Pharmaceutics. 2021 Jun 23;13(7):935. doi: 10.3390/pharmaceutics13070935.

ABSTRACT

Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit-risk balance and, consequently, patients' quality of life.

PMID:34201784 | DOI:10.3390/pharmaceutics13070935

J Clin Med. 2021 Jun 10;10(12):2568. doi: 10.3390/jcm10122568.

ABSTRACT

Effective pain management is a key component in the continuum of perioperative care to ensure optimal outcomes for surgical patients. The overutilization of opioids in the past few decades for postoperative pain control has been a major contributor to the current opioid epidemic. Multimodal analgesia (MMA) and enhanced recovery after surgery (ERAS) pathways have been repeatedly shown to significantly improve postoperative outcomes such as pain, function and satisfaction. The current review aims to examine the history of perioperative MMA strategies in ERAS and provide an update with recent evidence. Furthermore, this review details recent advancements in personalized pain medicine. We speculate that the next important step for improving perioperative pain management could be through incorporating these personalized metrics, such as clinical pharmacogenomic testing and patient-reported outcome measurements, into ERAS program.

PMID:34200695 | DOI:10.3390/jcm10122568

Cancers (Basel). 2021 Jun 10;13(12):2900. doi: 10.3390/cancers13122900.

ABSTRACT

The study of low-molecular-weight metabolites that exist in cells and organisms is known as metabolomics and is often conducted using mass spectrometry laboratory platforms. Definition of oncometabolites in the context of the metabolic phenotype of cancer cells has been accomplished through metabolomics. Oncometabolites result from mutations in cancer cell genes or from hypoxia-driven enzyme promiscuity. As a result, normal metabolites accumulate in cancer cells to unusually high concentrations or, alternatively, unusual metabolites are produced. The typical oncometabolites fumarate, succinate, (2R)-hydroxyglutarate and (2S)-hydroxyglutarate inhibit 2-oxoglutarate-dependent dioxygenases, such as histone demethylases and HIF prolyl-4-hydroxylases, together with DNA cytosine demethylases. As a result of the cancer cell acquiring this new metabolic phenotype, major changes in gene transcription occur and the modification of the epigenetic landscape of the cell promotes proliferation and progression of cancers. Stabilization of HIF1α through inhibition of HIF prolyl-4-hydroxylases by oncometabolites such as fumarate and succinate leads to a pseudohypoxic state that promotes inflammation, angiogenesis and metastasis. Metabolomics has additionally been employed to define the metabolic phenotype of cancer cells and patient biofluids in the search for cancer biomarkers. These efforts have led to the uncovering of the putative oncometabolites sarcosine, glycine, lactate, kynurenine, methylglyoxal, hypotaurine and (2R,3S)-dihydroxybutanoate, for which further research is required.

PMID:34200553 | DOI:10.3390/cancers13122900

Cells. 2021 Jun 7;10(6):1420. doi: 10.3390/cells10061420.

ABSTRACT

Natural Killer (NK) cells are natural cytotoxic, effector cells of the innate immune system. They can recognize transformed or infected cells. NK cells are armed with a set of activating and inhibitory receptors which are able to bind to their ligands on target cells. The right balance between expression and activation of those receptors is fundamental for the proper functionality of NK cells. One of the best known activating receptors is NKG2D, a member of the CD94/NKG2 family. Due to a specific NKG2D binding with its eight different ligands, which are overexpressed in transformed, infected and stressed cells, NK cells are able to recognize and attack their targets. The NKG2D receptor has an enormous significance in various, autoimmune diseases, viral and bacterial infections as well as for transplantation outcomes and complications. This review focuses on the NKG2D receptor, the mechanism of its action, clinical relevance of its gene polymorphisms and a potential application in various clinical settings.

PMID:34200375 | DOI:10.3390/cells10061420

Cancers (Basel). 2021 Jun 7;13(11):2837. doi: 10.3390/cancers13112837.

ABSTRACT

Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1.

