Drug Metabolism and Disposition最新文献

{"title":"Role of organic anion transporting polypeptides in pancreatic statin disposition and islet cell function in mice.","authors":"Chen Bei Hu, Rennian Wang, Rommel G Tirona, Ute I Schwarz","doi":"10.1016/j.dmd.2026.100339","DOIUrl":"10.1016/j.dmd.2026.100339","url":null,"abstract":"<p><p>Statins are widely prescribed and effective for reducing cardiovascular risk. However, their use has been associated with new-onset diabetes risk, involving impaired insulin secretion and sensitivity. Statins exert their lipid-lowering effect in the liver, where hepatic uptake is mediated by organic anion transporting polypeptides (OATPs). OATPs are also found in pancreatic islets, yet their importance to pancreas distribution and insulin secretion is unknown. The aim of this study was to investigate the role of OATPs in pancreatic statin distribution using the Oatp1a/1b cluster knockout (KO) mouse model, and to assess statin effects on islet cell function. We characterized Slco gene expression in adult mouse pancreas and islets, determined statin tissue distribution in Oatp1a/1b KO mice, assessed OATP-mediated statin uptake in HEK293T cells, and measured insulin secretion in rosuvastatin-treated primary mouse islets. All Slco1a/1b transcripts, except Slco1a5, were detected in pancreas and islets, with abundance of Slco1a6 in islets. Following oral statin dosing, KO mice exhibited reduced pancreas-to-plasma distribution ratios for atorvastatin, rosuvastatin, and pravastatin compared to wildtype, as was observed for liver and kidney. Almost all statins were Oatp1a1, Oatp1a4, and Oatp1a6 substrates. In islets, rosuvastatin reduced insulin secretion and content, whereas Oatp inhibition mitigated the latter effect. Our findings demonstrate expression of Oatp1a/1b transporters in pancreas and islets, their contribution to pancreas distribution of statins, and reduced insulin content. OATP-mediated statin distribution to the pancreas may represent a potential mechanism underlying statin-associated islet cell dysfunction. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (OATPs) are well known determinants of statin exposure and hepatic distribution, while their role in the pancreas is unknown. After confirming islet expression, we show reduced pancreas-to-plasma distribution ratios of oral atorvastatin, rosuvastatin, and pravastatin in Oatp1a/1b knockout mice versus wildtype, and reduced insulin content in rosuvastatin-treated isolated islets which was reversed by Oatp inhibition. Hence, Oatp1a/1b are key determinants of pancreatic statin disposition and Oatp-mediated statin uptake may contribute to β-cell dysfunction.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100339"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351093","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":"Age (juvenile to aged) and sex effects on in vitro CYP2A6 enzyme activity in African green monkeys using nicotine and coumarin.","authors":"Weilong Gu, Rachel F Tyndale","doi":"10.1016/j.dmd.2026.100335","DOIUrl":"10.1016/j.dmd.2026.100335","url":null,"abstract":"<p><p>CYP2A6 is the principal human enzyme metabolizing coumarin and nicotine; it demonstrates wide variation from genetics and environmental regulation, complicating the determination of human developmental profile and sex-related differences. African green monkeys (AGMs), with comparable CYP2A6 activity to humans, of both sexes across 5 developmental stages (N = 56) were used to investigate age and sex effects on CYP2A6 activity using 7-hydroxycoumarin formation from coumarin, and cotinine formation from nicotine. Age and sex differences were determined using two-way ANOVAs and post hoc tests. Age impacted microsomal protein per gram liver (determined by cytochrome P450 oxidoreductase activity). Age and sex differences, with interactions, were observed in liver and body weight, whereby older AGMs and males were heavier for both. Pooled microsomes per age-sex group were used to determine the kinetic parameters for 7-hydroxycoumarin (overall K_m = 1.5 ± 0.3 μM, V_max = 0.34 ± 0.06 nmol/min/mg) and cotinine (overall K_m = 37.4 ± 8.0 μM, V_max = 1.36 ± 0.23 nmol/min/mg) formation. Age impacted the velocity of 7-hydroxycoumarin and cotinine formation (individual AGMs assessed at substrate concentrations at ∼K_m and ∼10 × K_m), at per milligram of microsomal protein, per gram liver, and per whole liver normalized by body weight, whereby juveniles and adolescents had higher velocities. Both