J Am Coll Clin Pharm. 2022 Nov;5(11):1161-1175. doi: 10.1002/jac5.1699. Epub 2022 Aug 27.

ABSTRACT

The vast majority of patients possess one or more pharmacogenetic variants that can influence optimal medication use. When pharmacogenetic data are used to guide drug choice and dosing, evidence points to improved disease outcomes, fewer adverse effects, and lower healthcare spending. Although its science is well established, clinical use of pharmacogenetic data to guide drug therapy is still in its infancy. Pharmacogenetics essentially involves the intersection of an individual's genetic data with their medications, which makes pharmacists uniquely qualified to provide clinical support and education in this field. In fact, most pharmacogenetics implementations, to date, have been led by pharmacists as leaders or members of a multidisciplinary team or as individual practitioners. A successful large-scale pharmacogenetics implementation requires coordination and synergy among administrators, clinicians, informatics teams, laboratories, and patients. Because clinical implementation of pharmacogenetics is in its early stages, there is an urgent need for guidance and dissemination of shared experiences to provide a framework for clinicians. Many early adopters of pharmacogenetics have explored various strategies among diverse practice settings. This article relies on the experiences of early adopters to provide guidance for critical steps along the pathway to implementation, including strategies to engage stakeholders; evaluate pharmacogenetic evidence; coordinate laboratory testing, results interpretation and their integration into the electronic health record; identify reimbursement avenues; educate providers and patients; and maintain a successful program. Learning from early adopters' published experiences and strategies can allow clinicians leading a new pharmacogenetics implementation to avoid pitfalls and adapt and apply lessons learned by others to their own practice.

PMID:36589694 | PMC:PMC9799247 | DOI:10.1002/jac5.1699

Front Pharmacol. 2022 Dec 12;13:1063413. doi: 10.3389/fphar.2022.1063413. eCollection 2022.

ABSTRACT

Tuberculosis (TB) is an infectious disease that occurs globally. Treatment of TB has been hindered by problems with multidrug-resistant strains (MDR-TB). Fluoroquinolones are one of the main drugs used for the treatment of MDR-TB. The success of therapy can be influenced by genetic factors and their impact on pharmacokinetic parameters. This review was conducted by searching the PubMed database with keywords polymorphism and fluoroquinolones. The presence of gene polymorphisms, including UGT1A1, UGT1A9, SLCO1B1, and ABCB1, can affect fluoroquinolones pharmacokinetic parameters such as area under the curve (AUC), creatinine clearance (CCr), maximum plasma concentration (Cmax), half-life (t1/2) and peak time (tmax) of fluoroquinolones.

PMID:36588725 | PMC:PMC9798452 | DOI:10.3389/fphar.2022.1063413

Pharmacotherapy. 2023 Jan 1. doi: 10.1002/phar.2758. Online ahead of print.

ABSTRACT

Oral P2Y12 inhibitors are commonly prescribed for cardiovascular disease and include clopidogrel, prasugrel, and ticagrelor. Each of these drugs has its strengths and weaknesses. Prasugrel and ticagrelor are more potent inhibitors of platelet aggregation and were shown to be superior to clopidogrel in preventing major adverse cardiovascular events after an acute coronary syndrome and percutaneous coronary intervention (PCI) in the absence of genotyping. However, both are associated with an increased risk for non-coronary artery bypass-related bleeding. Clopidogrel is a prodrug requiring bioactivation, primarily via the CYP2C19 enzyme. Approximately 30% of individuals have a CYP2C19 no function allele and decreased or no CYP2C19 enzyme activity. Clopidogrel-treated carriers of a CYP2C19 no function allele have decreased exposure to the clopidogrel active metabolite and lesser inhibition of platelet aggregation, which likely contributed to reduced clopidogrel efficacy in clinical trials. The pharmacogenetic data for clopidogrel are most robust in the setting of PCI, but evidence is accumulating for other indications. Guidance is available from expert consensus groups and regulatory agencies to assist with integrating genetic information into P2Y12 inhibitor prescribing decisions, and CYP2C19 genotype-guided antiplatelet therapy after PCI is one of the most common examples of clinical pharmacogenetic implementation. Herein, we review the evidence for pharmacogenetic associations with clopidogrel response and outcomes with genotype-guided P2Y12 inhibitor selection and describe guidance to assist with pharmacogenetic implementation. We also describe processes for applying genotype data for P2Y12 inhibitor therapy selection and remaining gaps in the field. Ultimately, consideration of both clinical and genetic factors may guide selection of P2Y12 inhibitor therapy that optimally balances the atherothrombotic and bleeding risks.

