European Journal of Drug Metabolism and Pharmacokinetics最新文献

{"title":"The Loss-of-Function ATP Binding Cassette Subfamily G Member 2 Polymorphism ABCG2 c.421C>A Reduces Lamotrigine Trough Concentrations in Adults with Epilepsy.","authors":"Nada Božina, Iva Klarica Domjanović, Ivana Šušak Sporiš, Lana Ganoci, Mila Lovrić, Vladimir Trkulja","doi":"10.1007/s13318-024-00925-0","DOIUrl":"https://doi.org/10.1007/s13318-024-00925-0","url":null,"abstract":"<p><strong>Background and objectives: </strong>The commonly used antiseizure medication lamotrigine is a substrate to ATP binding cassette subfamily G member 2 (ABCG2) transporter. The objective of this study was to evaluate the effect of the common loss-of-function polymorphism ABCG2 c.421C>A (rs2231142) on the lamotrigine trough concentrations at steady state in adults with epilepsy.</p><p><strong>Methods: </strong>In two consecutive studies (Study 1, Study 2) in patients on lamotrigine monotherapy, carriers of the variant ABCG2 c.421C>A allele (CA/AA) were considered exposed, and wild-type homozygotes (CC) were considered controls. They were mutually balanced on covariates (age, sex, body weight, several polymorphisms in genes encoding other transporter proteins and lamotrigine-metabolizing enzymes that have been suggested to affect exposure to lamotrigine) to estimate the exposure effect (geometric means ratios, GMRs) in each study separately and overall (individual patient data meta-analysis). The overall estimate was evaluated for sensitivity to residual confounding.</p><p><strong>Results: </strong>In both studies (exposed n = 28 vs. controls n = 103; exposed n = 44 vs. controls n = 153, in Study 1 and Study 2, respectively) and overall (exposed n = 72 vs. controls n = 256), dose-corrected lamotrigine trough concentrations were moderately lower in the exposed patients: frequentist GMR [95% CI] = 0.82 [0.63-1.08]; GMR = 0.69 [0.60-0.81] and GMR = 0.72 [0.63-0.83] in Study 1, Study 2 and overall, respectively; Bayes GMR [95% CrI] = 0.83 [0.68-1.00]; GMR = 0.69 [0.58-0.83] and GMR = 0.75 [0.65-0.86] in Study 1, Study 2 and overall, respectively. Estimates appeared resistant to unmeasured confounding-the E-values for the pooled point estimates were high, and estimates corrected for a strong hypothetical bias were GMR = 0.78 [0.68-0.90] frequentist and GMR = 0.81 [0.70-0.93] Bayes.</p><p><strong>Conclusion: </strong>Polymorphism ABCG2 c.421C>A moderately reduces lamotrigine concentrations in adults with epilepsy.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acknowledgement to Referees.","authors":"","doi":"10.1007/s13318-024-00922-3","DOIUrl":"10.1007/s13318-024-00922-3","url":null,"abstract":"","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"657-659"},"PeriodicalIF":1.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Abuse Liability and Nicotine Pharmacokinetics of glo Heated Tobacco Products in a Randomized, Crossover Study.","authors":"Milly N Kanobe, Patrudu Makena, Kristen Prevette, Sarah A Baxter","doi":"10.1007/s13318-024-00921-4","DOIUrl":"10.1007/s13318-024-00921-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Heated tobacco products (HTPs) are a class of non-combustible, inhaled tobacco products with the potential to reduce the harm associated with cigarette smoking due to reduced cigarette smoke toxicant exposure. Subjective and nicotine pharmacokinetics measures taken over the course of product use provide a framework for abuse liability (AL) assessment of tobacco and nicotine products as well as information on adoption potential for a new tobacco product, which are important aspects for premarket tobacco product authorization by the US Food and Drug Administration. This study aimed to assess the AL of glo HTPs, operated in either Standard or Boost Modes, compared with high- and low-AL comparators (subjects' usual brand cigarettes and nicotine gum, respectively).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Nicotine uptake and pharmacodynamics measures (including subjective and physiological measures) were assessed in a clinical study of 75 healthy adult non-menthol or menthol smokers using an open-label, randomized crossover study design. Comparisons were made between glo HTPs (Standard or Boost Modes) and each of usual brand (UB) cigarettes and nicotine gum to evaluate nicotine exposure and subjective effects measures.