Drug Metabolism and Disposition最新文献

{"title":"Corrigendum to \"Deciphering the cell type-specific and zonal distribution of drug-metabolizing enzymes, transporters, and transcription factors in livers of mice using single-cell transcriptomics\".","authors":"","doi":"10.1016/j.dmd.2025.100088","DOIUrl":"https://doi.org/10.1016/j.dmd.2025.100088","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 6","pages":"100088"},"PeriodicalIF":4.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110150","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":"ABCC2 as a novel covariate influencing oxcarbazepine pharmacokinetics in pediatric epilepsy: Insights from population modeling.","authors":"Xianhuan Shen, Jiahao Zhu, Yaodong He, Xixuan Wang, Wenzhou Li, Xiaomei Fan","doi":"10.1016/j.dmd.2025.100090","DOIUrl":"https://doi.org/10.1016/j.dmd.2025.100090","url":null,"abstract":"<p><p>This study set out to establish a population pharmacokinetic (PPK) model of oxcarbazepine (OXC) in pediatric patients with epilepsy, with the goal of optimizing individualized dosage strategies. We collected steady-state trough plasma concentration data of the OXC active metabolite 10-hydroxycarbazepine from epileptic children. The effects of physiological factors, concomitant medications, and genetic factors on pharmacokinetic parameters were quantitatively examined. Subsequently, a Monte Carlo simulation was carried out to predict steady-state trough concentration under various dosing regimens. A total of 320 plasma samples were obtained from 91 epileptic children. The results of covariate analysis revealed that body weight and ABCC2 rs2273697 had a significant impact on the clearance of the 10-hydroxycarbazepine. The final model demonstrated stable and accurate predictive performance, with simulation results indicating that a dosing regimen of 20-30 mg/kg per day is generally suitable for most pediatric patients to reach therapeutic targets. For children under 2 years, doses over 40 mg/kg per day might be needed. However, for those over 12 kg (2 years), 40-60 mg/kg per day could lead to excessive drug exposure. Patients carrying the ABCC2 variant allele necessitate a lower maintenance dose in comparison to those with the wild-type allele. This study marks the first instance to incorporate the genetic polymorphism of ABCC2 into a PPK model of OXC. The developed PPK model provides a fundamental basis for personalized dosing recommendations of OXC in epileptic children. SIGNIFICANCE STATEMENT: The relationship between 10-hydroxycarbazepine exposure and body weight, as well as the ABCC2 rs2273697 in epileptic children, can be accurately investigated using an age-stratified population pharmacokinetic model. Wild-type ABCC2 rs2273697 exhibited a 25% and 14% higher 10-hydroxycarbazepine apparent clearance compared to homozygous and heterozygous variation patients, respectively. Based on our model, an optimized dosing regimen for oxcarbazepine has been proposed aiming for various subgroups of patients.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 6","pages":"100090"},"PeriodicalIF":4.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157434","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 strong clinical interaction between bupropion and CYP2D6 is primarily mediated through bupropion metabolites and their stereoisomers: A paradigm for evaluating metabolites in drug-drug interaction risk.","authors":"Irin Tanaudommongkon, Amir Rashidian, Brandon T Gufford, Jessica Bo Li Lu, Zeruesenay Desta","doi":"10.1016/j.dmd.2025.100070","DOIUrl":"10.1016/j.dmd.2025.100070","url":null,"abstract":"<p><p>Bupropion (BUP) is a potent clinical inhibitor of CYP2D6, although the specific mechanisms underlying this interaction are not fully understood. We comprehensively evaluated the inhibition potencies of racemic BUP and its stereoisomers, as well as its major metabolites (4-hydroxybupropion [OHBUP], threohydrobupropion [THBUP], and erythrohydrobupropion [EHBUP]), on CYP2D6-mediated dextromethorphan O-demethylation in pooled human liver microsomes. The K_i value for racemic EHBUP was 5.5-, 11.4-, and 13-fold lower than those for THBUP, OHBUP, and BUP, respectively. THBUP demonstrated over 2-fold greater potency than OHBUP and BUP. Additionally, RR-THBUP had a 2.1-fold lower K_i value than SS-THBUP, while S-BUP