PMID:36588476 | DOI:10.1002/phar.2758

J Adv Res. 2023 Jan;43:163-174. doi: 10.1016/j.jare.2022.03.004. Epub 2022 Mar 12.

ABSTRACT

INTRODUCTION: Although the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown.

OBJECTIVES: This study aimed to assess in vivo the physiological role of sEH-P.

METHODS: CRISPR/Cas9 was used to generate a novel knock-in (KI) rat line lacking the sEH-P activity.

RESULTS: The sEH-P KI rats has a decreased metabolism of lysophosphatidic acids to monoacyglycerols. KI rats grew almost normally but with less weight and fat mass gain while insulin sensitivity was increased compared to wild-type rats. This lean phenotype was more marked in males than in female KI rats and mainly due to decreased food consumption and enhanced energy expenditure. In fact, sEH-P KI rats had an increased lipolysis allowing to supply fatty acids as fuel to potentiate brown adipose thermogenesis under resting condition and upon cold exposure. The potentiation of thermogenesis was abolished when blocking PPARγ, a nuclear receptor activated by intracellular lysophosphatidic acids, but also when inhibiting simultaneously sEH-H, showing a functional interaction between the two domains. Furthermore, sEH-P KI rats fed a high-fat diet did not gain as much weight as the wild-type rats, did not have increased fat mass and did not develop insulin resistance or hepatic steatosis. In addition, sEH-P KI rats exhibited enhanced basal cardiac mitochondrial activity associated with an enhanced left ventricular contractility and were protected against cardiac ischemia-reperfusion injury.

CONCLUSION: Our study reveals that sEH-P is a key player in energy and fat metabolism and contributes together with sEH-H to the regulation of cardiometabolic homeostasis. The development of pharmacological inhibitors of sEH-P appears of crucial importance to evaluate the interest of this promising therapeutic strategy in the management of obesity and cardiac ischemic complications.

PMID:36585106 | DOI:10.1016/j.jare.2022.03.004

PLoS One. 2022 Dec 30;17(12):e0278839. doi: 10.1371/journal.pone.0278839. eCollection 2022.

ABSTRACT

Publication bias may lead to a misestimation in the association between pharmacogenetic biomarkers (PGx) and antiseizure drug's adverse effects (AEs). We aimed to assess its prevalence in this field. We searched for systematic reviews assessing PGx of antiseizure drug's AEs. For each unique association between a PGx, a drug and its AE, we used the available odds ratio (ORs) to generate corresponding funnel plots. We estimated the prevalence of publication bias using visual inspections and asymmetry tests. We explored the impact of publication bias using ORs adjusted for potential publication bias. Twenty-two associations were available. Our visual analysis suggested a publication bias in five out twenty-two funnel plots (23% [95%CI: 8; 45]). The Egger's test showed a significant publication bias in one (HLA-B*15:02 and phenytoin-induced Stevens-Johnson syndrome or toxic epidermal necrolysis, p = 0.03) out of nine (11% [95%CI: 0; 48]) and the Begg's test in one (HLA-B*15:02 and carbamazepine-induced serious cutaneous reactions, p = 0.02) out of ten (10% [95%CI: 0; 45]) assessable funnel plots. Adjusting for publication bias may reduce by half the ORs of the pharmacogenetics associations. Publication bias in the pharmacogenetic of antiseizure drug's AEs is not uncommon and may affect the estimation of the effect of such biomarkers. When conducting pharmacogenetic studies, it is critical to publish also the negative one.

PMID:36584134 | DOI:10.1371/journal.pone.0278839

J Antimicrob Chemother. 2022 Dec 30:dkac413. doi: 10.1093/jac/dkac413. Online ahead of print.

ABSTRACT

The interpretation of 'susceptible (S)' or 'resistant (R)' results of antimicrobial susceptibility testing is easily understood, but the interpretation of the 'intermediate (I)' category can be confusing. This review critically discusses how this categorization (clinical breakpoints) comes into being with the emphasis on the use of pharmacokinetics and pharmacodynamic data. It discusses the differences between the 'I' according to the CLSI and the EUCAST. This review also discusses the recent EUCAST change of the 'I' definition, and the impact of this change from laboratory and clinical points of view.

