Clinical Pharmacology & Therapeutics最新文献

{"title":"FDA Approval Summary: Nalmefene Nasal Spray for the Emergency Treatment of Known or Suspected Opioid Overdose.","authors":"Srikanth C Nallani, Zhihua Li, Jeffry Florian, Yun Xu, Sreedharan Sabarinath, Tanya Brescia-Oddo, Rigoberto A Roca, Ramana S Uppoor, Mehul U Mehta","doi":"10.1002/cpt.3514","DOIUrl":"https://doi.org/10.1002/cpt.3514","url":null,"abstract":"<p><p>On May 22, 2023, the United States Food and Drug Administration approved the first nalmefene hydrochloride nasal spray for the emergency treatment of known or suspected opioid overdose in adults and pediatric patients 12 years of age and older. This approval of a new prescription nalmefene hydrochloride nasal spray adds to the available opioid reversal options for hospitals, communities, harm reduction groups, and emergency responders. Due to the life-threatening nature of opioid overdose, conducting randomized, well-controlled clinical efficacy trials in the target patient population is neither ethical nor feasible. Clinical investigations of nalmefene nasal spray consisted of two pharmacokinetic studies and one pharmacodynamic study. Approval of the new drug application was based on the scientific bridge established by the two pharmacokinetic studies to the Agency's previous efficacy and safety findings for the listed drug nalmefene hydrochloride injection. Additionally, the pharmacodynamic study conducted in an opioid-induced respiratory depression model in healthy volunteers established the onset of action of nalmefene administered as a nasal spray. A high-level summary of regulatory and scientific considerations during the development and approval of nalmefene nasal spray are presented.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Chronic Inflammatory Diseases on Clinical Pharmacokinetics of Antibody-Based Therapeutic Proteins.","authors":"Xiaofan Tian, Yichao Yu, Harshith Neeli, Dilara Jappar","doi":"10.1002/cpt.3513","DOIUrl":"https://doi.org/10.1002/cpt.3513","url":null,"abstract":"<p><p>Antibody-based therapeutic proteins (TPs) emerged as a promising therapeutic modality for chronic inflammatory diseases. During clinical development, the impact of disease on pharmacokinetics (PK) should be carefully considered to reliably extrapolate PK from healthy volunteers (HVs) in early-phase studies to patients in later-phase studies. This paper aimed to provide an overview of the impact of chronic inflammatory diseases on the PK of antibody-based TPs. A literature search was conducted on Drugs@FDA and PubMed, yielding 30 TPs with author-drawn conclusions about PK differences between HVs and patients with inflammatory diseases. Nine out of 30 TPs suggested PK differences in patients with inflammatory diseases compared with HVs, and patients mostly appeared to have higher drug clearance or lower drug exposure compared with HVs. However, the remaining 21 TPs appeared to have no apparent PK differences between patients and HVs. Based on ratios of reported drug clearance in patients vs. HVs (N: 31 ratios for 22 TPs), the difference in TP clearance due to inflammatory diseases did not exceed twofold (mean clearance ratio: 1.23; standard deviation: 0.25), with the most noticeable difference (>50% higher clearance) observed in patients with inflammatory bowel diseases and rheumatoid arthritis. Covariate assessment in published population PK models of TPs revealed that higher baseline C-reactive proteins and lower baseline albumin levels tend to be correlated with higher TP clearance. Future investigation is necessary to further elucidate the mechanism behind the inflammatory disease-mediated PK differences.