Drug Metabolism and Disposition最新文献

{"title":"Microfluidic liver-chip to predict clinical drug-drug interaction net effects for precipitant drugs with dual CYP3A4 inhibition and induction potential.","authors":"Lina Mettler, Justine Badée, Felix Huth, Christian Lohasz, Johanna Alm, Judith Streckfuss, Hilmar Schiller, Peter Loskill, Birk Poller, Julia Riede","doi":"10.1016/j.dmd.2026.100359","DOIUrl":"10.1016/j.dmd.2026.100359","url":null,"abstract":"<p><p>Accurate predictions of complex clinical drug-drug interactions (DDIs), arising from dual induction and time-dependent inhibition (TDI) of CYP3A4, has remained challenging with conventional in vitro and static/dynamic modeling approaches. In this work, we aimed to anticipate the hepatic DDI effects of 6 CYP3A4 precipitant drugs using a liver-chip coupled to microfluidic perfusion, which enabled simulating clinically relevant pharmacokinetic (PK) time-concentration profiles. Midazolam clearance was measured in the liver-chip to determine the CYP3A4-mediated DDI net effect following exposure to precipitants under either dynamic or constant concentration conditions. For direct comparison, hepatic DDI reference values were generated based on clinical DDI studies by physiologically based PK modeling. Under microfluidic perfusion, CYP3A4 activity in the liver-chip was retained for 3 days and inducible by rifampicin. Although most precipitant drugs induced CYP3A4 mRNA levels, CYP3A4 activity net effects showed either induction or inhibition, in line with clinical observations. Compared with a mechanistic static net effect model and physiologically based PK simulations, liver-chip predictions showed closer alignment and higher accuracy relative to hepatic reference values. Although constant exposures offered the strongest quantitative performance, the ability to apply dynamic PK profiles represents a distinctive feature of this platform. Collectively, these findings position the human liver-chip as a novel translational platform for predicting complex hepatic CYP3A4 DDIs arising from dual TDI and induction in a single, holistic in vitro model. This approach aligns with the broader global regulatory shift toward human-relevant new approach methodologies. SIGNIFICANCE STATEMENT: Complex CYP3A4-mediated drug-drug interactions (DDIs), driven by concurrent time-dependent inhibition and induction, remain difficult to anticipate using conventional in vitro and modeling frameworks. This study establishes a human liver-chip model capable of capturing dual CYP3A4 inhibition and induction within a single experiment, and evaluates how clinical exposure regimes shape the quantitative prediction of hepatic DDI effects. Relative to modeling approaches, this platform demonstrates superior accuracy against hepatic DDI references, supporting more translational DDI risk assessments.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 8","pages":"100359"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648451","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":"Corrigendum to \"Investigation of biomarkers for azole antifungal-induced liver injury using primary human hepatocyte spheroids\" [Drug Metabolism and Disposition 54 (2026) 100343].","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.2026.100377","DOIUrl":"10.1016/j.dmd.2026.100377","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 8","pages":"100377"},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148653295","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":"A herb-drug interaction: The role of transporters in the modulation of atorvastatin absorption by Compound Danshen Tablets.","authors":"Ke Zhang, Fofo Jiang, Ziting Li, Feng Zhao, Yinling Ma","doi":"10.1016/j.dmd.2026.100380","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100380","url":null,"abstract":"<p><p>This study characterized the pharmacokinetic interaction between Compound Danshen Tablets (CDT) and atorvastatin (ATV) and investigated absorption- and transporter-related mechanisms underlying this interaction. ATV pharmacokinetics were evaluated after oral and intravenous administration in normal and hyperlipidemic/diabetic rats, with or without repeated CDT treatment. Mechanistic studies included single-pass intestinal perfusion, Caco-2 bidirectional transport assays, human multidrug resistance protein 1 inside-out vesicle transport assays, ileal P-glycoprotein (P-gp) immunoblotting, an in vivo digoxin probe-substrate experiment, and molecular docking. Repeated CDT administration increased oral ATV exposure in both normal and model rats, with the area under the plasma concentration-time curve from 0 to 24 hours and maximum plasma concentration increasing by up to 85.83% and 306.53%, respectively, whereas intravenous ATV pharmacokinetics were not significantly altered. In Caco-2 monolayers, ATV exhibited marked directional efflux, with an efflux ratio of 39.32, which was reduced to 10.99 by verapamil. CDT increased the apical-to-basolateral apparent permeability coefficient of ATV from 0.41 to 1.31 × 10^-6 cm/s and reduced the efflux ratio to 9.82, whereas the basolateral-to-apical apparent permeability coefficient decreased from 16.27 to 12.90 × 10^-6 cm/s. In human multidrug resistance protein 1 inside-out vesicles, CDT concentration dependently reduced ATP-dependent N-methylquinidine transport, with inhibition rates ranging from 24.97% to 80.45% at 50-800 μg/mL. Together with the ileal P-gp protein data and the digoxin probe-substrate experiment, these findings indicate that CDT enhances intestinal absorption of ATV primarily by attenuating