European Journal of Drug Metabolism and Pharmacokinetics最新文献

{"title":"Pharmacokinetic Study of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles HY-088 in Rats.","authors":"Xin Song, Minglan Zheng, Heping Hu, Lei Chen, Shuzhe Wang, Zhao Ding, Guangyi Fu, Luyao Sun, Liyuan Zhao, Ling Zhang, Bohua Xu, Yunliang Qiu","doi":"10.1007/s13318-024-00884-6","DOIUrl":"10.1007/s13318-024-00884-6","url":null,"abstract":"<p><strong>Background and objective: </strong>HY-088 injection is an ultrasmall superparamagnetic iron oxide nanoparticle (USPIOs) composed of iron oxide crystals coated with polyacrylic acid (PAA) on the surface. The purpose of this study was to investigate the pharmacokinetics, tissue distribution, and mass balance of HY-088 injection.</p><p><strong>Methods: </strong>The pharmacokinetics of [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 were investigated in 48 SD rats by intravenous injection of 8.5 (low-dose group), 25.5 (medium-dose group), and 85 (high-dose group) mg/100 μCi/kg. Tissue distribution was studied by intravenous injection of 35 mg/100 μCi/kg in 48 SD rats, and its tissue distribution in vivo was obtained by ex vivo tissue assay. At the same time, [¹⁴C]-HY-088 was injected intravenously at a dose of 25.5 mg/100 μCi/kg into 16 SD rats, and its tissue distribution in vivo was studied by quantitative whole-body autoradiography. [¹⁴C]-HY-088 and [⁵⁵Fe]-HY-088 were injected intravenously into 24 SD rats at a dose of 35 mg/100 μCi/kg, and their metabolism was observed.</p><p><strong>Results: </strong>In the pharmacokinetic study, [⁵⁵Fe]-HY-088 reached the maximum observed concentration (C_max) at 0.08 h in the low- and medium-dose groups of SD rats. [¹⁴C]-HY-088 reached C_max at 0.08 h in the three groups of SD rats. The area under the concentration-time curve (AUC) of [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 increased with increasing dose. In the tissue distribution study, [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes of both female and male rats. In the mass balance study conducted over 57 days, the radioactive content of ⁵⁵Fe from [⁵⁵Fe]-HY-088 was primarily found in the carcass, accounting for 86.42 ± 4.18% in females and 95.46 ± 6.42% in males. The radioactive recovery rates of [¹⁴C]-HY-088 in the urine of female and male rats were 52.99 ± 5.48% and 60.66 ± 2.23%, respectively.</p><p><strong>Conclusions: </strong>Following single intravenous administration of [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 in SD rats, rapid absorption was observed. Both [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes. During metabolism, the radioactivity of [⁵⁵Fe]-HY-088 is mainly present in the carcass, whereas the ¹⁴C-labeled [¹⁴C]-HY-088 shell PAA is eliminated from the body mainly through the urine.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930641","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":"Safety, Tolerability, and Pharmacokinetics of the Monoamine Oxidase B Inhibitor, HEC122505, and its Major Metabolite After Single- and Multiple- Ascending Dose, and Food Effect Study in Healthy Chinese Subjects.","authors":"Chuanfei Jin, Chao Yi, Kangzhi Chen, Haiping Liang","doi":"10.1007/s13318-024-00880-w","DOIUrl":"10.1007/s13318-024-00880-w","url":null,"abstract":"<p><strong>Background and objectives: </strong>HEC122505 is a potent and selectively monoamine oxidase B inhibitor that is safe and well-tolerated in preclinical models of Parkinson's disease. The objectives of single ascending dose and multiple dose pharmacokinetic trials of HEC122505 oral tablets were to determine the safety and tolerability of HEC122505, and to examine the food effect on the pharmacokinetic parameters of HEC122505 and its major metabolite HEC129870.</p><p><strong>Methods: </strong>The phase I study (NCT04625361) consisted of three arms: single ascending dose study (5, 20, 50, 100, 200, 300 or 400 mg HEC122505 tablets or placebo), multiple ascending dose study (20, 50 or 100 mg HEC122505 tablets or placebo once daily), and food effect (100 mg HEC122505 tablets single dose after a high-fat, high-calorie meal). All subjects completed all trial arms and were analyzed as planned.</p><p><strong>Results: </strong>Pharmacokinetic analysis showed that HEC122505 rapidly absorbed with the time to peak plasma concentration (T_max) ranged from 0.5 to 1.75 h. In addition, maximum plasma drug concentration (C_max) and area under the plasma concentration-time curve (AUC) increased in a dose proportional manner. Food effect study showed that a high-fat, high-calorie meal had no significant effect on the pharmacokinetics of HEC122505 and its major metabolite HEC129870, suggesting that HEC122505 could be administered in both fasted and fed state in clinical trials. The subsequent multiple-dose study evaluated doses from 20 to 100 mg dose once daily for up to 8 days. HEC122505 reached steady state after approximately 5 days with a once daily dose. In these studies, all dose of HEC122505 was generally safe and well tolerated. No grade ≥ 3 drug related adverse events (AEs) occurred.