Drug Metabolism and Disposition最新文献

{"title":"Development and Verification of a Full Physiologically Based Pharmacokinetic Model for Sublingual Buprenorphine in Healthy Adult Volunteers that Accounts for Nonlinear Bioavailability.","authors":"Matthijs W van Hoogdalem, Ryota Tanaka, Trevor N Johnson, Alexander A Vinks, Tomoyuki Mizuno","doi":"10.1124/dmd.124.001643","DOIUrl":"10.1124/dmd.124.001643","url":null,"abstract":"<p><p>Sublingual buprenorphine is used for opioid use disorder and neonatal opioid withdrawal syndrome. The study aimed to develop a full physiologically based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Four linear regression models (i.e., untransformed or log transformed for dose or proportion sublingually absorbed) were explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for verification. The PBPK model's predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O) area under the curve (AUC), peak concentration (C_max), and time to reach C_max (T_max) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2-32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC and C_max equaling 0.99 (0.86-1.12) and 1.24 (1.09-1.40), respectively, and median (5th to 95th percentile) for T_max equaling 1.11 (0.69-1.57). A verified PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. SIGNIFICANCE STATEMENT: The physiologically based pharmacokinetic (PBPK) model developed in this study is the first to adequately predict dose- and formulation-dependent sublingual buprenorphine pharmacokinetics. Accurate prediction was facilitated by the incorporation of a novel nonlinear absorption model. The developed model will serve as the foundation for maternal-fetal PBPK modeling to predict maternal and fetal buprenorphine exposures to optimize buprenorphine treatment for neonatal opioid withdrawal syndrome.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"785-796"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering Acetaminophen-Induced Hepatotoxicity: The Crucial Role of Transcription Factors like Nuclear Factor Erythroid 2-Related Factor 2 as Genetic Determinants of Susceptibility to Drug-Induced Liver Injury.","authors":"Ankit P Laddha, Hangyu Wu, José E Manautou","doi":"10.1124/dmd.124.001282","DOIUrl":"10.1124/dmd.124.001282","url":null,"abstract":"<p><p>Acetaminophen (APAP) is the most commonly used over-the-counter medication throughout the world. At therapeutic doses, APAP has potent analgesic and antipyretic effects. The efficacy and safety of APAP are influenced by multifactorial processes dependent upon dosing, namely frequency and total dose. APAP poisoning by repeated ingestion of supratherapeutic doses, depletes glutathione stores in the liver and other organs capable of metabolic bioactivation, leading to hepatocellular death due to exhausted antioxidant defenses. Numerous genes, encompassing transcription factors and signaling pathways, have been identified as playing pivotal roles in APAP toxicity, with the liver being the primary organ studied due to its central role in APAP metabolism and injury. Nuclear factor erythroid 2-related factor 2 (NRF2) and its array of downstream responsive genes are crucial in counteracting APAP toxicity. NRF2, along with its negative regulator Kelch-like ECH-associated protein 1, plays a vital role in regulating intracellular redox homeostasis. This regulation is significant in modulating the oxidative stress, inflammation, and hepatocellular death induced by APAP. In this review, we provide an updated overview of the mechanisms through which NRF2 activation and signaling critically influence the threshold for developing APAP toxicity. We also describe how genetically modified rodent models for NRF2 and related genes have been pivotal in underscoring the significance of this antioxidant response pathway. While NRF2 is a primary focus, the article comprehensively explores other genetic factors involved in phase I and phase II metabolism of APAP, inflammation, oxidative stress, and related pathways that contribute to APAP toxicity, thereby providing a holistic understanding of the genetic landscape influencing susceptibility to this condition. SIGNIFICANCE STATEMENT: This review summarizes the genetic elements and signaling pathways underlying APAP-induced liver toxicity, focusing on the crucial protective role of the transcription factor NRF2. This review also delves into the genetic intricacies influencing APAP safety and potential liver harm. It also emphasizes the need for deeper insight into the molecular mechanisms of hepatotoxicity, especially the interplay of NRF2 with other pathways.