intestinal P-gp-mediated efflux through reducing both P-gp transport activity and protein abundance. These results provide mechanistic evidence that modulation of intestinal efflux transport contributes to the increased systemic exposure of ATV after repeated CDT administration. SIGNIFICANT STATEMENT: This study identifies a clinically relevant herb-drug interaction in which repeated administration of compound Danshen tablets increases oral atorvastatin exposure in normal and hyperlipidemic/diabetic rats without materially altering intravenous atorvastatin pharmacokinetics. Integrated pharmacokinetic, single-pass intestinal perfusion, Caco-2 transport, human multidrug resistance protein 1 vesicle, ileal P-glycoprotein, and digoxin probe-substrate data support attenuation of intestinal P-glycoprotein-mediated efflux, through reduced transporter activity and protein abundance, as a mechanism enhancing atorvastatin absorption.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 10","pages":"100380"},"PeriodicalIF":3.6,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073931","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":"A novel in vitro permeability and efflux classification system for proteolysis targeting chimeras.","authors":"Siennah R Greenfield, Philip Sandoval, Sara P Puckett, Erika Kojima, Yipei Zhang, Matthew Crouthamel, Priyanka Kulkarni, Feng Hong, Chiaowen Joyce Hsiao, Hao Sun","doi":"10.1016/j.dmd.2026.100369","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100369","url":null,"abstract":"<p><p>Proteolysis targeting chimeras (PROTACs) have emerged as a promising modality over the past decade, with only a few advancing to clinical trials. As \"beyond rule-of-five\" compounds, PROTACs pose significant challenges for absorption, distribution, metabolism, and excretion, often necessitating iterative in vitro absorption, distribution, metabolism, and excretion assay optimization or reliance on in vivo pharmacokinetic studies, particularly to understand oral absorption. In this study, in vitro-in vivo correlations from clinically advanced PROTACs were leveraged to develop a novel classification system with results from optimized Madin-Darby Canine kidney cell line type 1 transfected with human multidrug resistance 1 and colorectal adenocarcinoma cell permeability and efflux assays that prioritizes compounds based on estimated mouse oral absorption. Receiver operating characteristic analysis was applied to define data-driven thresholds for effective permeability (P_eff) and efflux ratio (ER), enabling classification of compounds into mouse absorption-relevant buckets with good discriminative performance. In the Madin-Darby Canine kidney cell line type 1 transfected with human multidrug resistance 1 assay, both individual cutoffs for normalized P_eff (0.36) and normalized ER (1.72) and combined continuous score of log₁₀ normalized P_eff - 1.3∗log₁₀ normalized ER yielded reasonable classification of PROTACs with F_aF_g > 20%. In the colorectal adenocarcinoma assay, both individual cutoffs for normalized P_eff (0.021) and normalized ER (0.22) and combined continuous score of log₁₀ normalized P_eff - 1.2∗log₁₀ normalized ER yielded reasonable classification of PROTACs with F_aF_g > 20%. This approach aims to streamline in vitro workflows and minimize the need for extensive in vivo pharmacokinetic studies when evaluating novel PROTACs in preclinical discovery studies. SIGNIFICANT STATEMENT: This work establishes optimized assay conditions to assess permeability and a novel classification strategy that enables more reliable in vitro assessment of proteolysis targeting chimeras oral absorption potential. By streamlining workflows, it reduces the need for extensive in vivo pharmacokinetic studies when evaluating novel proteolysis targeting chimeras in drug discovery.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 10","pages":"100369"},"PeriodicalIF":3.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001424","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":"In vitro assay for quantitative prediction of human intestinal drug absorption with cryopreserved human intestinal mucosal epithelium-derived intestinal stem cells and 96-well Vitrigel inserts.","authors":"Keiichiro Nakamura, Ryuto Tomabechi, Kazuya Maeda","doi":"10.1016/j.dmd.2026.100306","DOIUrl":"10.1016/j.dmd.2026.100306","url":null,"abstract":"<p><p>This study aimed to establish a novel in vitro model by combining jejunal stem cells from commercially available cryopreserved human intestinal mucosal epithelium (CHIM), which can be used without ethical concerns, with 96-well Vitrigel inserts for high-throughput screening. Jejunal stem cells were successfully isolated from CHIM, and stable long-term expansion in spheroid culture was achieved. The differentiated cells exhibited mRNA expression and function of major pharmacokinetic-related genes. Comparable metabolic and transport activities were maintained even with 96-well Vitrigel inserts instead of the conventional 24-well culture inserts. In a 96-well transcellular transport assay, a significant correlation was observed between the in vitro P_app values and the reported FaFg values (the fraction of orally administered drugs reaching the portal vein) in humans for 10 compounds known to be primarily absorbed via passive diffusion, allowing us to construct a fitting curve. Applying this curve, the FaFg values of transporter substrates could also be estimated with reasonably high accuracy. Furthermore, to estimate human Fg values (the fraction of orally administered drugs escaping from