PMID:34200242 | DOI:10.3390/cancers13112837

J Pers Med. 2021 Jun 4;11(6):507. doi: 10.3390/jpm11060507.

ABSTRACT

BACKGROUND: Tamoxifen, as a treatment of estrogen receptor positive (ER+) breast cancer, is a weak anti-estrogen that requires metabolic activation to form metabolites with higher anti-estrogenic activity. Endoxifen is the most-studied active tamoxifen metabolite, and endoxifen concentrations are highly associated with CYP2D6 activity. Associations of tamoxifen efficacy with measured or CYP2D6-predicted endoxifen concentrations have been inconclusive. Another active metabolite, 4-OHtam, and other, less active metabolites, Z-4'-endoxifen and Z-4'-OHtam, have also been reported to be associated with tamoxifen efficacy.

METHOD: Genotype for 20 pharmacogenes was determined by VeriDose® Core Panel and VeriDose®CYP2D6 CNV Panel, followed by translation to metabolic activity phenotype following standard activity scoring. Concentrations of tamoxifen and seven metabolites were measured by UPLC-MS/MS in serum samples collected from patients receiving 20 mg tamoxifen per day. Metabolic activity was tested for association with tamoxifen and its metabolites using linear regression with adjustment for upstream metabolites to identify genes associated with each step in the tamoxifen metabolism pathway.

RESULTS: A total of 187 patients with genetic and tamoxifen concentration data were included in the analysis. CYP2D6 was the primary gene associated with the tamoxifen metabolism pathway, especially the conversion of tamoxifen to endoxifen. CYP3A4 and CYP2C9 were also responsible for the metabolism of tamoxifen. CYP2C9 especially impacted the hydroxylation to 4-OHtam, and this involved the OATP1B1 (SLCO1B1) transporter.

CONCLUSION: Multiple genes are involved in tamoxifen metabolism and multi-gene panels could be useful to predict active metabolite concentrations and guide tamoxifen dosing.

PMID:34199712 | DOI:10.3390/jpm11060507

J Pers Med. 2021 Jun 14;11(6):554. doi: 10.3390/jpm11060554.

ABSTRACT

UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that metabolize endogenous fatty acids such as arachidonic acid metabolites, as well as many prescription drugs, such as opioids, antiepileptics, and antiviral drugs. The UGT1A and 2B genes are highly polymorphic, and their genetic variants may affect the pharmacokinetics and hence the responses of many drugs and fatty acids. This study collected data and updated the current view of the molecular functionality of genetic variants on UGT genes that impact drug responses and the susceptibility to human diseases. The functional information of UGT genetic variants with clinical associations are essential to understand the inter-individual variation in drug responses and susceptibility to toxicity.

PMID:34198586 | DOI:10.3390/jpm11060554

Pharmacogenomics. 2021 Jul 1. doi: 10.2217/pgs-2021-0075. Online ahead of print.

NO ABSTRACT

PMID:34196599 | DOI:10.2217/pgs-2021-0075

Folia Med (Plovdiv). 2021 Jun 30;63(3):365-371. doi: 10.3897/folmed.63.e61484.

ABSTRACT

INTRODUCTION: Pharmacogenetics in psychiatry is currently gaining momentum. The efficiency of antipsychotic therapy is often limited by the lack of response and the presence of side effects. Pharmacogenetic variation is probably one of the causative factors for the observed interindividual differences in the response to and the side effects of antipsychotics, which could be addressed and whose negative effects could be avoided or mitigated.

AIM: The present study aimed to conduct a comprehensive analysis of the frequency of DRD2 rs1799732, COMT rs4680, MC4R rs489693, and HTR2C rs3813929 in Bulgarian psychiatric patients.

MATERIALS AND METHODS: The frequency of genotypes and the alleles of variants DRD2 rs1799732, COMT rs4680, MC4R rs489693, and HTR2C rs3813929 were studied in a cohort of 515 Bulgarian psychiatric patients using the polymerase chain reaction (PCR) method.