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"740-753"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Special Section on Mechanisms of Drug Metabolism in Acetaminophen-Induced Hepatotoxicity-Editorial.","authors":"Yurong Lai, Xiao-Bo Zhong","doi":"10.1124/dmd.124.001848","DOIUrl":"https://doi.org/10.1124/dmd.124.001848","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"52 8","pages":"704-706"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress.","authors":"Hartmut Jaeschke, Anup Ramachandran","doi":"10.1124/dmd.123.001279","DOIUrl":"10.1124/dmd.123.001279","url":null,"abstract":"<p><p>Acetaminophen (APAP) is an analgesic and antipyretic drug used worldwide, which is safe at therapeutic doses. However, an overdose can induce liver injury and even liver failure. Mechanistic studies in mice beginning with the seminal papers published by B.B. Brodie's group in the 1970s have resulted in important insight into the pathophysiology. Although the metabolic activation of APAP with generation of a reactive metabolite, glutathione depletion, and protein adduct formation are critical initiating events, more recently, mitochondria have come into focus as an important target and decision point of cell death. This review provides a comprehensive overview of the induction of mitochondrial superoxide and peroxynitrite formation and its propagation through a mitogen-activated protein kinase cascade, the mitochondrial permeability transition pore opening caused by iron-catalyzed protein nitration, and the mitochondria-dependent nuclear DNA fragmentation. In addition, the role of adaptive mechanisms that can modulate the pathophysiology, including autophagy, mitophagy, nuclear erythroid 2 p45-related factor 2 activation, and mitochondrial biogenesis, are discussed. Importantly, it is outlined how the mechanisms elucidated in mice translate to human hepatocytes and APAP overdose patients, and how this mechanistic insight explains the mechanism of action of the clinically approved antidote <i>N</i>-acetylcysteine and led to the recent discovery of a novel compound, fomepizole, which is currently under clinical development. SIGNIFICANCE STATEMENT: Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in western countries. Extensive mechanistic research over the last several decades has revealed a central role of mitochondria in the pathophysiology of APAP hepatotoxicity. This review article provides a comprehensive discussion of a) mitochondrial protein adducts and oxidative/nitrosative stress, b) mitochondria-regulated nuclear DNA fragmentation, c) adaptive mechanisms to APAP-induced cellular stress, d) translation of cell death mechanisms to overdose patients, and e) mechanism-based antidotes against APAP-induced liver injury.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"712-721"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10351083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Pharmacokinetic and CYP3A Drug-Drug Interaction Prediction of GDC-2394 Using Physiologically Based Pharmacokinetic Modeling and Biomarker Assessment.","authors":"Jesse Yu, Fei Tang, Fang Ma, Susan Wong, Jing Wang, Justin Ly, Liuxi Chen, Jialin Mao","doi":"10.1124/dmd.123.001633","DOIUrl":"10.1124/dmd.123.001633","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and drug-drug interaction (DDI) of GDC-2394. PBPK models were developed using in vitro and in vivo data to reflect the oral and intravenous PK profiles of mouse, rat, dog, and monkey. The learnings from preclinical PBPK models were applied to a human PBPK model for prospective human PK predictions. The prospective human PK predictions were within 3-fold of the clinical data from the first-in-human study, which was used to optimize and validate the PBPK model and subsequently used for DDI prediction. Based on the majority of PBPK modeling scenarios using the in vitro CYP3A induction data (mRNA and activity), GDC-2394 was predicted to have no-to-weak induction potential at 900 mg twice daily (BID). Calibration of the induction mRNA and activity data allowed for the convergence of DDI predictions to a narrower range. The plasma concentrations of the 4<i>β</i>-hydroxycholesterol (4<i>β</i>-HC) were measured in the multiple ascending dose study to assess the hepatic CYP3A induction risk. There was no change in plasma 4<i>β</i>-HC concentrations after 7 days of GDC-2394 at 900 mg BID. A dedicated DDI study found that GDC-2394 has no induction effect on midazolam in humans, which was reflected by the totality of predicted DDI scenarios. This work demonstrates