and RR-OHBUP exhibited 3.0-fold and 1.5-fold lower K_i values than R-BUP and SS-OHBUP, respectively, indicating modest stereoselective inhibition. The K_i values of stereoisomers EHBUP were comparable. Using a mechanistic static interaction model that incorporated in vitro K_i value and unbound steady-state concentration in plasma (C_max) or estimated liver concentrations of each inhibitor, we found significant underprediction of the observed clinical BUP-CYP2D6 interaction, indicating that no single inhibitor can predict observed in vivo BUP-CYP2D6 interaction. Accurate predictions of observed clinical interactions were achieved using all racemic (within 11.6%) or all stereoisomeric forms (within 5.4%) of BUP and its metabolites, along with their liver concentrations (but not plasma concentrations). Our findings highlight the crucial role of circulating BUP metabolites, particularly the summation of EHBUP and THBUP or their stereoisomers, in the in vivo inhibition of CYP2D6 by BUP. These data provide mechanistic and quantitative insight into the partially understood clinical CYP2D6-dependent interactions associated with BUP. SIGNIFICANCE STATEMENT: This article describes comprehensively the inhibition of CYP2D6 by racemic and stereoisomers of bupropion (BUP) and its main metabolites in pooled human liver microsomes. The strong interaction between BUP and CYP2D6 observed clinically is mainly due to BUP metabolites and inhibition is stereospecific. Accounting for inhibition constants and steady-state unbound estimated liver (but not plasma) concentrations of all racemic or all stereoisomers accurately predicted the clinically observed BUP-CYP2D6 interactions.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 5","pages":"100070"},"PeriodicalIF":4.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998767","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":"Cisplatin-induced acute kidney injury increased brain 5-hydroxytryptamine levels partly due to the hippuric acid-induced upregulation of CYP2D4 expression and function in the brain of rats.","authors":"Lingjue Lu, Nan Hu, Haoran Chen, Siqian Wang, Ying Deng, Zijin Lin, Zhongyan Wang, Xinyue Zhu, Xiaodong Liu, Li Liu, Ling Jiang","doi":"10.1016/j.dmd.2025.100068","DOIUrl":"10.1016/j.dmd.2025.100068","url":null,"abstract":"<p><p>Patients with acute kidney injury (AKI) are often associated with uremic encephalopathy, but its underlying mechanisms remain unclear. This study aimed to investigate how AKI induced neuropsychiatric disorders through cerebral 5-hydroxytryptamine (5-HT) dysregulation in cisplatin-induced AKI rats. Our findings demonstrated that AKI induced anxiety-like behaviors and increased cerebral 5-HT levels, which may be attributed to the upregulated CYP2D4 expression and activity. The intraventricular injection of quinine (CYP2D4 inhibitor) attenuated the elevated cortical 5-HT levels in AKI rats. Intraperitoneal administration of 5-methoxytryptamine (CYP2D4 substrate) also provoked anxiety-like behaviors and cerebral 5-HT accumulation, which were reversed by cotreatment with quinine. Hippuric acid (HA), as a classical uremic toxin, was severely accumulated in both the plasma and brain of AKI rats. In vitro experiments demonstrated that HA-induced reactive oxygen species (ROS) upregulated expression of CYP2D6 (over 70% homology with rat CYP2D4) via suppressing Nrf2/HO-1 pathway in SH-SY5Y cells. These effects were reversed by ROS scavenger N-acetylcysteine, Nrf2 activator sulforaphane, and HO-1 activator cobalt-protoporphyrin IX. Similarly, either Nrf2 inhibitor ML385 or HO-1 inhibitor zinc-protoporphyrin IX exerted up-regulatory effects on CYP2D6 expression. In vivo studies confirmed that HA treatment induced AKI-like behavioral abnormalities in rats, accompanied by increased cerebral 5-HT levels and CYP2D4 expression as well as induced production of ROS, decreased Nrf2 and HO-1 protein levels. Our findings elaborate a novel mechanism between kidney failure and neuropsychiatric complications. Specifically, cisplatin-induced AKI upregulates CYP2D4 expression via HA-mediated ROS release, subsequently promoting generation of cerebral 5-HT by CYP2D4 and revealing material basis of AKI-associated uremic encephalopathy. SIGNIFICANCE STATEMENT: This study revealed that the psychiatric disorders of cisplatin-induced acute kidney injury rats are partly attributed to the increased 5-hydroxytryptamine levels induced by brain CYP2D. The induction of CYP2D4 is mainly due to brain accumulation of hippuric acid via inactivation of Nrf2/HO-1 pathway by reactive oxygen species.