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMS and EEG Pharmacodynamic Effects of a Selective Sphingosine-1-Phosphate Subtype 1 Receptor Agonist on Cortical Excitability in Healthy Subjects.","authors":"Catherine M K E de Cuba, Annika A de Goede, Erica S Klaassen, Marije E Otto, Robert J Doll, Jessica Kim, Mark A Demitrack, Ruihua Chen, Geert Jan Groeneveld, Jules A A C Heuberger","doi":"10.1002/cpt.3521","DOIUrl":"https://doi.org/10.1002/cpt.3521","url":null,"abstract":"<p><p>Current anti-epileptic drugs lack efficacy, cause many side effects and one third of all patients are treatment-resistant. Drugs targeting the sphingosine-1-phosphate receptor show potential anti-convulsant effects in animal models and decrease cortical excitability in patients with multiple sclerosis, but available compounds alter lymphocyte trafficking and cause immunosuppression, limiting their clinical anti-epileptic potential. TRV045 is a selective sphingosine-1-phosphate subtype 1 receptor agonist without effects on lymphocyte trafficking, demonstrating efficacy in animal models of epilepsy, with the potential to target abnormal cortical excitability. This randomized, double-blind, placebo-controlled, two-way cross-over, multiple-dose study evaluated the effects of TRV045 on cortical excitability in healthy male adults, measured by pharmaco-electroencephalography and transcranial magnetic stimulation (TMS). Subjects received TRV045 250 mg or placebo, once daily for 4 days, in randomized order. Endpoints were analyzed with a mixed effects model analysis of covariance. Twenty-five of the 27 subjects completed the study. There was a significant increase in alpha power with eyes open after treatment with TRV045 on Day 1, increasing after 4 days of dosing. Less pronounced significant effects in beta, gamma, and delta power were observed after 4 days. For TMS-Electromyography there was a non-significant decreased post-dose single-pulse peak-to-peak amplitude on Day 1 only, and there were no effects on paired-pulse parameters. Several significant TMS-Electroencephalography clusters were seen after 4 days of dosing. These findings show that TRV045 has central nervous system activity with evolving effects following repeated dosing. These data support further studies to elucidate the mechanism of action of TRV045 and its potential anti-epileptic effects.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Systems Pharmacology-Based Digital Twins Approach Supplements Clinical Trial Data for Enzyme Replacement Therapies in Pompe Disease","authors":"Chanchala Kaddi,&nbsp;Mengdi Tao,&nbsp;Silke Bergeler,&nbsp;Kelly George,&nbsp;Hugo Geerts,&nbsp;Piet H. van der Graaf,&nbsp;Julie L. Batista,&nbsp;Meredith Foster,&nbsp;Catherine Ortemann-Renon,&nbsp;Atef Zaher,&nbsp;Kristina An Haack,&nbsp;Susana Zaph","doi":"10.1002/cpt.3498","DOIUrl":"10.1002/cpt.3498","url":null,"abstract":"<p>Pompe disease is a rare, progressive neuromuscular disease caused by deficient lysosomal glycogen degradation, and includes both late-onset (LOPD) and severe infantile-onset (IOPD) phenotypes. Due to very small patient numbers in IOPD and the high phenotypic heterogeneity observed in this population, a quantitative systems pharmacology (QSP)-based “digital twin” approach was developed to perform an <i>in silico</i> comparison of the efficacy of avalglucosidase alfa vs. the standard of care, in a virtual population of IOPD patients. A QSP model was developed that represents key elements of Pompe disease pathophysiology, including tissue glycogen accumulation and the elevation of the biomarker urine Hex4 in both LOPD and IOPD patients. In this approach, the QSP model was used to generate digital twins of each IOPD patient enrolled in the avalglucosidase alfa clinical program, considering their respective disease burden, demographics, and treatment history. This virtual cohort supplemented clinical observations by simulating and comparing tissue glycogen and urine Hex4 following avalglucosidase alfa treatment vs. the standard of care. The digital twin analysis supports the interpretation that the enhanced reduction in urine Hex4 observed following avalglucosidase alfa treatment is attributable to greater tissue glycogen clearance. Overall, this study provides mechanism-based insight into avalglucosidase alfa efficacy across the phenotypic spectrum of Pompe disease and demonstrates the value of applying a QSP-based digital twin analysis to support rare disease drug development.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 2","pages":"579-588"},"PeriodicalIF":6.