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Nicotine uptake, as reflected in the area under the curve (AUC) at 15 and 240 min after product use (AUC&lt;sub&gt;0-15&lt;/sub&gt; and AUC&lt;sub&gt;0-240&lt;/sub&gt;, respectively) and maximum nicotine concentration (C&lt;sub&gt;max&lt;/sub&gt;) were significantly lower for all glo HTPs compared to UB cigarettes, regardless of the glo device mode. AUC&lt;sub&gt;0-15&lt;/sub&gt; values for glo HTPs ranged from 41.26 to 75.71 ng × min/mL, versus 158.04 to 165.53 ng × min/mL for UB cigarettes. Similarly, AUC&lt;sub&gt;0-240&lt;/sub&gt; values for glo HTPs ranged from 379 to 596 ng × min/mL, compared to 1123.73 and 1283.37 ng × min/mL for UB cigarettes. The C&lt;sub&gt;max&lt;/sub&gt; for glo HTPs ranged from 5.46 to 9.00 ng/mL, whereas UB cigarettes had C&lt;sub&gt;max&lt;/sub&gt; values of 16.29 to 16.76 ng/mL. The time to reach maximum nicotine concentration (T&lt;sub&gt;max&lt;/sub&gt;) was significantly shorter for glo HTPs (4-5 min) compared to UB cigarettes (6-7 min), except for one variant of glo HTP in Standard Mode. Nicotine gum exhibited a slower nicotine absorption profile, with a T&lt;sub&gt;max&lt;/sub&gt; of 45 min and C&lt;sub&gt;max&lt;/sub&gt; of 4.60 ng/mL. AUC&lt;sub&gt;0-15&lt;/sub&gt; and AUC&lt;sub&gt;0-240&lt;/sub&gt; values for nicotine gum were 6.18 and 5.22 ng × min/mL, and 647.80 and 687.68 ng × min/mL for non-menthol and menthol groups, respectively. Subjective measures indicated that glo HTPs were rated significantly lower than UB cigarettes in terms of product liking, smoking urge reduction, product effects, and intent to use again, but were comparable to nicotine gum.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;glo HTPs demonstrated lower AL than combustible cigarettes while delivering sufficient nicotine to support product adoption among current smokers. This positions glo HTPs as a poten","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"733-750"},"PeriodicalIF":1.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Fimasartan Fluidized Solid Dispersion and Its Tablet: Preparation, Crystallinity, Solubility, Dissolution, and Pharmacokinetics in Beagle Dogs.","authors":"Dong Chul Shin, Jung Hyun Cho, Fakhar Ud Din, Sung Giu Jin, Han-Gon Choi","doi":"10.1007/s13318-024-00919-y","DOIUrl":"10.1007/s13318-024-00919-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>Fimasartan, an angiotensin II receptor antagonist, exhibits low bioavailability due to its poor solubility; consequently, using solubilization technologies is essential to improve its bioavailability. In this study, novel fimasartan fluidized solid dispersion (FFSD) was developed using a fluid bed granulator to enhance the drug solubility and oral bioavailability.</p><p><strong>Methods: </strong>An appropriate FFSD was prepared in 50% ethanol using a fluid bed granulator, and its drug dissolution, morphology, and crystallinity were evaluated in comparison to the powdered drug. Moreover, the dissolution in various pH conditions and pharmacokinetics of the FFSD tablet in beagle dogs were investigated compared to the commercial fimasartan tablet.</p><p><strong>Results: </strong>Among the hydrophilic polymers tested, hydroxypropyl methylcellulose (HPMC) showed the highest solubility. The FFSD, composed of fimasartan, HPMC, and microcrystalline cellulose at the weight ratio of 20:10:25, gave a granular aggregation of several particles with a smooth surface. The drug in this FFSD existed as an amorphous state, leading to a greatly increased drug dissolution. The FFSD tablet was prepared by compressing a mixture of FFSD, mannitol, croscarmellose sodium, and magnesium stearate at the weight ratio of 55:40:5:1. The FFSD tablet gave significantly higher drug dissolution, plasma concentrations, maximum plasma concentration (C_max) and area under the whole blood concentration-time curve (AUC) values than did the commercial fimasartan tablet. In the beagle dogs, the FFSD tablet (140.39 ± 27.40 ng·h/ml) had about a 1.7-fold higher AUC than the commercial fimasartan tablet (80.58 ± 22.18 ng·h/ml), indicating an enhancement in the bioavailability.</p><p><strong>Conclusions: </strong>This novel FFSD tablet could be a potential oral pharmaceutical product with the improved oral bioavailability of fimasartan.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"723-732"},"PeriodicalIF":1.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vancomycin in Pediatric Patients with Cystic Fibrosis: Dose Optimization Using Population Pharmacokinetic Approach","authors":"Aysenur Yaliniz, Mathieu Blouin, Marie-Élaine Métras, Marie-Christine Boulanger, Karine Cloutier, Marie-Hélène Dubé, Julie Autmizguine, Amélie Marsot","doi":"10.1007/s13318-024-00913-4","DOIUrl":"https://doi.org/10.1007/s13318-024-00913-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>An increase in <i>Staphylococcus aureus</i> infections has been reported in pediatric patients with cystic fibrosis (CF) over the last few years. This pathogen is commonly treated with vancomycin, an antibiotic for which therapeutic drug monitoring (TDM) is recommended. Updated guidelines were recently published regarding new targets of exposure for the TDM of vancomycin through a Bayesian approach, using population pharmacokinetic (popPK) models.