age and sex impacted 7-hydroxycoumarin and cotinine formation per whole liver, but in contrast, older AGMs and males had higher velocities. In conclusion, age but not sex impacted CYP2A6 activity, which was higher in younger AGMs for essentially all denominators except following extrapolation to the whole liver, where activity was influenced by larger livers in adults and males. SIGNIFICANCE STATEMENT: Microsomal CYP2A6 activity was higher in younger African green monkeys (AGMs), with no sex differences. Once extrapolated to the whole liver, representing the total rate of metabolism, the velocity was faster in older AGMs and males, primarily due to age and sex differences in liver weight. There were significant age differences in CYP2A6 activity, where younger AGMs had higher velocity per milligram-microsomal protein, gram liver, and whole liver normalized to body weight levels, while older and male AGMs had higher whole liver velocity.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100335"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283567","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":"Reduction of secondary 3-keto bile acids by aldo-keto reductase 1C1 and 1C4.","authors":"Keith D Green, Graham K Thomason, Lindsay C Czuba","doi":"10.1016/j.dmd.2026.100340","DOIUrl":"10.1016/j.dmd.2026.100340","url":null,"abstract":"<p><p>Secondary \"keto\" bile acids (BAs) are produced by the gut microbiome and contain one or more ketones on the steroid core. Plasma concentrations of keto BAs are limited by hepatic reductase activity, leading to hydroxylation of keto BAs. Although the aldo-keto reductase 1 (AKR1) family is implicated, it is not known which enzymes provide this function in the liver. We hypothesized that AKR1C1 and AKR1C4 metabolize 3-keto BAs. Six BAs with 3-keto groups were tested as potential substrates using purified, recombinant His₆-tagged AKR1C1-4, and kinetic parameters were determined. AKR1C1 and AKR1C4 were found to exhibit isoform-specific substrate specificity, which may be explained in part by the hydroxylation pattern at carbon 12 of the BA core. This may suggest distinct biological roles in mediating BA homeostasis in humans. Both enzymes produced only α-OH products, as determined by liquid chromatography-mass spectrometry. We further hypothesized that fatty acids would impair reductase activity. AKR1C4 was more susceptible to inhibition compared to AKR1C1, but unsaturated fatty acids, such as linoleic acid, were the most potent inhibitors for both. We observed a 2- to 10-fold difference in the IC₅₀ of fatty acids for AKR1C4 depending on the tested substrate. Further mechanistic and structure-function studies aim to characterize the substrate-specific kinetic and inhibition patterns observed and to evaluate the translational impact of AKR activity on plasma BA concentrations and cellular signaling. SIGNIFICANCE STATEMENT: Keto bile acids are bioactive secondary metabolites that are reduced upon enterohepatic recycling to the liver. Here, the substrate specificity, kinetics, and inhibition potential of 2 aldo-keto reductase enzymes, AKR1C1 and AKR1C4, were evaluated. This study suggests that AKR1C1 and AKR1C4 exhibit disparate substrate specificity patterns, reductase activity, and susceptibility to inhibition by fatty acids, which may have broad implications in understanding changes in bile acid homeostasis in metabolic diseases.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100340"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387505","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":"Investigation of biomarkers for azole antifungal-induced liver injury using primary human hepatocyte spheroids.","authors":"Masaki Kumondai, Ayaka Yagi, Masahiro Watanabe, Yanlin Lyu, Ryosuke Segawa, Mayumi Sato, Ryo Tadakuma, Kenji Inoue, Hideki Watanabe, Masahiro Takeda, Yoshiteru Ohshima, Masamitsu Maekawa, Nariyasu Mano","doi":"10.1016/j.dmd.2026.100343","DOIUrl":"10.1016/j.dmd.2026.100343","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) is one of the most serious adverse drug reactions in clinical practice and a major concern in toxicity assessment during drug development. In particular, DILI caused by antifungals can become life-threatening in severe cases; therefore, early detection and appropriate intervention are essential. Here, potential early biomarkers of DILI induced by azole antifungals were explored by performing metabolomic analysis of the supernatants from spheroid cultures of primary human