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 5","pages":"100068"},"PeriodicalIF":4.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972622","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":"Chronic liver injury decreases levels of cerebral carnitine and acetylcarnitine in rats partly due to the downregulation of organic cation transporters OCT1/2 and OCTN2 at the blood-brain barrier.","authors":"Hao Zhi, Zhongyan Wang, Xinyue Zhu, Wenhan Wu, Lu Yang, Yidong Dai, Zehua Wang, Ling Jiang, Yongmei Tan, Xiaodong Liu, Li Liu","doi":"10.1016/j.dmd.2025.100072","DOIUrl":"10.1016/j.dmd.2025.100072","url":null,"abstract":"<p><p>Liver failure often causes hepatic encephalopathy, partly due to dysregulation in cerebral energy metabolism. Carnitine and acetylcarnitine play essential roles in energy metabolism by transporting fatty acids from the cytosol into mitochondria, whose transport across the blood-brain barrier (BBB) is primarily mediated by organic cation transporters (OCTs) and organic cation/carnitine transporters (OCTNs). This study aimed to investigate whether liver injury alters the expression of OCTs and OCTNs at the BBB, leading to decreased cerebral carnitine and acetylcarnitine levels and impaired energy metabolism using thioacetamide-induced chronic liver injury (CLI) in rats. The results showed that CLI significantly downregulated the expressions of OCT1, OCT2, and OCTN2 at the BBB; decreased cerebral carnitine/acetylcarnitine levels; and increased the adenosine diphosphate/ adenosine triphosphate ratio. Elevated plasmic levels of chenodeoxycholic acid (CDCA) and 17β-estradiol (E2) were detected in CLI rats. In hCMEC/D3 cells, E2 downregulated the expressions of OCT2 and OCTN2, which were attenuated by the estrogen receptor-α (ER-α) inhibitor and silencing. CDCA downregulated the expression of OCT1 and OCTN2, which was reversed by the farnesoid X receptor inhibitor and silencing. These in vitro findings were confirmed in rats treated with CDCA or E2. Additionally, HEK-293-OCT1 and HEK-293-OCT2 cells demonstrated an uptake of carnitine and acetylcarnitine, with uptake in HEK-293-OCT2 cells being 6-fold and 14-fold higher, respectively, than in HEK-293-OCT1 cells. In conclusion, thioacetamide-induced CLI downregulated the expressions of OCT1, OCT2, and OCTN2 at the BBB by activating both E2/ER-α and CDCA/farnesoid X receptor pathways, leading to decreased cerebral carnitine and acetylcarnitine levels, disrupted energy metabolism, and contributing to hepatic encephalopathy. SIGNIFICANCE STATEMENT: This study revealed that the deficiency of brain carnitine and acetylcarnitine in thioacetamide-induced chronic liver injury rats is mainly attributed to the downregulation of organic cation transporter 1/2 and organic cation/carnitine transporter 2 expressions at the blood-brain barrier. The increased circulating levels of chenodeoxycholic acid and 17β-estradiol play a significant role in the downregulation of organic cation transporter 1/2 and organic cation/carnitine transporter 2 expression in chronic liver injury.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 5","pages":"100072"},"PeriodicalIF":4.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964359","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":"Coproporphyrin I as an in vitro fluorescent probe to measure OATP1B1 transport activity.","authors":"Elizabeth R Hayden, Vivian Xu, Lisa Krotz, Jessica J Hockler, Benjamin D Kaczynski, Jason A Sprowl","doi":"10.1016/j.dmd.2025.100073","DOIUrl":"10.1016/j.dmd.2025.100073","url":null,"abstract":"<p><p>The organic anion transporting polypeptide 1B1 (OATP1B1) is a major pharmacologically relevant hepatic uptake transporter that mediates the clearance of many drugs. The OATP1B1 substrate coproporphyrin I (CPI) has been continually shown to be a reliable and specific clinical biomarker of transport activity. These investigations, and others that have characterized OATP1B activity and transport kinetics, have largely relied on expensive, time-consuming, and nonfluorescent methods to detect