the prospective utilization of PBPK for human PK and DDI prediction in early drug development of GDC-2394. PBPK modeling accompanied with CYP3A biomarkers can serve as a strategy to support clinical pharmacology development plans. SIGNIFICANCE STATEMENT: This work presents the application of physiologically based pharmacokinetic modeling for prospective human pharmacokinetic (PK) and drug-drug interaction (DDI) prediction in early drug development. The strategy taken in this report represents a framework to incorporate various approaches including calibration of in vitro induction data and consideration of CYP3A biomarkers to inform on the overall CYP3A-related DDI risk of GDC-2394.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"765-774"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac Uptake of the Adrenergic Imaging Agent <i>meta</i>-Iodobenzylguanidine (mIBG) Is Mediated by Organic Cation Transporter 3 (Oct3).","authors":"Antonio J López Quiñones, Letícia Salvador Vieira, Joanne Wang","doi":"10.1124/dmd.124.001709","DOIUrl":"10.1124/dmd.124.001709","url":null,"abstract":"<p><p>Heart failure (HF) is a chronic disease affecting 1%-2% of the global population.¹²³I-labeled <i>meta</i>-iodobenzylguanidine (mIBG) is US Food and Drug Administration-approved for cardiac imaging and prognosis risk assessment in patients with HF. As a norepinephrine analog, mIBG is believed to be transported into adrenergic nerve terminals by the neuronal norepinephrine transporter (NET) and hence image sympathetic innervation of the myocardium. We previously showed that mIBG is an excellent substrate of organic cation transporter 3 (OCT3), an extraneuronal transporter expressed in cardiomyocytes. Here, we evaluated the in vivo impact of Oct3 on mIBG disposition and tissue distribution using Oct3 knockout mice. <i>Oct3</i> ^+/+ and <i>Oct3</i> ^-/- mice were administered with mIBG intravenously, and mIBG plasma pharmacokinetics and tissue exposures were determined. In <i>Oct3</i> ^+/+ mice, mIBG exhibited extensive accumulation in multiple tissues (heart, salivary gland, liver, and adrenal gland). No difference was observed in overall plasma exposure between <i>Oct3</i> ^+/+ <i>and Oct3</i> ^-/- mice. Strikingly, cardiac mIBG was depleted in <i>Oct3</i> ^-/- mice, resulting in 83% reduction in overall cardiac exposure (AUC_{0-24 h}: 12.7 vs. 2.1 <i>μ</i>g × h/g). mIBG tissue exposure (AUC_{0-24 h}) was also reduced by 66%, 36%, and 31% in skeletal muscle, salivary gland, and lung, respectively, in <i>Oct3</i> ^-/- mice. Our data demonstrated that Oct3 is the primary transporter responsible for cardiac mIBG uptake in vivo and suggested that cardiac mIBG imaging mainly measures OCT3 activity in cardiomyocytes but not NET-mediated uptake in adrenergic nerve endings. Our findings challenge the current paradigm in interpreting cardiac mIBG imaging results and suggest OCT3 as a potential genetic risk marker for HF prognosis. SIGNIFICANCE STATEMENT: ¹²³I-labeled <i>meta</i>-iodobenzylguanidine is used for cardiac imaging and risk assessment in heart failure patients. Contrary to the current belief that <i>meta</i>-iodobenzylguanidine (mIBG) tracks cardiac sympathetic innervation due to its uptake by the neuronal norepinephrine transporter, the authors demonstrated that cardiac mIBG uptake is mediated by the extraneuronal transporter Oct3. Their findings warrant a re-evaluation of the scientific rationale behind cardiac mIBG scan and further suggest organic cation transporter 3 as a risk factor for disease progression in heart failure patients.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"899-905"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Disposition in Neonatal Göttingen Minipigs: Exploring Effects of Perinatal Asphyxia and Therapeutic Hypothermia.","authors":"Marina-Stefania Stroe, Miao-Chan Huang, Pieter Annaert, Karen Leys, Anne Smits, Karel Allegaert, Lieselotte Van Bockstal, Allan Valenzuela, Miriam Ayuso, Chris Van Ginneken, Steven Van Cruchten","doi":"10.1124/dmd.124.001677","DOIUrl":"10.1124/dmd.124.001677","url":null,"abstract":"<p><p>Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology, altered pharmacokinetics (PK) and pharmacodynamics (PD) are expected. Given that TH is the standard of care for PA with moderate to severe hypoxic-ischemic encephalopathy, disentangling the effect of PA versus TH on PK/PD is not possible in clinical settings. However, animal models can provide insights into this matter. The (neonatal) Göttingen Minipig, the recommended strain for nonclinical drug development, was selected as