary to find biological predictors for further individualized treatment of erlotinib in NSCLC patients.MethodsOur present study enrolled 87 cases of NSCLC patients who had been administrated erlotinib with a fixed dose (150 mg/d). Eleven polymorphisms in seven genes of drug-metabolizing enzymes and transporters were genotyped and the steady state trough concentrations were also determined.ResultsThere were significant variances in the steady-state erlotinib trough plasma concentrations, ranging from 315.6 ng/ml to 4479.83 ng/ml. Erlotinib steady state trough concentration was remarkably lower in current smoking patients. The steady state trough concentration of GG in rs1048943 of CYP1A1 was significantly higher than that of AA allele carriers. The polymorphism of CYP1A2 was significantly associated with the severity of skin rash, and the development of diarrhea was associated with SNPs in ABCB1 and CYP3A5. We also observed that GG allele in CYP1A1 was accompanied with a longer PFS in our study.ConclusionA large variability of erlotinib steady state trough concentration was found among Chinese Han population. SNPs in CYP1A1 appeared to influence the steady state trough concentration of erlotinib. Correlation between CYP1A2 polymorphisms and severity of skin rash was observed, together with the correlation between the development of diarrhea and SNPs in ABCB1 and CYP3A5.

Pharmacogenetic-Pharmacokinetic Interactions in Drug Marketing Authorization Applications via the European Medicines Agency Between 2014 and 2017.

This study aimed to determine to which extent data on potential pharmacogenetic‐pharmacokinetic (PG‐PK) interactions are provided to, and assessed by, the European Medicines Agency (EMA) in novel drug marketing authorization applications (MAAs), and whether regulatory assessment of PG‐PK interactions is adequate or could be optimized. For this purpose, we retrospectively analyzed MAAs of small molecule drugs assessed by the EMA between January 2014 and December 2017. As per two key requirements in the EMA’s guideline, we analyzed cases where (i) a single functionally polymorphic drug metabolizing enzyme (DME) metabolizes > 25% of the drug, or (ii) the drug’s PK shows high interindividual variability not explained by other factors than PG. Results showed that, of 113 drugs analyzed, 53 (47%) had ≥ 1 functionally polymorphic DME accounting for > 25% of the drug’s metabolism, yielding 55 gene‐drug pairs. For 36 of 53 (68%) of the products, CYP3A4 was the major DME. Compliance with European Union (EU) guidance on PG‐PK issues in drug development was notably different for CYP3A4 substrates vs. non‐CYP3A4 substrates. Adequate PG‐PK data were provided during registration in 89% (16/18) of cases concerning non‐CYP3A4 substrates, compared with 32% (12/37) of cases concerning CYP3A4 substrates. Concluding, PG‐PK interactions related to non‐CYP3A4 substrate drugs were, in general, addressed adequately in EU MAAs. PG‐PK information on CYP3A4 substrates was available less frequently, despite some available evidence on the functional relevance of CYP3A4 polymorphisms. A more harmonized approach toward assessment of PG‐PK issues in EU MAAs seems warranted, and a discussion on the relevance of CYP3A4 polymorphisms, such as CYP3A4*22, is recommended.

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.