RESULTS: We found no significant difference between our cohort and the dataset of the 1000 Genomes Project. Moreover, we found that 433 out of 515 patients carried at least one, and 191 out of 515 carried at least two variants which, based on multiple scientific sources with consistent findings, could potentially alter the expected response rate, time to respond and/or risk of side effects to antipsychotic medications.

CONCLUSIONS: Considering the consistent data about the frequency of these pharmacogenetic variants, testing these genetic variants may prove useful in clinical practice. Further studies regarding the clinical interpretation and frequency distribution in larger cohorts and different populations are warranted.

PMID:34196139 | DOI:10.3897/folmed.63.e61484

J Endocr Soc. 2021 May 15;5(8):bvab092. doi: 10.1210/jendso/bvab092. eCollection 2021 Aug 1.

ABSTRACT

CONTEXT: Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects.

OBJECTIVE: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study's (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study.

METHODS: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD.

RESULTS: One variation (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings.

CONCLUSION: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.

PMID:34195528 | PMC:PMC8237849 | DOI:10.1210/jendso/bvab092

Oncotarget. 2021 Jun 22;12(13):1256-1270. doi: 10.18632/oncotarget.27981. eCollection 2021 Jun 22.

ABSTRACT

L-type amino acid transporter 1 (LAT1)/SLC7A5 is the first identified CD98 light chain disulfide linked to the CD98 heavy chain (CD98hc/SLC3A2). LAT1 transports large neutral amino acids, including leucine, which activates mTOR, and is highly expressed in human cancers. We investigated the oncogenicity of human LAT1 introduced to NIH/3T3 cells by retrovirus infection. NIH/3T3 cell lines stably expressing human native (164C) or mutant (164S) LAT1 (naLAT1/3T3 or muLAT1/3T3, respectively) were established. We confirmed that endogenous mouse CD98hc forms a disulfide bond with exogenous human LAT1 in naLAT1/3T3, but not in muLAT1/3T3. Endogenous mouse CD98hc mRNA increased in both naNIH/3T3 and muLAT1/3T3, and a similar amount of exogenous human LAT1 protein was detected in both cell lines. Furthermore, naLAT1/3T3 and muLAT1/3T3 cell lines were evaluated for cell growth-related phenotypes (phosphorylation of ERK, cell-cycle progression) and cell malignancy-related phenotypes (anchorage-independent cell growth, tumor formation in nude mice). naLAT1/3T3 had stronger growth- and malignancy- related phenotypes than NIH/3T3 and muLAT1/3T3, suggesting the oncogenicity of native LAT1 through its interaction with CD98hc. Anti-LAT1 monoclonal antibodies significantly inhibited in vitro cell proliferation and in vivo tumor growth of naLAT1/3T3 cells in nude mice, demonstrating LAT1 to be a promising anti-cancer target.

PMID:34194623 | PMC:PMC8238248 | DOI:10.18632/oncotarget.27981

Front Genet. 2021 Jun 14;12:675053. doi: 10.3389/fgene.2021.675053. eCollection 2021.