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 Trial of the Pharmacokinetic Interaction Between Cannabidiol and Tacrolimus.","authors":"Gerald C So, Jessica Bo Li Lu, Sachiko Koyama, Ying-Hua Cheng, Debora L Gisch, Kelsey McClara, Paul R Dexter, Asif A Sharfuddin, Jumar Etkins, Emma M Tillman, Travis R Beamon, Zachary Cowsert, Jennifer S Stuart, Zeruesenay Desta, Michael T Eadon","doi":"10.1002/cpt.3504","DOIUrl":"10.1002/cpt.3504","url":null,"abstract":"<p><p>One in six Americans uses cannabidiol-based or cannabis-derived products. Cannabidiol is a substrate of CYP3A, but its role as a potential CYP3A inhibitor remains unclear. We hypothesized that cannabidiol would inhibit CYP3A-mediated metabolism of tacrolimus. This report is an interim analysis of an open-label, three-period, fixed-sequence, crossover study in healthy participants. Participants first received a single dose of tacrolimus 5 mg orally. After washout, participants later received cannabidiol titrated to 5 mg/kg twice daily for 14 days to reach a steady state, followed by a second single dose of tacrolimus 5 mg orally. Tacrolimus concentrations in whole blood were measured by UHPLC-MS/MS method. Pharmacokinetic parameters were calculated by noncompartmental analysis. Twelve participants completed all periods of the study. The maximum concentration (C_max) of tacrolimus increased 4.2-fold (P < 0.0001) with cannabidiol (40.2 ± 13.5 ng/mL) compared with without cannabidiol (9.85 ± 4.63 ng/mL). The area under the concentration-vs.-time curve (AUC_0-∞) increased 3.1-fold (P < 0.0001). No change in half-life (t_1/2) was observed. This study demonstrates that cannabidiol increases tacrolimus exposure. Our data suggest the need for dose reduction in tacrolimus and frequent therapeutic dose monitoring in transplant patients taking cannabidiol concomitantly. Whether this observed interaction occurred due to the inhibition of CYP3A4 and/or CYP3A5 in the liver, intestine, or both, or intestinal drug transporters (e.g., p-glycoprotein) during the first-pass elimination remains to be elucidated.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxygenation Effects of Antihypertensive Agents in Intensive Care: A Prospective Comparative Study of Nicardipine and Urapidil.","authors":"Florimond Suard, Martin Mombrun, Marc-Olivier Fischer, Jean-Luc Hanouz, Jean-Baptiste Decros, Sébastien Derville, Clément Gakuba, Gulbhar Al Issa, Caroline Menard, Basile Chretien, Richard Descamps","doi":"10.1002/cpt.3509","DOIUrl":"https://doi.org/10.1002/cpt.3509","url":null,"abstract":"<p><p>Acute arterial hypertension within the critical care context may necessitate the administration of intravenous antihypertensive agents. Nicardipine and urapidil are notable for their application in intensive care units. Nonetheless, dihydropyridine calcium channel inhibitors (DCCIs) such as nicardipine are implicated in the impairment of hypoxic pulmonary vasoconstriction, potentially disrupting oxygenation. This study aimed to assess the differences in patient oxygenation when these antihypertensive agents are administered intravenously. This bicentric, prospective, observational investigation spanning five intensive care units evaluated patients requiring intravenous nicardipine or urapidil. Oxygenation data were recorded from the start of therapy until the 12th hour. Comparative analysis was performed between patient groups based on the antihypertensive agent administered, along with subgroup investigations to identify populations with an elevated risk of hypoxemia. From November 2021 to November 2023, 197 patients were included: 98 (50%) were treated with nicardipine, and 99 (50%) were treated with urapidil. Hypoxemia occurred in 97 (49%) patients and was more prevalent in the nicardipine cohort, affecting 65 (66%) patients, as opposed to 32 (32%) patients in the urapidil cohort (RR 2.05, 95% CI [1.48-2.82], P < 0.001). Subgroup analysis revealed a significant association between patients with pulmonary atelectasis (RR 2.30, 95% CI [1.4-3.7], P < 0.001) and obesity (RR 2.7, 95% CI [1.5-4.6], P < 0.001). Considering these findings, cautious consideration of the patient's respiratory status should be exercised when initiating intravenous DCCI treatment. However, given the limitations of this study, a controlled trial on hypertension management in the ICU is needed.