CPI, such as liquid chromatography-tandem mass spectrometry. In consideration of porphyrin fluorescent properties, we hypothesized that CPI fluorescence can serve as a marker of OATP1B1 transport activity. Cellular accumulation of CPI specifically due to OATP1B1 was measured via fluorescence in the presence or absence of various Food and Drug Administration-approved tyrosine kinase inhibitors (TKIs). Our findings indicate that CPI fluorescence is an appropriate marker of OATP1B1 in vitro activity in overexpressing HEK293 cells. It was also observed that nilotinib, a TKI previously reported as an OATP1B1 inhibitor, could reduce 50% of CPI uptake at a concentration of 1.0 ± 0.5 μM. Using CPI and 8-(2-[Fluoresceinyl]aminoethylthio) adenosine- 3', 5'- cyclic monophosphate, 15 other TKIs were identified as potential OATP1B1 inhibitors, including tivozanib, which was observed to inhibit 50% of OATP1B1 activity at 4.0 ± 2.0 μM. Overall, our findings provide evidence to show that CPI fluorescence can be used as a method to assess OATP1B1-mediated transport in vitro and investigate the potential for drug-drug interactions. SIGNIFICANCE STATEMENT: This paper outlines a methodology for assessing coproporphyrin I accumulation in vitro specific to organic anion transporting polypeptide 1B1 (OATP1B1)-mediated transport. Coproporphyrin I is a reported sensitive clinical biomarker of OATP1B1 activity, and its fluorescent properties serve to provide a substrate with translational relevance in measuring drug-drug interactions in vitro with a low cost and time requirement. This method confirms nilotinib as an effective OATP1B1 inhibitor and identifies new inhibitors that can potentially promote life-threatening drug interactions using a clinically relevant biomarker.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 5","pages":"100073"},"PeriodicalIF":4.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974107","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":"Contribution of Japanese scientists to drug metabolism and disposition.","authors":"Miki Nakajima, Hiroshi Yamazaki, Kouichi Yoshinari, Kaoru Kobayashi, Yuji Ishii, Daisuke Nakai, Hidetaka Kamimura, Toshiyuki Kume, Yoshiro Saito, Kazuya Maeda, Hiroyuki Kusuhara, Ikumi Tamai","doi":"10.1016/j.dmd.2025.100071","DOIUrl":"10.1016/j.dmd.2025.100071","url":null,"abstract":"<p><p>Japanese researchers have played a pivotal role in advancing the field of drug metabolism and disposition, as demonstrated by their substantial contributions to the journal Drug Metabolism and Disposition (DMD) over the past 5 decades. This review highlights the historical and ongoing impact of Japanese scientists on DMD, celebrating their achievements in elucidating drug metabolism, membrane transport, pharmacokinetics, and toxicology. From the discovery of cytochrome P450 by Tsuneo Omura and Ryo Sato in 1962 to subsequent advances in drug transport research, Japan has maintained a leading position in the field. A geographical analysis of DMD publications reveals a notable increase in contributions from Japan during the 1980s, ranking second globally and maintaining this position through the 2000s. However, recent years have seen a slight decline in output, likely influenced by the COVID-19 pandemic and increased online journals as well as structural changes within academia and industry. Importantly, this trend is not unique to Japan. To sustain excellence and innovation in this field, it is crucial to strengthen funding for absorption, distribution, metabolism, excretion, and toxicity research and promote collaborations between academia, industry, and regulatory agencies. By prioritizing the translation of fundamental discoveries into drug development and clinical applications, scientists in this area can further advance global efforts toward achieving optimal drug efficacy and safety. This review underscores the enduring contributions of Japanese researchers to DMD and calls for renewed efforts to drive innovation and progress in this vital area of science. SIGNIFICANCE STATEMENT: Over the past 5 decades, Japanese scientists have made significant contributions to Drug Metabolism and Disposition through groundbreaking discoveries and advancements in the study of drug-metabolizing enzymes, transporters, pharmacokinetics analysis, and related areas. These contributions continue to shape the field, offering a foundation for future innovation in this area. We hope that the next generation of Japanese scientists will further solidify their global leadership in this area to advance drug development and proper pharmacotherapy.