</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>This study aims to assess the predictive performance of vancomycin popPK models in pediatric patients with CF and to recommend optimal initial dosing regimens based on simulations.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Patient data were collected from two centers in Canada, and a literature review was conducted to identify all published vancomycin popPK models for pediatric CF patients. External evaluation and simulations were performed according to patient and occasion of treatment.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A total of 53 vancomycin concentrations were collected from six pediatric CF patients. Only two popPK models of vancomycin for pediatric CF patients were identified through the literature review. The external evaluation results for both centers combined revealed a population bias of 28.1% and an imprecision of 33.7%. A re-estimation of parameters was performed to improve predictive performance. The optimal initial dosing regimen was 15 mg/kg/dose administered every 6 hours according to the per occasion remodel.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The predictive performance and identified optimal initial dosing regimens associated with the model were different depending on the data used, showing external evaluation’s importance before implementing a model in clinical practice.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":"9 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole Body Physiologically Based Pharmacokinetic Model to Explain A Patient With Drug–Drug Interaction Between Voriconazole and Flucloxacillin","authors":"Heshu Abdullah-Koolmees, Julia F. van den Nieuwendijk, Simone M. K. ten Hoope, David C. de Leeuw, Linda G. W. Franken, Medhat M. Said, Maarten R. Seefat, Eleonora L. Swart, N. Harry Hendrikse, Imke H. Bartelink","doi":"10.1007/s13318-024-00916-1","DOIUrl":"https://doi.org/10.1007/s13318-024-00916-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objectives</h3><p>Voriconazole administered concomitantly with flucloxacillin may result in subtherapeutic plasma concentrations as shown in a patient with <i>Staphylococcus aureus</i> sepsis and a probable pulmonary aspergillosis. After switching our patient to posaconazole, therapeutic concentrations were reached. The aim of this study was to first test our hypothesis that flucloxacillin competes with voriconazole not posaconazole for binding to albumin ex vivo, leading to lower total concentrations in plasma.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A physiologically based pharmacokinetic (PBPK) model was then applied to predict the mechanism of action of the drug–drug interaction (DDI). The model included non-linear hepatic metabolism and the effect of a severe infectious disease on cytochrome P450 (CYP) enzymes activity.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The unbound voriconazole concentration remained unchanged in plasma after adding flucloxacillin, thereby rejecting our hypothesis of albumin-binding site competition. The PBPK model was able to adequately predict the plasma concentration of both voriconazole and posaconazole over time in healthy volunteers. Upregulation of CYP3A4, CYP2C9, and CYP2C19 through the pregnane X receptor (PXR) gene by flucloxacillin resulted in decreased voriconazole plasma concentrations, reflecting the DDI observations in our patient. Posaconazole metabolism was not affected, or was only limitedly affected, by the changes through the PXR gene, which agrees with the observed plasma concentrations within the target range in our patient.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Ex vivo experiments reported that the unbound voriconazole plasma concentration remained unchanged after adding flucloxacillin. The PBPK model describes the potential mechanism driving the drug–drug and drug–disease interaction of voriconazole and flucloxacillin, highlighting the large substantial influence of flucloxacillin on the PXR gene and the influence of infection on voriconazole plasma concentrations, and suggests a more limited effect on other triazoles.