translational model. Four drugs-midazolam (MDZ), fentanyl (FNT), phenobarbital (PHB), and topiramate (TPM)-were intravenously administered under four conditions: control (C), therapeutic hypothermia (TH), hypoxia (H), and hypoxia plus TH (H+TH). Each group included six healthy male neonatal Göttingen Minipigs anesthetized for 24 hours. Blood samples were drawn at 0 (predose) and 0.5, 2, 2.5, 3, 4, 4.5, 6, 8, 12, and 24 hours post drug administration. Drug plasma concentrations were determined using validated bioanalytical assays. The PK parameters were estimated through compartmental and noncompartmental PK analysis. The study showed a statistically significant decrease in FNT clearance (CL; 66% decrease), with an approximately threefold longer half-life (t_1/2) in the TH group. The H+TH group showed a 17% reduction in FNT CL, with a 62% longer t_1/2 compared with the C group; however, it was not statistically significant. Although not statistically significant, trends toward lower CL and longer t_1/2 were observed in the TH and H+TH groups for MDZ and PHB. Additionally, TPM demonstrated a 28% decrease in CL in the H group compared with controls. SIGNIFICANCE STATEMENT: The overarching goal of this study using the neonatal Göttingen Minipig model was to disentangle the effects of systemic hypoxia and TH on PK using four model drugs. Such insights can subsequently be used to inform and develop a physiologically based pharmacokinetic model, which is useful for drug exposure prediction in human neonates.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"824-835"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Mechanistic Biomarkers in Understanding Acetaminophen Hepatotoxicity in Humans.","authors":"Mitchell R McGill","doi":"10.1124/dmd.123.001281","DOIUrl":"10.1124/dmd.123.001281","url":null,"abstract":"<p><p>Our understanding of the fundamental molecular mechanisms of acetaminophen (APAP) hepatotoxicity began in 1973 to 1974, when investigators at the US National Institutes of Health published seminal studies demonstrating conversion of APAP to a reactive metabolite that depletes glutathione and binds to proteins in the liver in mice after overdose. Since then, additional groundbreaking experiments have demonstrated critical roles for mitochondrial damage, oxidative stress, nuclear DNA fragmentation, and necrotic cell death as well. Over the years, some investigators have also attempted to translate these mechanisms to humans using human specimens from APAP overdose patients. This review presents those studies and summarizes what we have learned about APAP hepatotoxicity in humans so far. Overall, the mechanisms of APAP hepatotoxicity in humans strongly resemble those discovered in experimental mouse and cultured hepatocyte models, and emerging biomarkers also suggest similarities in liver repair. The data not only validate the first mechanistic studies of APAP-induced liver injury performed 50 years ago but also demonstrate the human relevance of numerous studies conducted since then. SIGNIFICANCE STATEMENT: Human studies using novel translational, mechanistic biomarkers have confirmed that the fundamental mechanisms of acetaminophen (APAP) hepatotoxicity discovered in rodent models since 1973 are the same in humans. Importantly, these findings have guided the development and understanding of treatments such as <i>N</i>-acetyl-<i>l</i>-cysteine and 4-methylpyrazole over the years. Additional research may improve not only our understanding of APAP overdose pathophysiology in humans but also our ability to predict and treat serious liver injury in patients.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"729-739"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71421674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Good Cells Go Bad: Immune Dysregulation in the Transition from Acute Liver Injury to Liver Failure After Acetaminophen Overdose.","authors":"James P Luyendyk, Elena Morozova, Bryan L Copple","doi":"10.1124/dmd.123.001280","DOIUrl":"10.1124/dmd.123.001280","url":null,"abstract":"<p><p>The role of inflammatory cells and other components of the immune system in acetaminophen (APAP)-induced liver injury and repair has been extensively investigated. Although this has resulted in a wealth of information regarding the function and regulation of immune cells in the liver after injury, apparent contradictions have fueled controversy around the central question of whether the immune system is beneficial or detrimental after APAP overdose. Ultimately, this may not be a simple assignment of \"good\" or \"bad.