PMID:36583270 | DOI:10.1093/jac/dkac413

Bone Rep. 2022 Dec 15;18:101648. doi: 10.1016/j.bonr.2022.101648. eCollection 2023 Jun.

ABSTRACT

BACKGROUND: Prior studies of the pharmacogenomics of osteonecrosis of the jaw (ONJ) have had various methodological limitations, including using candidate gene selection as their sole strategy, a small number of ONJ cases, or a study population based on an oncology setting.

OBJECTIVES: The aim of our case-control study was to evaluate previously reported associations between genetic factors and ONJ, which were based on either genome-wide association studies (GWAS) or candidate gene approaches. Furthermore, we aimed to identify genetic risk factors for ONJ by using GWAS to determine single-nucleotide polymorphisms (SNPs) with statistically significant differences in frequency between ONJ patients and osteoporosis controls.

METHODS: Patients with medically confirmed ONJ and who were registered in the Scandinavian Cohort of ONJ patients were included. Controls from the general population were matched on age (±5 years), sex, and cumulative antiresorptive drug exposure. The ONJ diagnosis date for cases corresponded to the index date for matched controls. DNA isolation, genotyping, and data analyses were performed by Q2/EA Genomics using standard protocols and best practices. Blood or tissue samples for 55 ONJ cases and 125 controls were collected. Due to the low quality of the tissue samples, final analyses were based on blood samples of 40 ONJ cases and 124 controls.

RESULTS: We detected no significant genome-wide associations. Of the 43 SNPs with ONJ association in prior studies, none were replicated in our study.

CONCLUSIONS: Even though our study sample is the largest to date, we had limited statistical power for GWAS but adequate power for replication analyses. Our study provides no evidence for any genetic predisposition to ONJ. Future studies could increase their statistical power by combining ONJ GWAS datasets and by performing a meta-analysis or pursuing a sequencing strategy in order to identify rare variants.

PMID:36582190 | PMC:PMC9792722 | DOI:10.1016/j.bonr.2022.101648

Curr Neuropharmacol. 2022 Dec 29. doi: 10.2174/1570159X21666221229154830. Online ahead of print.

ABSTRACT

Parkinson's disease (PD) is the second most common neurodegenerative disease with a significant public health burden. It is characterized by the gradual degeneration of dopamine neurons in the central nervous system. Although symptomatic pharmacological management remains the primary therapeutic method for PD, clinical experience reveals significant inter-individual heterogeneity in treatment effectiveness and adverse medication responses. The mechanisms behind the observed interindividual variability may be elucidated by investigating the role of genetic variation in human-to-human variances in medication responses and adverse effects. </P> <P> Objective: This review aims to explore the impact of gene polymorphism on the efficacy of anti- parkinsonian drugs. The identification of factors associated with treatment effectiveness variability might assist the creation of a more tailored pharmacological therapy with higher efficacy, fewer side outcomes, and cheaper costs. </P> <P> Methods: In this review, we conducted a thorough search in databases such as PubMed, Web of Science, and Google Scholar, and critically examined current discoveries on Parkinson&#39;s disease pharmacogenetics. The ethnicity of the individuals, research methodologies, and potential bias of these studies were thoroughly compared, with the primary focus on consistent conclusions. </P> <P> Results: This review provides a summary of the existing data on PD pharmacogenetics, identifies their its limitations, and offers insights that may be beneficial for future research. Previous studies have investigated the impact of gene polymorphism on the effectiveness and adverse effects of levodopa. The trendiest genes are the COMT gene, DAT gene, and DRD2 gene. However, limited study on other anti-Parkinson&#39;s drugs has been conducted. </P> <P> Conclusion: Therefore, In order to develop an individualized precision treatment for PD, it is an inevitable trend to carry out multi-center, prospective, randomized controlled clinical trials of PD pharmacogenomics covering common clinical anti-PD drugs in large, homogeneous cohorts.

PMID:36582064 | DOI:10.2174/1570159X21666221229154830

BMC Cardiovasc Disord. 2022 Dec 30;22(1):575. doi: 10.1186/s12872-022-02988-w.

ABSTRACT

BACKGROUNDS: Remarkable interindividual variability in clopidogrel response is observed, genetic polymorphisms in P2RY12 and its signal pathway is supposed to affect clopidogrel response in CHD patients.