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 5","pages":"100071"},"PeriodicalIF":4.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991684","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":"Substrate-specific inhibition of organic cation transporter 1 revealed using a multisubstrate drug cocktail.","authors":"Vincent Rönnpagel, Felix Morof, Sarah Römer, Marleen J Meyer-Tönnies, Mladen V Tzvetkov","doi":"10.1016/j.dmd.2025.100074","DOIUrl":"10.1016/j.dmd.2025.100074","url":null,"abstract":"<p><p>Transporters of the SLC22 family, such as organic cation transporter 1 (OCT1), possess very broad substrate specificity. It is unclear to what extent the inhibitory potencies of OCT1 depend on the substrate used. Here, we describe a multisubstrate drug cocktail that allows for the simultaneous testing of drug-drug interactions using 8 different victim drugs: fenoterol, salbutamol, sumatriptan, zolmitriptan, ipratropium, trospium, methylnaltrexone, and metformin. There were no significant differences in Michaelis constant (K_M) and v_max of the OCT1-mediated uptake of the substrates alone or in the cocktail. Depending on the victim drug analyzed, we observed 6.7-fold differences in the inhibitory potency of fenoterol (IC₅₀ of 0.75 μM for metformin and 5.1 μM for sumatriptan). Similarly, the inhibitory potency of verapamil varied 6.7-fold (IC₅₀ of 1.3 μM for zolmitriptan and 8.7 μM for ipratropium). Two groups of inhibitors showed strong correlations in their victim-dependent inhibitory potencies. Group 1 comprised verapamil, quinidine, fenoterol, and ipratropium, and group 2 comprised metformin, sumatriptan, and trimethoprim. By comparing OCT1 paralogs and orthologs, the broadest substrate spectra were observed for OCT1 and multidrug and toxin extrusion 1, followed by OCT2, multidrug and toxin extrusion 2-K, and OCT3. In contrast, organic cation transporters novel 1 and organic cation transporters novel 2 exhibited very narrow substrate specificity, transporting only L-carnitine and L-ergothioneine, respectively. In conclusion, OCT1 demonstrates substantial differences in inhibitory potencies, depending on the victim drug used. We developed a cocktail approach that enables rapid screening for such differences, facilitating the identification of drug-drug interactions at the early stages of drug development. This approach can be extended to other transporters with broad substrate specificity. SIGNIFICANCE STATEMENT: Polyspecific transporters have a broad substrate-binding cavity with no defined single binding position. Consequently, inhibitors may exhibit different inhibitory potencies depending on the victim drug used for testing. Here, we demonstrate this for organic cation transporter 1 (OCT1, SLC22A1) and presents a drug cocktail designed to identify varying inhibitory potencies in vitro and prevent false-negative drug-drug interaction results during early drug development. This approach can be extended to other polyspecific drug transporters.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 5","pages":"100074"},"PeriodicalIF":4.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987980","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":"Erlotinib-A substrate and inhibitor of OATP2B1: pharmacokinetics and CYP3A-mediated metabolism in rSlco2b1^-/- and SLCO2B1^+/+ rats.","authors":"Marta A Rysz, Anima M Schäfer, Jonny Kinzi, Nikolaos Paloumpis, Katja In-Albon, Seraina Schmidlin, Isabell Seibert, Daniel Ricklin, Henriette E Meyer Zu Schwabedissen","doi":"10.1016/j.dmd.2025.100069","DOIUrl":"10.1016/j.dmd.2025.100069","url":null,"abstract":"<p><p>The tyrosine kinase inhibitor erlotinib is recognized as a substrate of cytochrome P450 enzymes and drug transporters. Indeed, erlotinib's extensive metabolism to the active metabolite OSI-420 (desmethyl erlotinib) mainly involves CYP3A enzymes. Additionally, erlotinib is assumed to interact with the organic anion transporting polypeptide (OATP)2B1. In this study, we aimed to investigate the role of human OATP2B1 in erlotinib's metabolism through in