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":"13 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142250130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Personalized Medicine Approach to Proteomics and Metabolomics of Cytochrome P450 Enzymes: A Narrative Review","authors":"John Fetse, Emmanuel Oladayo Olawode, Subrata Deb","doi":"10.1007/s13318-024-00912-5","DOIUrl":"https://doi.org/10.1007/s13318-024-00912-5","url":null,"abstract":"<p>Cytochrome P450 enzymes (CYPs) represent a diverse family of heme-thiolate proteins involved in the metabolism of a wide range of endogenous compounds and xenobiotics. In recent years, proteomics and metabolomics have been used to obtain a comprehensive insight into the role of CYPs in health and disease aspects. The objective of the present work is to better understand the status of proteomics and metabolomics in CYP research in optimizing therapeutics and patient safety from a personalized medicine approach. The literature used in this narrative review was procured by electronic search of PubMed, Medline, Embase, and Google Scholar databases. The following keywords were used in combination to identify related literature: “proteomics,” “metabolomics,” “cytochrome P450,” “drug metabolism,” “disease conditions,” “proteome,” “liquid chromatography-mass spectrometry,” “integration,” “metabolites,” “pathological conditions.” We reviewed studies that utilized proteomics and metabolomics approaches to explore the multifaceted roles of CYPs in identifying disease markers and determining the contribution of CYP enzymes in developing treatment strategies. The applications of various cutting-edge analytical techniques, including liquid chromatography-mass spectrometry, nuclear magnetic resonance, and bioinformatics analyses in CYP proteomics and metabolomics studies, have been highlighted. The identification of CYP enzymes through metabolomics and/or proteomics in various disease conditions provides key information in the diagnostic and therapeutic landscape. Leveraging both proteomics and metabolomics presents a powerful approach for an exhaustive exploration of the multifaceted roles played by CYP enzymes in personalized medicine. Proteomics and metabolomics have enabled researchers to unravel the complex connection between CYP enzymes and metabolic markers associated with specific diseases. As technology and methodologies evolve, an integrated approach promises to further elucidate the role of CYPs in human health and disease, potentially ushering in a new era of personalized medicine.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":"4 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of Concomitant Administration of Proton Pump Inhibitors on the Pharmacokinetics of CDK4/6 Inhibitors in Rats: Implications for the Evaluation of Hepatic and Transporter-Mediated Drug-Drug Interactions.","authors":"Prajakta Harish Patil, Mrunal Desai, Sumit Birangal, Gautham Shenoy Gurupur, Mahadev Rao, Anandkumar Yadav, Vishwanath Kurawattimath, Avinash Chaudhari, Tarun Sharma, Jakir Pinjari, Jagadish Puralae Channabasavaiah","doi":"10.1007/s13318-024-00909-0","DOIUrl":"10.1007/s13318-024-00909-0","url":null,"abstract":"<p><strong>Background and objectives: </strong>Numerous clinical concerns have been expressed regarding the potential worsening of cyclin-dependent kinase 4/6 inhibitor effects in breast cancer patients because of co-administration of proton pump inhibitors. Hence, this study evaluated the effects of proton pump inhibitors on the pharmacokinetics of palbociclib and ribociclib in terms of  cytochrome P450 (CYP) 3A4 and P-glycoprotein involvement.</p><p><strong>Methods: </strong>The effects of omeprazole and rabeprazole on drug metabolism and efflux of these drugs were investigated using molecular docking, metabolic stability assay in rat liver microsomes, human recombinant CYP3A4 (rCYP3A4) enzymes, and Caco-2 cell monolayers, and in vivo pharmacokinetics with omeprazole and rabeprazole in (5 and 10 mg/kg) 30 min and 7 days before orally dosing palbociclib and ribociclib (10 mg/kg).</p><p><strong>Results: </strong>Omeprazole and rabeprazole inhibited CYP3A4 enzyme activity in rCYP3A4 baculosomes with a 50-60% inhibition at 30 μM. Additionally, both omeprazole and rabeprazole (10 µm) significantly reduced the P-glycoprotein-mediated drug efflux of palbociclib and ribociclib. The 7-day pretreatment of omeprazole at a dose of 10 mg/kg resulted in 24% and 26% reductions in palbociclib's mean maximum plasma concentration) C_max and area under the plasma concentration-time curve (AUC_{0-24 h}), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC_{0-24 h}.</p><p><strong>Conclusion: </strong>The findings indicate that long-term treatment with therapeutic doses of both omeprazole and rabeprazole can alter the pharmacokinetics of palbociclib and ribociclib. The co-administration of rabeprazole may alter the pharmacokinetics of palbociclib and ribociclib via CYP enzyme and P-glycoprotein inhibition.