hepatocytes. Primary human hepatocytes obtained from 2 different donors were independently cultured under 3-dimensional spheroid conditions and exposed to 9 antifungal agents. Culture supernatants were collected and analyzed using untargeted metabolomics. The sampling time point was determined based on longitudinal evaluation of cell viability, and the latest time point at which concentration-dependent cytotoxicity was observed was selected for analysis. In parallel, the levels of conventional liver injury markers, aspartate aminotransferase and alanine aminotransferase, were also evaluated in the supernatants. Cell viability was assessed at the time of supernatant collection. Several candidate biomarkers associated with hepatotoxicity were identified, whereas conventional liver injury markers, including aspartate aminotransferase and alanine aminotransferase, showed no clear concentration-dependent changes. Among these, one compound was identified as glycocholic acid through comparison with an authentic standard. Another metabolite detected in positive ion mode could not be conclusively identified and requires further characterization. These findings support the development of novel biomarkers for the early detection of DILI and highlight their potential applications in toxicity screening during drug development and in clinical biomarker research. SIGNIFICANCE STATEMENT: This study identifies novel metabolite-based biomarkers for azole antifungal-induced liver injury using 3-dimensional-cultured primary human hepatocytes and untargeted metabolomics. Glycocholic acid and an additional unidentified metabolite showed stronger associations with hepatotoxicity than conventional markers (aspartate aminotransferase and alanine aminotransferase). These findings highlight the potential of advanced in vitro models and metabolomics to improve early detection of drug-induced liver injury in drug development and clinical settings.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100343"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410953","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":"Mechanistic Study on the Species Differences in Metabolism and Excretion Pathways of Ivarmacitinib (SHR0302) between Humans and Rats","authors":"Xintong Huang, Dongyu Zhuang, Yuandong Zheng, Dafang Zhong, Xingxing Diao","doi":"10.1016/j.dmd.2026.100373","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100373","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"1 1","pages":"100373-100373"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672149","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":"Finding the dispersion number (D_N) of the dispersion model from perfused rat and human liver studies.","authors":"K Sandy Pang, Rommel G Tirona, Betty P Li, Andreas J Schwab","doi":"10.1016/j.dmd.2026.100298","DOIUrl":"10.1016/j.dmd.2026.100298","url":null,"abstract":"<p><p>The dispersion number (D_N), which relates to intrahepatic mixing and impacts hepatic clearance (CL_H), is assessed routinely in liver perfusion studies. However, the estimation methods are nonuniform, and estimates for human livers are unknown. Schwab et al (1998) identified D_N estimates for red cells, albumin, sucrose, and water for closed (CBC) (0.31 ± 0.13) and mixed (MBC) boundary conditions (0.22 ± 0.07) (P < .05) from perfused rat livers with inclusion of t₀, transit time of large vessels (4.1 ± 0.7 seconds) and MTT_cath (mean transit time for catheters/injection devices), which defined the nonhepatic transfer function (TF_NH). To address the importance of t₀ and TF_NH, we refitted the digitized data of Schwab by omitting TF_NH, which yielded similar D_N estimates (0.28 ± 0.11 for CBC and 0.21 ± 0.11 for MBC) but a longer time lag (t_lag) (9-10 seconds) that equaled (t₀ + MTT_cath). Fitting without t₀ or t_lag provided much lower D_N estimates (0.020-0.078) for red cells, albumin, and sucrose though less for water (0.263 ± 0.006 for CBC and 0.223 ± 0.006 MBC) due to improper correction of the mean transit time (MTT_corr), rendering a lower CV² (variance/MTT_corr²) and therefore D_N. Notably, fitting of digitized human liver perfusion data without TF_NH (=0) but t_lag (>0) yielded sound D_Ns of 0.31 ± 0.12 for CBC and 0.24 ± 0.12 for MBC and t_lags of 8.3-10.5 seconds, values reminiscent of rat livers. These results suggest that human livers display closely similar D_N values (0.2-0.3) as those of rat livers, with predicted intrinsic clearance values that differ only by 10%-13% between the CBC and MBC to yield the same CL_H. SIGNIFICANCE STATEMENT: Dispersion numbers (D_N) based on fitting liver perfusion data to the dispersion model (DM) requires a time lag (t_lag) or large vessel transit time (t₀), but the nonhepatic transfer function (TF_NH) is not strictly required. Fitting of rat and human liver perfusion data with t_lag provides sound D_Nestimates: 0.26-0.31 and 0.22-0.24, respectively, for closed and mixed boundary conditions (P>.05). These D_N values suggest that the intrinsic clearance (CL_int,DM) values for MBC/CBC differ only by 13% in their prediction of hepatic clearance.