vitro and in vivo experiments. Using Madin-Darby canine kidney cells expressing human OATP2B1 for competitive counterflow experiments, we confirmed erlotinib as inhibitor and substrate of the transporter. Moreover, in vitro transport experiments revealed higher cellular accumulation of erlotinib at pH 5.5 than that at pH 7.4. Pharmacokinetic evaluation of orally administered erlotinib in male SLCO2B1^+/+ and rSlco2b1^-/- rats revealed that the human OATP2B1 does not significantly alter serum levels of erlotinib or its main metabolite OSI-420, although we observed a longer mean residence time of the metabolite in humanized rats. Although there was no difference in the OSI-420:erlotinib ratio over time in SLCO2B1^+/+ and rSlco2b1^-/- rats, we assessed the role of CYP3A1 and CYP3A2 in the metabolism of erlotinib. In vitro experiments showed a contribution of both enzymes to the formation of OSI-420. For CYP3A1, we found significantly higher expression in liver microsomes of male SLCO2B1^+/+ rats, while the knockout genotype showed significantly higher levels of CYP3A2. However, these differences did not affect the systemic exposure of erlotinib or OSI-420 in the rats. Our findings provide further insight into the role of OATP2B1 in the disposition of orally administered erlotinib. SIGNIFICANCE STATEMENT: This study confirms that erlotinib is a substrate of the human organic anion transporting polypeptide 2B1 transporter in vitro. In vivo experiments in rat models, however, showed no significant impact of organic anion transporting polypeptide 2B1 on the systemic exposure of erlotinib or its metabolite, OSI-420. Despite variations in CYP3A enzyme expression in SLCO2B1^+/+ rats, the OSI-420:erlotinib ratio remained unchanged. Although SLCO2B1^+/+ rats exhibited a longer mean residence time for OSI-420, this did not significantly alter overall exposure in orally treated animals.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 5","pages":"100069"},"PeriodicalIF":4.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985225","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":"Human absorption, distribution, metabolism, and excretion studies: Conventional or microtracer?","authors":"Sean Xiaochun Zhu","doi":"10.1016/j.dmd.2025.100067","DOIUrl":"10.1016/j.dmd.2025.100067","url":null,"abstract":"<p><p>A human absorption, distribution, metabolism, and excretion (hADME) study is an essential clinical pharmacology study for small-molecule drugs. The study provides insights into circulating drug-related materials and the drug's elimination pathways in humans, which can guide future studies on safety and drug-drug interaction of metabolites as well as organ impairment and drug-drug interaction of the parent drug. The 2 hADME study types, namely conventional and microtracer, are comprehensively compared in this manuscript. A review of literature found that conventional hADME studies were approximately 7 times that of microtracer hADME studies for small molecule and peptide drugs based on publications in 3 peer-reviewed journals from 2010 to 2024. Each study type has advantages and disadvantages. The advantages of conventional hADME studies primarily include the ease, low cost, and flexibility of radiometric sample analysis. In contrast, the advantages of microtracer hADME studies primarily include exemption from prerequisite studies and use of non-good manufacturing practice ¹⁴C-labeled materials. The disadvantages of each study type are essentially the advantages of the other. The manuscript also discusses scenarios where a microtracer hADME study may be preferable. Finally, recommendations are provided on selecting the appropriate hADME study type for an investigational drug. SIGNIFICANCE STATEMENT: The manuscript discusses 2 primary human absorption, distribution, metabolism, and excretion study types: conventional and microtracer. It covers published literature studies, the pros and cons of each type, scenarios for conducting microtracer studies, and a recommended decision tree for selecting the appropriate human absorption, distribution, metabolism, and excretion study type.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 5","pages":"100067"},"PeriodicalIF":4.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810735","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}