METHODS: 539 CHD patients treated with clopidogrel were recruited. The platelet reaction index (PRI) indicated by VASP-P level were detected in 12-24 h after clopidogrel loading dose or within 5-7 days after initiation of maintain dose clopidogrel. A total of 13 SNPs in relevant genes were genotyped in sample A (239 CHD patients). The SNPs which have significant differences in PRI will be validated in another sample (sample B, 300 CHD patients).

RESULTS: CYP2C19*2 increased the risk of clopidogrel resistance significantly. When CYP2C19*2 and CYP2C19*3 were considered, CYP2C19 loss of function (LOF) alleles were associated with more obviously increased the risk of clopidogrel resistance; P2RY12 rs6809699C > A polymorphism was also associated with increased risk of clopidogrel resistance (AA vs CC: P = 0.0398). This difference still existed after stratification by CYP2C19 genotypes. It was also validated in sample B. The association was also still significant even in the case of stratification by CYP2C19 genotypes in all patients (sample A + B).

CONCLUSION: Our data suggest that P2RY12 rs6809699 is associated with clopidogrel resistance in CHD patients. Meanwhile, the rs6809699 AA genotype can increase on-treatment platelet activity independent of CYP2C19 LOF polymorphisms.

PMID:36581799 | DOI:10.1186/s12872-022-02988-w

Curr Opin Pharmacol. 2022 Dec 27;68:102320. doi: 10.1016/j.coph.2022.102320. Online ahead of print.

ABSTRACT

Tumor necrosis factor alpha (TNFα) inhibitors are a mainstay of treatment for rheumatoid arthritis (RA) patients after failed responses to conventional disease-modifying antirheumatic drugs (DMARDs). Despite the clinical efficacy of TNFα inhibitors (TNFi), many RA patients experience TNFi treatment failure due to the development of anti-drug antibodies (ADAs) that can neutralize drug levels and lead to RA disease relapse. Methotrexate (MTX) therapy with concomitant TNFα inhibitors decreases the risk of TNFi immunogenicity, but additional and/or alternative strategies are needed to reduce MTX-associated toxicities and to further increase its potency for preventing TNFα inhibitor immunogenicity. In this review, we highlight the limitations of MTX for mitigating TNFα inhibitor immunogenicity, and we discuss potential alternative pharmacological targets for decreasing the risk of immunogenicity during TNFα inhibitor therapy based on the key kinases, second messengers, and shared signaling mechanisms of lymphocyte receptor signaling.

PMID:36580770 | DOI:10.1016/j.coph.2022.102320

PLoS One. 2022 Dec 29;17(12):e0278115. doi: 10.1371/journal.pone.0278115. eCollection 2022.

ABSTRACT

BACKGROUND: Women of African ancestry are highly predisposed to preeclampsia which continues to be a major cause of maternal death in Africa. Common variants in the APOL1 gene are potent risk factor for a spectrum of kidney disease. Recent studies have shown that APOL1 risk variants contribute to the risk of preeclampsia. The aim of the study is to understand the contribution of APOL1 risk variants to the development of preeclampsia in pregnant women in Ghana.

METHODS: The study is a case-control design which started recruitment in 2019 at the Korle Bu Teaching Hospital in Ghana. The study will recruit pregnant women with a target recruitment of 700 cases of preeclampsia and 700 normotensives. Clinical and demographic data of mother- baby dyad, with biospecimens including cord blood and placenta will be collected to assess clinical, biochemical and genetic markers of preeclampsia. The study protocol was approved by Korle Bu Teaching Hospital Institutional Review Board (Reference number: KBTH-IRB/000108/2018) on October 11, 2018.

PRELIMINARY RESULTS: As of December 2021, a total of 773 mother-baby pairs had been recruited and majority of them had complete entry of data for analysis. The participants are made up of 384 preeclampsia cases and 389 normotensive mother-baby dyad. The mean age of participants is 30.69 ± 0.32 years for cases and 29.95 ± 0.32 for controls. Majority (85%) of the participants are between 20-30years. At booking, majority of cases had normal blood pressure compared to the time of diagnosis where 85% had a systolic BP greater than 140mmHg and a corresponding 82% had diastolic pressure greater than 90mmHg.

CONCLUSION: Our study will ultimately provide clinical, biochemical and genotypic data for risk stratification of preeclampsia and careful monitoring during pregnancy to improve clinical management and outcomes.

PMID:36580463 | DOI:10.1371/journal.pone.0278115

Eur Arch Psychiatry Clin Neurosci. 2022 Dec 29. doi: 10.1007/s00406-022-01542-1. Online ahead of print.