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100298"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359941","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":"Construction of a curated human pharmacokinetics database for molecular fragment analysis and machine learning applications.","authors":"Lianjin Cai, Mai McWilliams, Jingchen Zhai, Lei Xie, Junmei Wang","doi":"10.1016/j.dmd.2026.100341","DOIUrl":"10.1016/j.dmd.2026.100341","url":null,"abstract":"<p><p>Pharmacokinetic (PK) data analysis in drug discovery is challenged by the inherent variability of experimental and clinical study designs, which hinders data integration and predictive modeling. To address this, we have curated a comprehensive, human-derived, and machine learning (ML)-ready PK dataset from authoritative, multiedition sources. This novel resource represents a systematically curated, human-derived PK dataset that integrates compound structures, clinical study design information, and experimental variability annotations, providing a structured foundation for data-driven analysis and modeling of human pharmacokinetics. We first implemented a rigorous standardization and filtering protocol to prepare the ML-ready dataset, and we demonstrated its utility through chemoinformatic analysis and ML classification model evaluations at across multiple classification systems. Fragment analysis showed a clear association between molecular structure and PK behavior, with hydrophilic fragments correlating with low distribution and high excretion, while lipophilic fragments were linked to enhanced absorption and plasma protein binding. By leveraging consensus predictions from an ensemble of classification models trained on calculated properties and molecular descriptors for each PK parameter, we achieved the most accurate predictions: ternary classifiers excelled in total clearance, whereas binary classifiers performed better for the others. In conclusion, this study provides a solid foundation for PK parameter classification and predictive modeling using a well curated human PK dataset. Integrating comprehensive data curation with ML presents a powerful strategy for accelerating drug design and enhancing rational therapeutic decision making. SIGNIFICANCE STATEMENT: Accurate prediction of absorption, distribution, metabolism, and excretion and pharmacokinetics (PK) properties is crucial for drug discovery and development. Data curation and availability is invaluable to the progress of the development of robust machine learning models to predict drug PK behavior. Standardized labeling and/or classification of human PK parameters would provide better interpretability and predictability. Integrating comprehensive data curation with machine learning presents a powerful strategy for accelerating drug design and enhancing rational therapeutic decision making.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100341"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367514","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":"Prediction of pharmacokinetics and central nervous system effects of fentanyl and alfentanil in mice, rats, and humans using a cross-species physiologically based pharmacokinetic-pharmacodynamic model and in vitro pharmacokinetic/pharmacodynamic parameters.","authors":"Qingxuan Shao, Ying Deng, Weiye Gu, Lu Yang, Nan Hu, Xiaodong Liu, Li Liu","doi":"10.1016/j.dmd.2026.100319","DOIUrl":"10.1016/j.dmd.2026.100319","url":null,"abstract":"<p><p>As direct human experiments are often restricted by ethical concerns and safety risks, a cross-species physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model was developed to integrate pharmacokinetics (PKs) and pharmacodynamics of drugs using in vitro-in vivo extrapolation. Fentanyl and alfentanil, 2 μ-opioid receptor agonists with extensive clinical data, were selected as model drugs. Key in vitro parameters