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"631-644"},"PeriodicalIF":1.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision Medicine Strategies to Improve Isoniazid Therapy in Patients with Tuberculosis.","authors":"Levin Thomas, Arun Prasath Raju, Surulivelrajan Mallayasamy, Mahadev Rao","doi":"10.1007/s13318-024-00910-7","DOIUrl":"10.1007/s13318-024-00910-7","url":null,"abstract":"<p><p>Due to interindividual variability in drug metabolism and pharmacokinetics, traditional isoniazid fixed-dose regimens may lead to suboptimal or toxic isoniazid concentrations in the plasma of patients with tuberculosis, contributing to adverse drug reactions, therapeutic failure, or the development of drug resistance. Achieving precision therapy for isoniazid requires a multifaceted approach that could integrate various clinical and genomic factors to tailor the isoniazid dose to individual patient characteristics. This includes leveraging molecular diagnostics to perform the comprehensive profiling of host pharmacogenomics to determine how it affects isoniazid metabolism, such as its metabolism by N-acetyltransferase 2 (NAT2), and studying drug-resistant mutations in the Mycobacterium tuberculosis genome for enabling targeted therapy selection. Several other molecular signatures identified from the host pharmacogenomics as well as other omics-based approaches such as gut microbiome, epigenomic, proteomic, metabolomic, and lipidomic approaches have provided mechanistic explanations for isoniazid pharmacokinetic variability and/or adverse drug reactions and thereby may facilitate precision therapy of isoniazid, though further validations in larger and diverse populations with tuberculosis are required for clinical applications. Therapeutic drug monitoring and population pharmacokinetic approaches allow for the adjustment of isoniazid dosages based on patient-specific pharmacokinetic profiles, optimizing drug exposure while minimizing toxicity and the risk of resistance. Current evidence has shown that with the integration of the host pharmacogenomics-particularly NAT2 and Mycobacterium tuberculosis genomics data along with isoniazid pharmacokinetic concentrations in the blood and patient factors such as anthropometric measurements, comorbidities, and type and timing of food administered-precision therapy approaches in isoniazid therapy can be tailored to the specific characteristics of both the host and the pathogen for improving tuberculosis treatment outcomes.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"541-557"},"PeriodicalIF":1.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Competitive Counterflow Assay for Identifying Drugs Transported by Solute Carriers: Principle, Applications, Challenges/Limits, and Perspectives.","authors":"Olivier Fardel, Amélie Moreau, Jennifer Carteret, Claire Denizot, Marc Le Vée, Yannick Parmentier","doi":"10.1007/s13318-024-00902-7","DOIUrl":"10.1007/s13318-024-00902-7","url":null,"abstract":"<p><p>The identification of substrates for solute carriers (SLCs) handling drugs is an important challenge, owing to the major implication of these plasma membrane transporters in pharmacokinetics and drug-drug interactions. In this context, the competitive counterflow (CCF) assay has been proposed as a practical and less expensive approach than the reference functional uptake assays for discriminating SLC substrates and non-substrates. The present article was designed to summarize and discuss key-findings about the CCF assay, including its principle, applications, challenges and limits, and perspectives. The CCF assay is based on the decrease of the steady-state accumulation of a tracer substrate in SLC-positive cells, caused by candidate substrates. Reviewed data highlight the fact that the CCF assay has been used to identify substrates and non-substrates for organic cation transporters (OCTs), organic anion transporters (OATs), and organic anion transporting polypeptides (OATPs). The performance values of the CCF assay, calculated from available CCF study data compared with reference functional uptake assay data, are, however, rather mitigated, indicating that the predictability of the CCF method for assessing SLC-mediated transportability of drugs is currently not optimal. Further studies, notably aimed at standardizing the CCF assay and developing CCF-based high-throughput approaches, are therefore required in order to fully precise the interest and relevance of the CCF assay for identifying substrates and non-substrates of SLCs.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"527-539"},"PeriodicalIF":1.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}