</p><p><strong>Conclusion: </strong>HEC122505 was generally safe and well tolerated in the single ascending dose (ranging from 5 to 400 mg) and multiple ascending dose (50 to 200 mg once daily doses) studies. All the drug related adverse events (AEs) were Grade ≤ 2. There were no deaths, no subjects discontinued the trial due to AEs, and there were no other serious AEs. The safety and pharmacokinetic profile support once daily administration of HEC122505.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038985","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":"Predicting Pharmacokinetics of Drugs Using Artificial Intelligence Tools: A Systematic Review.","authors":"Mahnaz Ahmadi, Bahareh Alizadeh, Seyed Mohammad Ayyoubzadeh, Mahdiye Abiyarghamsari","doi":"10.1007/s13318-024-00883-7","DOIUrl":"10.1007/s13318-024-00883-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Pharmacokinetic studies encompass the examination of the absorption, distribution, metabolism, and excretion of bioactive compounds. The pharmacokinetics of drugs exert a substantial influence on their efficacy and safety. Consequently, the investigation of pharmacokinetics holds great importance. However, laboratory-based assessment necessitates the use of numerous animals, various materials, and significant time. To mitigate these challenges, alternative methods such as artificial intelligence have emerged as a promising approach. This systematic review aims to review existing studies, focusing on the application of artificial intelligence tools in predicting the pharmacokinetics of drugs.</p><p><strong>Methods: </strong>A pre-prepared search strategy based on related keywords was used to search different databases (PubMed, Scopus, Web of Science). The process involved combining articles, eliminating duplicates, and screening articles based on their titles, abstracts, and full text. Articles were selected based on inclusion and exclusion criteria. Then, the quality of the included articles was assessed using an appraisal tool.</p><p><strong>Results: </strong>Ultimately, 23 relevant articles were included in this study. The clearance parameter received the highest level of investigation, followed by the  area under the concentration-time curve (AUC) parameter, in pharmacokinetic studies. Among the various models employed in the articles, Random Forest and eXtreme Gradient Boosting (XGBoost) emerged as the most commonly utilized ones. Generalized Linear Models and Elastic Nets (GLMnet) and Random Forest models showed the most performance in predicting clearance.</p><p><strong>Conclusion: </strong>Overall, artificial intelligence tools offer a robust, rapid, and precise means of predicting various pharmacokinetic parameters based on a dataset containing information of patients or drugs.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058983","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":"A Phase I, Open-Label, Mass Balance Study of [¹⁴C]-Iberdomide in Healthy Subjects.","authors":"Yiming Cheng, Xiaomin Wang, Liangang Liu, Jose Silva, Michael Thomas, Yan Li","doi":"10.1007/s13318-024-00886-4","DOIUrl":"10.1007/s13318-024-00886-4","url":null,"abstract":"<p><strong>Background: </strong>Iberdomide is a novel potent cereblon modulator (CELMoD^®) agent, which is currently under clinical development for hematological malignancies. A human mass balance study was conducted to characterize the biotransformation and excretion pathways of iberdomide.</p><p><strong>Method: </strong>After a single dose of radiolabelled [¹⁴C]-iberdomide (1 mg) in six healthy subjects. Blood, urine, and fecal samples were collected for pharmacokinetics, mass balance, and clinical laboratory assessments.</p><p><strong>Results: </strong>Results showed that a single oral dose of 1 mg iberdomide was generally well tolerated in healthy subjects. The recovery of [¹⁴C]-iberdomide-derived radioactivity in humans was 45.9% in urine and 42.6% in feces. Based on exposure (area under the concentration-time curve [AUC_0-24]), iberdomide and M12 (metabolites) accounted for approximately 59% and 14% of circulating total radioactivity (TRA) exposure, respectively. Of the 88.5% TRA excreted, approximately 27% was excreted as unchanged iberdomide and 62% as metabolites, with similar amounts of excreted metabolites in the urine (16%) and feces (11%).</p><p><strong>Conclusion: </strong>Biotransformation of iberdomide in humans included multiple oxidations of the morpholino moiety as well as glutarimide ring hydrolysis of parent and oxidized metabolites and a combination of these pathways. Iberdomide was the predominant component in human plasma, with metabolite M12 being the most prominent circulating metabolite. In excreta, similar iberdomide-derived radioactivity was found in urine and feces.</p><p><strong>Trial registration number: </strong>NCT03294603.