\" Clinical studies have clearly demonstrated an association between immune dysregulation and a poor outcome in patients with severe liver damage/liver failure induced by APAP overdose. To date, studies in mice have not uniformly replicated this connection. The apparent disconnect between clinical and experimental studies has perhaps stymied progress and further complicated investigation of the immune system in APAP-induced liver injury. Mouse models are often dismissed as not recapitulating the clinical scenario. Moreover, clinical investigation is most often focused on the most severe APAP overdose patients, those with liver failure. Notably, recent studies have made it apparent that the functional role of the immune system in the pathogenesis of APAP-induced liver injury is highly context dependent and greatly influenced by the experimental conditions. In this review, we highlight some of these recent findings and suggest strategies seeking to resolve and build on existing disconnects in the literature. SIGNIFICANCE STATEMENT: Acetaminophen overdose is the most frequent cause of acute liver failure in the United States. Studies indicate that dysregulated innate immunity contributes to the transition from acute liver injury to acute liver failure. In this review, we discuss the evidence for this and the potential underlying causes.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"722-728"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138482178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Account of Distinct Change in Organic Anion Transporting Polypeptide 1B (OATP1B) Substrate Pharmacokinetics during OATP1B-Mediated Drug-Drug Interactions Using Physiologically Based Pharmacokinetic Modeling.","authors":"Pooja V Hegde, Bridget L Morse","doi":"10.1124/dmd.124.001708","DOIUrl":"10.1124/dmd.124.001708","url":null,"abstract":"<p><p>The role of transporters in drug clearance is widely acknowledged, directly and indirectly by facilitating tissue/enzyme exposure. Through the latter, transporters also affect volume of distribution. Drug-drug interactions (DDIs) involving organic anion transporting polypeptides (OATPs) 1B1/1B3 and <i>SLCO1B1</i> pharmacogenetics lead to altered pharmacokinetics of OATP1B substrates; however, several factors may confound direct interpretation of pharmacokinetic parameters from these clinical studies using noncompartmental analysis (NCA). A review of clinical data herein indicates a single dose of OATP1B inhibitor rifampin almost never leads to increased substrate half-life but often a decrease and that most clinical OATP1B substrates are CYP3A4 substrates and/or undergo enterohepatic cycling (EHC). Using hypothetically simple OATP1B substrate physiologically based pharmacokinetic (PBPK) models, simulated effect of rifampin differed from specific OATP1B inhibition due to short rifampin half-life causing dissipation of OATP1B inhibition over time combined with CYP3A4 induction. Calculated using simulated tissue data, volume of distribution indeed decreased with OATP1B inhibition and was expectedly limited to the contribution of liver volume. However, an apparent and counterintuitive effect of rifampin on volume greater than that on clearance resulted for CYP3A4 substrates using NCA. The effect of OATP1B inhibition and rifampin on OATP1B substrate models incorporating EHC plus or minus renal clearance was distinct compared with simpler models. Using PBPK models incorporating reversible lactone metabolism for clinical OATP1B substrates atorvastatin and pitavastatin, DDIs reporting decreased half-life with rifampin were reproduced. These simulations provide an explanation for the distinct change in OATP1B substrate pharmacokinetics observed in clinical studies, including changes in volume of distribution and additional mechanisms. SIGNIFICANCE STATEMENT: Transporters are involved in drug clearance and volume of distribution, and distinct changes in OATP1B substrate pharmacokinetics are observed with OATP1B inhibitor rifampin. Using hypothetical and validated PBPK models and simulations, this study addresses the limitations of single-dose rifampin and complicated clinical OATP1B substrate disposition in evaluating the pharmacokinetic parameters of OATP1B substrates during rifampin drug-drug interactions (DDIs). These models account for change in volume of distribution and identify additional mechanisms underlying apparent pharmacokinetic changes in OATP1B DDIs.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":"886-898"},"PeriodicalIF":4.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}