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and Physiologically Based Pharmacokinetic Model Evaluations of Adagrasib Drug-Drug Interactions.","authors":"Cornelius Cilliers, Eleanor Howgate, Hannah M Jones, Lisa Rahbaek, Jonathan Q Tran","doi":"10.1002/cpt.3506","DOIUrl":"https://doi.org/10.1002/cpt.3506","url":null,"abstract":"<p><p>Adagrasib is a potent, highly selective, orally available, small molecule, covalent inhibitor of G12C mutated KRAS. As both a substrate and strong inhibitor of cytochrome P450 (CYP) 3A4, adagrasib inhibits its own CYP3A4-mediated metabolism following multiple dosing, resulting in time-dependent drug-drug interaction (DDI) liabilities. A physiologically-based pharmacokinetic (PBPK) model was developed and verified using a combination of physicochemical, in vitro and clinical pharmacokinetic (PK) data from healthy volunteers and cancer patients. The PBPK model well-described the single and multiple-dose adagrasib PK data as well as DDI data with itraconazole, rifampin, midazolam, warfarin, dextromethorphan, and digoxin, with model predictions within 1.5-fold of the observed clinical data. The PBPK model was used to predict untested scenarios including the clinical victim and perpetrator DDI liabilities at the approved dosing regimen of 600 mg twice daily (b.i.d.) in cancer patients. Strong, moderate, and weak inhibitors of CYP3A4 are predicted to have a negligible effect on the steady-state exposure of adagrasib 600 mg b.i.d. resulting from the significant inactivation of CYP3A4 by adagrasib. Additionally, strong and moderate inducers of CYP3A4 are predicted to decrease adagrasib exposure by 68% and 22%, respectively. As a perpetrator, adagrasib 600 mg b.i.d. is predicted to be a strong inhibitor of CYP3A4, a moderate inhibitor of CYP2C9 and CYP2D6, and an inhibitor of P-glycoprotein (P-gp). These results successfully supported regulatory interactions with the United States Food and Drug Administration regarding dosing recommendations for when adagrasib is used concomitantly with other medications, supporting a range of label claims in lieu of clinical trials.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"French-Speaking Network of Pharmacogenetics (RNPGx) Recommendations for Clinical Use of Mavacamten","authors":"Louis Lebreton,&nbsp;Jean-Christophe Boyer,&nbsp;Claire Lafay-Chebassier,&nbsp;Benjamin Hennart,&nbsp;Sarah Baklouti,&nbsp;Séverine Cunat,&nbsp;Paul Vilquin,&nbsp;Yves Medard,&nbsp;Elodie Gautier-Veyret,&nbsp;Clara Laffitte-Redondo,&nbsp;Céline Verstuyft,&nbsp;Abd El Kader Ait Tayeb,&nbsp;Vincent Haufroid,&nbsp;Julien Wils,&nbsp;Fabien Lamoureux,&nbsp;Alexandre Evrard,&nbsp;Julie Davaze-Schneider,&nbsp;Mouna Ben-Sassi,&nbsp;Nicolas Picard,&nbsp;Sylvie Quaranta,&nbsp;Estelle Ayme-Dietrich,&nbsp;the French-Speaking Network of Pharmacogenetics (RNPGx)","doi":"10.1002/cpt.3502","DOIUrl":"10.1002/cpt.3502","url":null,"abstract":"<p>Mavacamten, the first drug in the class of β-cardiac myosin modulator, is used for the treatment of patients with hypertrophic cardiomyopathy. This orally administered drug demonstrates wide interpatient variability in pharmacokinetics parameters, due in part to variant <i>CYP2C19</i> alleles. Individuals who are CYP2C19 poor metabolizers have increased exposure and are at increased risk of reduced cardiac hypercontractility. To ensure the safety of all patients, European Medicines Agency recommends <i>CYP2C19</i> preemptive genotyping, and consecutively, to adapt maintenance and initial mavacamten doses, and to manage drug–drug interactions, according to CYP2C19 phenotype. In this article, we summarize evidence from the literature supporting the association between CYP2C19 phenotype and pharmacological features of mavacamten and provide, beyond biologic guidelines, therapeutic recommendations for the use of mavacamten based on <i>CYP2C19</i> and <i>CYP3A4/CYP3A5</i> genotype.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 2","pages":"387-397"},"PeriodicalIF":6.