ABSTRACT

Background: Adverse drug reactions (ADR) are a major clinical problem accounting for significant hospital admission rates, morbidity, mortality, and health care costs. One-third of people with diabetes experience at least one ADR. However, there is notable interindividual heterogeneity resulting in patient harm and unnecessary medical costs. Genomics is at the forefront of research to understand interindividual variability, and there are many genotype-drug response associations in diabetes with inconsistent findings. Here, we conducted a systematic review to comprehensively examine and synthesize the effect of genetic polymorphisms on the incidence of ADRs of oral glucose-lowering drugs in people with type 2 diabetes. Methods: A literature search was made to identify articles that included specific results of research on genetic polymorphism and adverse effects associated with oral glucose-lowering drugs. The electronic search was carried out on 3rd October 2020, through Cochrane Library, PubMed, and Web of Science using keywords and MeSH terms. Result: Eighteen articles consisting of 10, 383 subjects were included in this review. Carriers of reduced-function alleles of organic cation transporter 1 (OCT 1, encoded by SLC22A1) or reduced expression alleles of plasma membrane monoamine transporter (PMAT, encoded by SLC29A4) or serotonin transporter (SERT, encoded by SLC6A4) were associated with increased incidence of metformin-related gastrointestinal (GI) adverse effects. These effects were shown to exacerbate by concomitant treatment with gut transporter inhibiting drugs. The CYP2C9 alleles, * 2 (rs1799853C>T) and * 3 (rs1057910A>C) that are predictive of low enzyme activity were more common in subjects who experienced hypoglycemia after treatment with sulfonylureas. However, there was no significant association between sulfonylurea-related hypoglycemia and genetic variants in the ATP-binding cassette transporter sub-family C member 8 (ABCC8)/Potassium Inwardly Rectifying Channel Subfamily J Member 11 (KCNJ11). Compared to the wild type, the low enzyme activity C allele at CYP2C8* 3 (rs1057910A>C) was associated with less weight gain whereas the C allele at rs6123045 in the NFATC2 gene was significantly associated with edema from rosiglitazone treatment. Conclusion: In spite of limited studies investigating genetics and ADR in diabetes, some convincing results are emerging. Genetic variants in genes encoding drug transporters and metabolizing enzymes are implicated in metformin-related GI adverse effects, and sulfonylurea-induced hypoglycemia, respectively. Further studies to investigate newer antidiabetic drugs such as DPP-4i, GLP-1RA, and SGLT2i are warranted. In addition, pharmacogenetic studies that account for race and ethnic differences are required.

PMID:34194474 | PMC:PMC8236944 | DOI:10.3389/fgene.2021.675053

Cell Death Dis. 2021 Jun 30;12(7):660. doi: 10.1038/s41419-021-03946-8.

NO ABSTRACT

PMID:34193829 | DOI:10.1038/s41419-021-03946-8

Exp Biol Med (Maywood). 2021 Jun 30:15353702211026579. doi: 10.1177/15353702211026579. Online ahead of print.

ABSTRACT

Thiopurines are commonly used in the treatment of acute lymphoblastic leukaemia and autoimmune conditions, can be limited by myelosuppression. The NUDT15 c.415C>T variant is strongly associated with thiopurine-induced myelosuppression, especially in Asians. The purpose of this study was to develop a fast and reliable genotyping method for NUDT15 c.415C>T and investigate the polymorphic distribution among different races in China. A single-tube multiplex real-time PCR assay for NUDT15 c.415C>T genotyping was established using allele-specific TaqMan probes. In 229 samples, the genotyping results obtained through the established method were completely concordant with those obtained by Sanger sequencing. The distributions of NUDT15 c.415C>T among 173 Han Chinese, 48 Miaos, 40 Kazakhs, and 40 Kirghiz were different, with allelic frequencies of 0.06, 0.02, 0.07, and 0, respectively. This method will provide a powerful tool for the implementation of the genotyping-based personalized prescription of thiopurines in clinical settings.

PMID:34192970 | DOI:10.1177/15353702211026579

Int J Infect Dis. 2021 Jun 27:S1201-9712(21)00539-7. doi: 10.1016/j.ijid.2021.06.052. Online ahead of print.

ABSTRACT

OBJECTIVES: We aimed to describe population pharmacokinetics of intravenous colistin use in children and propose optimal dosage regimens.

METHODS: A prospective, multicenter, population pharmacokinetic (PPK) study was conducted. PhoenixTM 64 version 8.3 was used for PPK analysis. Simulations were performed to estimate the probability of target attainment of patients achieving target plasma colistin average steady-state concentrations (Css,avg).