ABSTRACT

Evidence regarding effectiveness and safety of clozapine once- vs. multiple-daily dosing is limited. We compared demographic and clinical parameters between patients with once- vs. multiple-daily dosing in the Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (AGATE dataset), and the Department of Psychiatry, Lausanne University Hospital, Switzerland, using non-parametric tests. Effectiveness and safety outcomes were available in the AGATE dataset. We performed a systematic review in PubMed/Embase until February 2022, meta-analyzing studies comparing clozapine once- vs. multiple-daily-dosing. We estimated a pooled odds ratio for adverse drug-induced reactions (ADRs) and meta-analyzed differences regarding clinical symptom severity, age, percentage males, smokers, clozapine dose, and co-medications between patients receiving once- vs. multiple-daily dosing. Study quality was assessed using the Newcastle-Ottawa-Scale. Of 1494 and 174 patients included in AGATE and Lausanne datasets, clozapine was prescribed multiple-daily in 74.8% and 67.8%, respectively. In the AGATE cohort, no differences were reported for the clinical symptoms severity or ADR rate (p > 0.05). Meta-analyzing eight cohorts with a total of 2810 clozapine-treated individuals, we found more severe clinical symptoms (p = 0.036), increased ADR risk (p = 0.01), higher clozapine doses (p < 0.001), more frequent co-medication with other antipsychotics (p < 0.001), benzodiazepines (p < 0.001), anticholinergics (p = 0.039), and laxatives (p < 0.001) in patients on multiple- vs. once-daily dosing. Of six studies, five were rated as good, and one as poor quality. Patients responding less well to clozapine may be prescribed higher doses multiple-daily, also treated with polypharmacy, potentially underlying worse safety outcomes. Patient preferences and adherence should be considered during regimen selection.

PMID:36580106 | DOI:10.1007/s00406-022-01542-1

J Pers Med. 2022 Nov 2;12(11):1821. doi: 10.3390/jpm12111821.

ABSTRACT

PGx testing requires a complex set of activities undertaken by practitioners and patients, resulting in varying implementation success. This systematic review aimed (PROSPERO: CRD42019150940) to identify barriers and enablers to practitioners and patients implementing pharmacogenomic testing. We followed PRISMA guidelines to conduct and report this review. Medline, EMBASE, CINAHL, PsycINFO, and PubMed Central were systematically searched from inception to June 2022. The theoretical domain framework (TDF) guided the organisation and reporting of barriers or enablers relating to pharmacogenomic testing activities. From the twenty-five eligible reports, eleven activities were described relating to four implementation stages: ordering, facilitating, interpreting, and applying pharmacogenomic testing. Four themes were identified across the implementation stages: IT infrastructure, effort, rewards, and unknown territory. Barriers were most consistently mapped to TDF domains: memory, attention and decision-making processes, environmental context and resources, and belief about consequences.

PMID:36579514 | DOI:10.3390/jpm12111821

Chin Med. 2022 Dec 28;17(1):146. doi: 10.1186/s13020-022-00701-9.

ABSTRACT

BACKGROUND: Ginsenoside compound K (GC-K) potentially alleviates ulcerative colitis involved in gut microbiota, which is significantly associated with the occurrence and development of colitis. However, the effect and mechanism of GC-K on anti-colitis in relation to gut microbiota are not clear. This study focused on the prevention and mechanism of GC-K on Dextran sulfate sodium (DSS)-induced colitis of mice pertinent to gut microbiota.

METHODS: DSS was used to establish a chronic colitis mouse model. Body weight analysis, colon length measurement, HE staining, and inflammatory factors levels were processed in animal experiments. Flow cytometry was employed to analyze Th17/Treg cells in the mouse spleen and blood. 16S rRNA sequencing was utilized to analyze gut microbiota. Fecal microbiota transplantation (FMT) experiment was employed to verify the anti-colitis efficacy of GC-K by reshaping gut microbiota.

RESULTS: GC-K significantly relieved colitis-related symptoms due to decreased disease activity index (DAI) scores, spleen weight, and increased colon length. Additionally, the tight junction proteins were increased, and the pro-inflammatory cytokines, such as TNF-α, IL-6, IL-1β and IL-17, were decreased after GC-K treatment. Furthermore, Bacteroides spp. significantly increased after modeling. Moreover, FMT experiments confirmed that GC-K-driven gut microbiota greatly relieved DSS-induced colitis.

CONCLUSION: GC-K alleviated colitis via the modulation of gut microbiota.