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovering Severe Adverse Reactions From Pharmacokinetic Drug-Drug Interactions Through Literature Analysis and Electronic Health Record Verification.","authors":"Eugene Jeong, Yu Su, Lang Li, You Chen","doi":"10.1002/cpt.3500","DOIUrl":"10.1002/cpt.3500","url":null,"abstract":"<p><p>While drug-drug interactions (DDIs) and their pharmacokinetic (PK) mechanisms are well-studied prior to drug approval, severe adverse drug reactions (SADRs) caused by DDIs often remain underrecognized due to limitations in pre-marketing clinical trials. To address this gap, our study utilized a literature database, applied natural language processing (NLP) techniques, and conducted multi-source electronic health record (EHR) validation to uncover underrecognized DDI-SADR signals that warrant further investigation. PubMed abstracts related to DDIs from January 1962 to December 2023 were retrieved. We utilized PubTator Central for Named Entity Recognition (NER) to identify drugs and SADRs and employed SciFive for Relation Extraction (RE) to extract DDI-SADR signals. The extracted signals were cross-referenced with the DrugBank database and validated using logistic regression, considering risk factors including patient demographics, drug usage, and comorbidities, based on EHRs from Vanderbilt University Medical Center (VUMC) and the All of Us research program. From 160,321 abstracts, we identified 111 DDI-SADR signals. Seventeen were statistically significant (13 by one EHR and 4 by both EHR databases), with 9 being previously not recorded in the DrugBank. These included methadone-ciprofloxacin-respiratory depression, oxycodone-fluvoxamine-clonus, tramadol-fluconazole-hallucination, simvastatin-fluconazole-rhabdomyolysis, ibrutinib-amiodarone-atrial fibrillation, fentanyl-diltiazem-delirium, clarithromycin-voriconazole-acute kidney injury, colchicine-cyclosporine-rhabdomyolysis, and methadone-voriconazole-arrhythmia (odds ratios (ORs) ranged from 1.9 to 35.83, with P-values ranging from < 0.001 to 0.017). Utilizing NLP to extract DDI-SADRs from Biomedical Literature and validating these findings through multiple-source EHRs represents a pioneering approach in pharmacovigilance. This method uncovers clinically relevant SADRs resulting from DDIs that were not evident in pre-marketing trials or the existing DDI knowledge base.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distribution Characteristics and Impacting Factors of Drug CYP Enzymes and Transporters in the Gastrointestinal Tract of Chinese Healthy Subjects.","authors":"Miao Zhang, Lei Zhang, Baojun Suo, Yudong Wei, Yue Xu, Muhan Jiang, Jing Dong, Xiaodong Li, Zhiqiang Song, Dongyang Liu","doi":"10.1002/cpt.3497","DOIUrl":"https://doi.org/10.1002/cpt.3497","url":null,"abstract":"<p><p>The abundance of drug metabolic enzymes (DMEs) and transporters (DTs) in the human gastrointestinal tract significantly affects xenobiotic exposure in the circulating system, the basis of these compounds acting on humans. However, accurately predicting individual exposure in healthy subjects remains challenging due to limited data on protein levels throughout the gastrointestinal tract within the same individuals and inadequate assessment of factors influencing these levels. Therefore, we conducted a clinical study to obtain biopsy samples from 8 different gastrointestinal segments in 24 healthy Chinese volunteers. Concurrently, blood and fecal samples were collected for genotypic analysis and fecal microbiota metagenomic sequencing. Using an optimized LC-MS/MS method, we quantified the absolute protein abundance of CYP2C9, CYP2C19, CYP2D6, CYP3A4, P-gp, and BCRP from the stomach to the colon. Our results revealed significant regional differences in protein expression: CYP3A4 was the most abundant in the small intestine, whereas CYP2C9 was predominantly found in the colon. CYP2D6 was primarily located in the ileum, while other DMEs/DTs showed higher concentrations in the jejunum. Meanwhile, the enzyme abundance in the small intestine and colon and the relative ratio of transporters in different regions to the jejunum were accurately calculated, providing valuable data for refining the physiological parameters in the virtual gastrointestinal tract of Chinese healthy population in PBBMs. Additionally, BMI, IBW, sex, age, genotype, and fecal microbiota were identified as critical factors influencing the protein levels of these DMEs/DTs throughout the gastrointestinal tract, with notable regional differences. Consequently, this study provides a unique foundation for understanding xenobiotic absorption in humans.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}