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140193626","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":"Correction: Population Pharmacokinetic Analysis of Vancomycin in Patients with Solid or Hematological Malignancy in Relation to the Quick Sequential Organ Failure Assessment Scores.","authors":"Yasumasa Tsuda, Masahiro Takahashi, Fumiya Watanabe, Kazumi Goto, Hirotoshi Echizen","doi":"10.1007/s13318-024-00890-8","DOIUrl":"10.1007/s13318-024-00890-8","url":null,"abstract":"","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140143008","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":"Kinetic Characterization of Estradiol Glucuronidation by Liver Microsomes and Expressed UGT Enzymes: The Effects of Organic Solvents.","authors":"Caimei Wu, Meixue Luo, Dihao Xie, Simin Zhong, Jiahao Xu, Danyi Lu","doi":"10.1007/s13318-024-00888-2","DOIUrl":"10.1007/s13318-024-00888-2","url":null,"abstract":"<p><strong>Background and objective: </strong>In vitro glucuronidation of 17β-estradiol (estradiol) is often performed to assess the role of uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) in xenobiotic/drug metabolism. The objective of this study was to determine the effects of four commonly used organic solvents [i.e., dimethyl sulfoxide (DMSO), methanol, ethanol, and acetonitrile] on the glucuronidation kinetics of estradiol, which can be glucuronidated at C3 and C17 positions.</p><p><strong>Methods: </strong>The impacts of organic solvents on estradiol glucuronidation were determined by using expressed UGT enzymes and liver microsomes from both human and animals.</p><p><strong>Results: </strong>In human liver microsomes (HLM), methanol, ethanol, and acetonitrile significantly altered estradiol glucuronidation kinetics with increased V_max (up to 2.6-fold) and CL_max (up to 2.8-fold) values. Altered estradiol glucuronidation in HLM was deduced to be attributed to the enhanced metabolic activities of UGT1A1 and UGT2B7, whose activities differ at the two glucuronidation positions. The effects of organic solvents on estradiol glucuronidation were glucuronidation position-, isozyme-, and solvent-specific. Furthermore, both ethanol and acetonitrile have a greater tendency to modify the glucuronidation activity of estradiol in animal liver microsomes.</p><p><strong>Conclusion: </strong>Organic solvents such as methanol, ethanol, and acetonitrile showed great potential in adjusting the glucuronidation of estradiol. DMSO is the most suitable solvent due to its minimal influence on estradiol glucuronidation. Researchers should be cautious in selecting appropriate solvents to get accurate results when assessing the metabolism of a new chemical entity.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109697","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":"Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies in Migraine: Focus on Drug Interactions.","authors":"Slobodan M Janković, Snežana V Janković","doi":"10.1007/s13318-024-00887-3","DOIUrl":"10.1007/s13318-024-00887-3","url":null,"abstract":"<p><p>Calcitonin gene-related peptide neurotransmission was the target for recent development of monoclonal antibodies that effectively prevent attacks of both episodic and chronic migraine. The aim of this narrative review was to offer deeper insight into drug-drug, drug-food and drug-disease interactions of monoclonal antibodies approved for prevention of migraine attacks. For this narrative review, relevant literature was searched for in MEDLINE and Google Scholar databases, covering the 1966-2023 and 2006-2023 periods, respectively. The ClinicalTrials.gov database was also searched for relevant clinical studies whose results had not been published previously in medical journals, covering 2000-2023. Monoclonal antibodies (erenumab, fremanezumab, galcanezumab and eptinezumab) augment prophylactic action of gepants and onabotulinumtoxin A and somewhat increase efficacy of triptans used to abort migraine attacks; however, their adverse reactions may also be augmented. Pharmacokinetic interactions and interactions in general with drugs used for other indications except migraine are negligible, as are drug-food interactions. However, monoclonal antibodies may worsen diseases with already weakened CGRP neurotransmission, Raynaud phenomenon and constipation. Monoclonal antibodies used for prevention of migraine do not engage in significant pharmacokinetic interactions with other drugs; however, they do engage in pharmacodynamic interactions with other anti-migraine drugs, additively augmenting their prophylactic action, but also increasing frequency and severity of adverse reactions, which are a consequence of the CGRP neurotransmission interruption.