RESULTS: A total of 334 plasma colistin concentrations were obtained from 79 pediatric patients with a median age (interquartile range) of 2.6 years (0.8-6.8 years); 73 (92.4%) were admitted to intensive care units. Colistin pharmacokinetics were adequately described by a one-compartment model with first-order elimination along with serum creatinine (SCr) as a significant covariate on colistin clearance. The simulation demonstrated that the recommended dose of 5 mg of colistin base activity (CBA)/kg/day resulted in 18.2-63.0% probability to achieve a target Css,avg of 2 mg/L. With a lower targeted Css,avg of 1 mg/L, colistin dosing with 7.5 and 5 mg of CBA/kg/day were adequate for children with SCr levels of 0.1-0.3 and >0.3 mg/dL, respectively.

CONCLUSIONS: SCr is a significant covariate on colistin clearance in children. Colistin dosing should be selected regarding the patient's SCr level and the desired target Css,avg.

PMID:34192578 | DOI:10.1016/j.ijid.2021.06.052

Int J Clin Pract. 2021 Jun 30:e14435. doi: 10.1111/ijcp.14435. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomics testing aims to optimise therapy and reduce the inter-individual variation in drug response. One of the major barriers against the implementation of pharmacogenomics testing is the low level of knowledge on the topic.

AIMS: This study aimed to evaluate the need for pharmacogenomics education among pharmacists in the West Bank of Palestine.

METHODS: This study was cross-sectional and included 370 pharmacists, among different cities in the West Bank of Palestine between October and December 2020. The questionnaire consisted of 25 close-ended questions that evaluated the exposure to pharmacogenomics education, attitude toward the role of pharmacogenomics testing in clinical practice and self-capability of pharmacists in pharmacogenomics testing.

RESULTS: It was found that 60% of the respondents disagreed that pharmacogenomics was an integral part of the pharmacy school curriculum and/or experiential education. The vast majority of the respondents (94%) agreed that pharmacists should be required to have some knowledge of pharmacogenomics. The majority of the respondents (88.6%) believe that pharmacogenomics testing will improve pharmacists' ability to more effectively control drug therapy expenditures. However, only 38% of the respondents could identify medications that require pharmacogenomics testing, and only 35.1% could identify reliable sources of information regarding pharmacogenomics for healthcare providers and patients.

CONCLUSION: It is seen from the results of this study that there is a high need to learn about pharmacogenomics testing, which can help the pharmacists make pharmacotherapy decisions. Additionally, current pharmacists have low self-confidence in making decisions depending on the results of pharmacogenomics testing. It is recommended to increase the exposure of pharmacogenomics knowledge by including the subject in courses and workshops in pharmacy school curricula in the West Bank of Palestine.

PMID:34191402 | DOI:10.1111/ijcp.14435

Pharmgenomics Pers Med. 2021 Jun 23;14:745-755. doi: 10.2147/PGPM.S305020. eCollection 2021.

ABSTRACT

OBJECTIVE: Individual differences in glycemic response to metformin in antidiabetic treatment exist widely. Although some associated genetic variations have been discovered, they still cannot accurately predict metformin response. In the current study, we set out to investigate novel genetic variants affecting metformin response in Chinese type 2 diabetes (T2D) patients.

METHODS: A two-stage study enrolled 500 T2D patients who received metformin, glibenclamide or a combination of both were recruited from 2009 to 2012 in China. Change of HbA1c, adjusted by clinical covariates, was used to evaluate glycemic response to metformin. Selected single nucleotide polymorphisms (SNPs) were genotyped using the Infinium iSelect and/or Illumina GoldenGate genotyping platform. A linear regression model was used to evaluate the association between SNPs and response.

RESULTS: A total of 3739 SNPs were screened in Stage 1, of which 50 were associated with drug response. Except for one genetic variant preferred to affect glibenclamide, the remaining SNPs were subsequently verified in Stage 2, and two SNPs were successfully validated. These were PRKAG2 rs2727528 (discovery group: β=-0.212, P=0.046; validation group: β=-0.269, P=0.028) and PRKAG2 rs1105842 (discovery group: β=0.205, P=0.048; validation group: β=0.273, P=0.025). C allele carriers of rs2727528 and C allele carriers of rs1105842 would have a larger difference of HbA1c level when using metformin.