such as transport parameters across hCMEC/D3 cell monolayers (blood-brain barrier), hepatic metabolic clearance in liver microsomes, and unbound fractions in the brain were experimentally measured. PK and analgesic effects of the 2 drugs following an intravenous dose to mice were also documented. The affinity to receptor (K_d) to μ-opioid receptor were cited from the literature. A mouse PBPK-PD model was first constructed. It was assumed that the effects of the central nervous system were linked to unbound drug concentrations in brain parenchyma, which is illustrated using the E_max model. The developed PBPK-PD model, following validation using observations in mice, was extrapolated to rats and humans in sequence. The PK profiles and their central nervous system effects (such as analgesic effect, respiratory depression, and miosis) of fentanyl and alfentanil following intravenous administration to rats and humans were predicted and validated using observations. The results showed that the majority of observed values fell within the 5th-95th percentiles of simulations from 1000 virtual individuals. In conclusion, the developed cross-species PBPK-PD model, based on physiological parameters, in vitro PK/pharmacodynamic parameters, was successfully used to predict the PK and central nervous system effects of fentanyl and alfentanil in mice, rats, and humans, demonstrating the applicability and feasibility. SIGNIFICANCE STATEMENT: The developed cross-species physiologically based pharmacokinetic-pharmacodynamic model, based on physiological parameters, in vitro drug metabolic parameters, and in vitro pharmacokinetic parameters, was successfully used to predict the pharmacokinetic and central nervous system effects of fentanyl and alfentanil in mice, rats, and humans, demonstrating the applicability and feasibility.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100319"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419671","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":"Loss of palmitoylation impacts the interaction between the organic anion transporting polypeptide (OATP) 1B1 and OATP1B3.","authors":"Cecilia E Villanueva, Whitney M Nolte, Priscilla Flores-Ascencio, Bruno Hagenbuch","doi":"10.1016/j.dmd.2026.100330","DOIUrl":"10.1016/j.dmd.2026.100330","url":null,"abstract":"<p><p>The organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are hepatic transporters that mediate the uptake of numerous therapeutics like antibiotics and statins. Various post-translational modifications, eg, phosphorylation and glycosylation, have been shown to impact OATP1B1 and OATP1B3 function and localization. S-palmitoylation (also known as S-acylation or palmitoylation) is a reversible post-translational modification that adds palmitic acid (C16:0) to cysteine residues and can influence a protein's function, localization, and protein-protein interactions. In this study, we investigated and characterized palmitoylation in OATP1B1 and OATP1B3. Using site-directed mutagenesis and acyl-resin-assisted capture assays, residue Cys24 was identified as the palmitoylation site for both these proteins. Uptake function and surface biotinylation experiments demonstrated that palmitoylation does not affect the individual function and surface expression of OATP1B1 and OATP1B3. Coexpression studies revealed a decrease in OATP1B1-OATP1B3 interactions when nonpalmitoylated OATP1B1 or nonpalmitoylated OATP1B3 are coexpressed with their wild-type counterparts, suggesting that S-palmitoylation regulates protein-protein interactions between OATP1B1 and OATP1B3. SIGNIFICANCE STATEMENT: This study identified and characterized palmitoylation of the organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Both OATP1B1 and OATP1B3 can be palmitoylated on the conserved Cys24 residue. Palmitoylation of these 2 transporters does not impact their individual function or surface expression. However, the interaction between these 2 proteins is affected when their palmitoylation state is altered.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100330"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270786","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":"Virtual special section: Novel animal models.","authors":"Hiroshi Yamazaki","doi":"10.1016/j.dmd.2026.100334","DOIUrl":"10.1016/j.dmd.2026.100334","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100334"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216896","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}