PMID:36578000 | DOI:10.1186/s13020-022-00701-9

Clin Pharmacol Ther. 2022 Dec 28. doi: 10.1002/cpt.2816. Online ahead of print.

NO ABSTRACT

PMID:36576133 | DOI:10.1002/cpt.2816

JAAPA. 2023 Jan 1;36(1):12-13. doi: 10.1097/01.JAA.0000902916.16504.e0.

ABSTRACT

Medications often are prescribed without knowledge of a patient's pharmacogenetic profile. Initial therapy may require subsequent modification due to adverse reactions or lack of efficacy. Although many variables, including changes in pharmacokinetics, pharmacodynamics, or patient nonadherence, may account for these outcomes, information about a patient's ability to metabolize or transport drugs across membranes may be used to optimize therapy, resulting in improved medication outcomes.

PMID:36573809 | DOI:10.1097/01.JAA.0000902916.16504.e0

Front Oncol. 2022 Dec 7;12:938561. doi: 10.3389/fonc.2022.938561. eCollection 2022.

ABSTRACT

Translation of genomic knowledge into public health benefits requires the implementation of evidence-based recommendations in clinical practice. In this study, we moved beyond BRCA1/2 susceptibility testing in breast and ovarian cancer patients to explore the application of pharmacogenetics across multiple genes participating in homologous recombination DNA damage repair. This involved the utilisation of next-generation sequencing (NGS) at the intersection of research and service delivery for development of a comprehensive genetic testing platform in South Africa. Lack of international consensus regarding risk categorization of established cancer susceptibility genes and the level of evidence required for prediction of drug response supported the development of a central database to facilitate clinical interpretation. Here we demonstrate the value of this approach using NGS to 1) determine the variant spectrum applicable to targeted therapy and implementation of prevention strategies using the 15-gene Oncomine™ BRCA Expanded Panel, and 2) searched for novel and known pathogenic variants in uninformative cases using whole exome sequencing (WES). Targeted NGS performed as a routine clinical service in 414 South African breast and/or ovarian cancer patients resulted in the detection of 48 actionable variants among 319 (15%) cases. BRCA1/2-associated cancers were identified in 70.8% of patients (34/48, including two double-heterozygotes), with the majority (35.3%, 12/34) representing known South African founder variants. Detection of actionable variants in established non-BRCA1/2 risk genes contributed 29% to the total percentage (14/48), distributed amongst ATM, CHEK2, BARD1, BRIP1, PALB2 and TP53. Experimental WES using a virtually constructed multi-cancer NGS panel in 16 genetically unresolved cases (and four controls) revealed novel protein truncating variants in the basal cell carcinoma gene PTCH1 (c.4187delG) and the signal transmission and transduction gene KIT (c.930delA) involved in crucial cellular processes. Based on these findings, the most cost-effective approach would be to perform BRCA1/2 founder variant testing at referral, followed by targeted multigene panel testing if clinically indicated and addition of WES in unresolved cases. This inventive step provides a constant flow of new knowledge into the diagnostic platform via a uniquely South African pathology-supported genetic approach implemented for the first time in this context to integrate research with service delivery.

PMID:36568162 | PMC:PMC9768488 | DOI:10.3389/fonc.2022.938561

Arch Pharm Res. 2022 Dec 23. doi: 10.1007/s12272-022-01423-0. Online ahead of print.

ABSTRACT

Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone. Thus, we studied the effects of CYP2C19 genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different CYP2C19 genotypes received a single oral dose of 150 mg tolperisone with 240 mL of water, and blood samples were collected up to 12 h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher Cmax and lower CL/F values than the CYP2C19EM and CYP2C19IM groups. The AUCinf of the CYP2C19PM group was 2.86-fold and 3.00-fold higher than the CYP2C19EM and CYP2C19IM groups, respectively. In conclusion, the genetic polymorphism of CYP2C19 significantly affected tolperisone pharmacokinetics.

PMID:36564599 | DOI:10.1007/s12272-022-01423-0

Genes Chromosomes Cancer. 2022 Dec 22. doi: 10.1002/gcc.23121. Online ahead of print.

NO ABSTRACT

PMID:36562080 | DOI:10.1002/gcc.23121

Cancer Rep (Hoboken). 2022 Dec 22:e1773. doi: 10.1002/cnr2.1773. Online ahead of print.

NO ABSTRACT

PMID:36560873 | DOI:10.1002/cnr2.1773