CONCLUSION: Two variants rs2727528 and rs1105842 in PRKAG2, encoding γ2 subunit of AMP-activated protein kinase (AMPK), were found to be associated with metformin response in Chinese T2D patients. These findings may provide some novel information for personalized pharmacotherapy of metformin in China.

PMID:34188521 | PMC:PMC8236263 | DOI:10.2147/PGPM.S305020

Pharmacogenet Genomics. 2021 Aug 1;31(6):125-132. doi: 10.1097/FPC.0000000000000430.

ABSTRACT

BACKGROUND: Pharmacogenetics (PGx) science has evolved significantly with a huge number of studies exploring the effect of genetic variants on interindividual variability of drug response. In this study, we assessed the knowledge, attitudes and preparedness of Pharm-D vs. medical students toward PGx.

METHOD: A paper-based cross-sectional survey was performed. A pilot-tested questionnaire consisting of 21 questions (demographics 5, knowledge 6, attitude 6, and preparedness 4) was administered to 900 healthcare students at different years of study. Descriptive and inferential analyses were used.

RESULTS: Out of the 900 students approached, 852 (94.7%) completed the questionnaire. The overall students' mean (SD) percentage knowledge score (PKS) was poor [46.7% (18.7)]. The mean (SD) attitude and preparedness scores for all students were 4.68 (1.32), and 1.9 (1.40), respectively, indicating overall positive attitudes, but low preparedness to apply PGx to clinical care. Pharm-D students' overall PKS was significantly higher than medical students (P < 0.0001). However, there was no significant difference in terms of attitude and preparedness scores. Interestingly, as the year of study increased, the knowledge scores increased as well, with 6th-year students had the highest knowledge scores, while preparedness in applying PGx was higher among the junior students (the 3rd and 4th year of study).

CONCLUSION: Pharm-D and medical students have inadequate knowledge and low preparedness despite the overall positive attitude towards PGx. There is a need to raise knowledge and to enhance the level of preparedness of medical and Pharm-D students towards PGx and its applications in clinical practice.

PMID:34187984 | DOI:10.1097/FPC.0000000000000430

Arh Hig Rada Toksikol. 2021 Jun 28;72(3):114-128. doi: 10.2478/aiht-2021-72-3549.

ABSTRACT

Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice.

PMID:34187111 | DOI:10.2478/aiht-2021-72-3549

Arh Hig Rada Toksikol. 2021 Jun 28;72(3):129-134. doi: 10.2478/aiht-2021-72-3499.

ABSTRACT

The enzymes of the cytochrome P450 superfamily play a critical role in phase I drug metabolism. Among them, CYP2C9 and CYP2C19 are clinically important, as they can mediate severe toxicity, therapy failure, and increased susceptibility to cancer and other diseases caused by chemicals. The aim of this study was to determine the prevalence of pharmacologically most important allelic variants of the CYP2C9 and CYP2C19 genes in the general population of the Republic of Srpska (Bosnia and Herzegovina) and to compare them with other populations. For this purpose we determined the genotype profile and allele frequency of 216 randomly selected healthy volunteers using real-time polymerase chain reaction (RT-PCR). The prevalence of the CYP2C9 *2 and *3 alleles was 13.6 and 7.4 %, respectively. Based on these frequencies, of the 216 participants four (1.86 %) were predicted to be poor metabolisers, 78 (36.11 %) intermediate, and the remaining 134 (62.03 %) normal metabolisers. Based on the prevalence of CYP2C19 *2 and *17 variants - 16.2 and 20.4 %, respectively - nine (4.17 %) were predicted to be poor, 57 (26.39 %) rapid, and nine (4.17 %) ultra-rapid metabolisers. We found no significant differences in allele frequencies in our population and populations from other European countries. These findings suggest that genetically determined phenotypes of CYP2C9 and CYP2C19 should be taken into consideration to minimise individual risk and improve benefits of drug therapy in the Republic of Srpska.

PMID:34187105 | DOI:10.2478/aiht-2021-72-3499