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058982","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":"Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies in Migraine: Focus on Clinical Pharmacokinetics.","authors":"Slobodan M Janković, Snežana V Janković","doi":"10.1007/s13318-024-00885-5","DOIUrl":"10.1007/s13318-024-00885-5","url":null,"abstract":"<p><p>The calcitonin gene-related peptide transmission was the target for recent development of drugs that effectively prevent attacks of both episodic and chronic migraine. The aim of this narrative review was to offer deeper insight into pharmacokinetics of monoclonal antibodies approved for prevention of migraine attacks. For this narrative review, relevant literature was searched for in MEDLINE and Google Scholar databases, covering periods 1966-2023 and 2006-2023, respectively. The ClinicalTrials.gov database was also searched for relevant clinical studies whose results had not been published previously in medical journals, covering the period 2000-2023. The monoclonal antibodies from this group are distributed mainly in the plasma and part of the extracellular space; they are neither metabolized in the liver nor excreted via the kidneys. The elimination of galcanezumab, eptinezumab and fremanezumab takes place only by a non-specific linear process via the reticuloendothelial system in the liver, while erenumab is eliminated by a non-specific process and by a specific, saturable process because of binding to receptors located on the cell membrane. Since the elimination processes do not have a large capacity, the half-life is about 2 weeks for erenumab and about 4 weeks for other monoclonal antibodies. Variability in the pharmacokinetics of these monoclonal antibodies is small in different subpopulations, and body weight is the only parameter to consider when choosing the dose of these drugs.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140093602","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 the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.","authors":"Xiaoxing Wang, Martin E Dowty, Sakambari Tripathy, Vu H Le, Yeamin Huh, Madelyn Curto, Jennifer A Winton, Melissa T O'Gorman, Gary Chan, Bimal K Malhotra","doi":"10.1007/s13318-024-00893-5","DOIUrl":"10.1007/s13318-024-00893-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated.</p><p><strong>Methods: </strong>Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives).</p><p><strong>Results: </strong>After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUC_inf) and the maximum concentration (C_max) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUC_inf of caffeine by 40% with lack of effect on C_max.</p><p><strong>Conclusions: </strong>Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives.</p><p><strong>Clinical trials registration: </strong>ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11052784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140329730","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 Use of Microdosing for In vivo Phenotyping of Cytochrome P450 Enzymes: Where Do We Stand? A Narrative Review","authors":"Lisa T. van der Heijden, Frans L. Opdam, Jos H. Beijnen, Alwin D. R. Huitema","doi":"10.1007/s13318-024-00896-2","DOIUrl":"https://doi.org/10.1007/s13318-024-00896-2","url":null,"abstract":"<p>Cytochrome P450 (CYP) enzymes play a central role in the elimination of approximately 80% of all clinically used drugs. Differences in CYP enzyme activity between individuals can contribute to interindividual variability in exposure and, therefore, treatment outcome. In vivo CYP enzyme activity could be determined with phenotyping. Currently, (sub)therapeutic doses are used for in vivo phenotyping, which can lead to side effects. The use of microdoses (100 µg) for in vivo phenotyping for CYP enzymes could overcome the limitations associated with the use of (sub)therapeutic doses of substrates. The aim of this review is to provide a critical overview of the application of microdosing for in vivo phenotyping of CYP enzymes. A literature search was performed to find drug–drug interaction studies of CYP enzyme substrates that used microdoses of the respective substrates. A substrate was deemed sensitive to changes in CYP enzyme activity when the pharmacokinetics of the substrate significantly changed during inhibition and induction of the enzyme. On the basis of the currently available evidence, the use of microdosing for in vivo phenotyping for subtypes CYP1A2, CYP2C9, CYP2D6, and CYP2E1 is not recommended. Microdosing can be used for the in vivo phenotyping of CYP2C19 and CYP3A. The recommended microdose phenotyping test for CYP2C19 is measuring the omeprazole area-under-the-concentration-time curve over 24 h (AUC_0–24) after administration of a single 100 µg dose. CYP3A activity could be best determined with a 0.1–75 µg dose of midazolam, and subsequently measuring AUC extrapolated to infinity (AUC_∞) or clearance. Moreover, there are two metrics available for midazolam using a limited sampling strategy: AUC over 10 h (AUC_0–10) and AUC from 2 to 4 h (AUC_2–4).</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841871","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}