intestinal metabolism), we assessed 5 compounds known to be metabolized by intestinal enzymes. Their predicted Fg values closely matched the reported Fg ones, indicating that our cell model enables their accurate prediction. These findings suggest that a combination of CHIM-derived jejunal stem cells and 96-well Vitrigel inserts provides a practical in vitro model for the quantitative prediction of human intestinal absorption of orally administered drugs. SIGNIFICANCE STATEMENT: In this study, we demonstrated that a combination of commercially available cryopreserved human intestinal mucosal epithelium-derived intestinal stem cells, whose use is free from ethical concerns and restricted tissue availability, and 96-well Vitrigel inserts enables a high-throughput assay that quantitatively predicts human intestinal absorption with high accuracy.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100306"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301265","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":"Physiologically based pharmacokinetics of dexamethasone in rats featuring nonlinear tissue binding.","authors":"Wensi Wu, Nitheesh Yanamandala, William J Jusko","doi":"10.1016/j.dmd.2026.100328","DOIUrl":"10.1016/j.dmd.2026.100328","url":null,"abstract":"<p><p>Dexamethasone (DEX) is a synthetic glucocorticoid used to manage severe inflammatory conditions, including cytokine release syndrome and autoimmune diseases. Although DEX pharmacokinetics (PK) have been characterized in healthy and inflamed rats, tissue distribution under inflammatory conditions and extended exposure were not assessed. This study characterizes the PK of DEX in lipopolysaccharide-challenged rats and updates a previously published physiologically based PK (PBPK) model. Male Wistar rats received subcutaneous DEX at 0.005, 0.025, 0.225, or 2.25 mg/kg doses, followed by 5.0 mg/kg lipopolysaccharide administered intraperitoneally to induce cytokine release syndrome. Plasma, heart, and lung tissues were collected over 48 hours for DEX, and the PK data were integrated with our previous data to refine the PBPK model. Extended sampling revealed a polyexponential decline in plasma and tissues, including a prolonged terminal phase that was not previously captured. The new PBPK model with nonlinear tissue partitioning reflects tissue-specific target-mediated drug disposition. The updated PBPK model accounts for a wide range of DEX doses and reveals prolonged tissue persistence that also appears relevant for several other species. SIGNIFICANCE STATEMENT: The updated physiologically based pharmacokinetic model characterizes dexamethasone (DEX) pharmacokinetics in healthy and lipopolysaccharide-challenged rats, capturing a long terminal phase in plasma and tissues. Incorporating a range of doses, extended sampling times, and tissue-specific nonlinear partitioning, the target-mediated drug disposition model can be used to predict DEX exposure in target organs. These findings enhance the understanding of DEX pharmacokinetics under healthy and inflammatory conditions and provide translational expectations across species.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100328"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148224166","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 insights into edoxaban's nonlinear pharmacokinetics and quinidine interaction via P-glycoprotein using physiologically based pharmacokinetic modeling.","authors":"Wen Kou, Toshiaki Tsuchitani, Kazuya Maeda, Ryuto Tomabechi, Yuichi Sugiyama","doi":"10.1016/j.dmd.2026.100333","DOIUrl":"10.1016/j.dmd.2026.100333","url":null,"abstract":"<p><p>Edoxaban, a direct factor Xa inhibitor and known P-glycoprotein (P-gp) substrate, exhibits nonlinear increases in systemic exposure after oral administration and significant interaction with quinidine, a P-gp inhibitor. However, it remains unclear how P-gp in each organ contributes to these phenomena. We developed a physiologically based pharmacokinetic (PK) model to describe PK of edoxaban after oral (0.05-60 mg) and intravenous administration (30 mg), as well as its interaction with quinidine following edoxaban intravenously. Parameters were estimated using the Cluster Gauss-Newton method through top-down and middle-out approaches. Accurate description of renal clearance, which required incorporation of a hypothetical basolateral uptake process, underscoring the importance of unidentified renal transporters involved in edoxaban urinary secretion. Nonlinearity of dose-normalized area under blood concentration-time curve was highly sensitive to K_mP-gp, with intestinal unbound concentrations exceeding K_mP-gp at clinically relevant doses, consistent with intestinal P-gp saturation as the major driver of nonlinearity. In intravenous edoxaban-oral quinidine drug-drug interaction analysis, quinidine markedly reduced renal clearance and modestly increased hepatic availability, reflecting inhibition of renal and, to a lesser extent, hepatic P-gp. In conclusion, an edoxaban physiologically based PK model incorporating renal uptake transport enabled physiologically consistent description of renal clearance. Saturation of intestinal P-gp was identified as the primary contributor to nonlinear PK, while inhibition of renal P-gp was the main mechanism underlying the edoxaban intravenously administered with quinidine. These findings provide mechanistic insight into transporter contributions to edoxaban disposition and drug-drug interactions and highlight the importance of tissue-specific transporter processes in nonlinear pharmacokinetics. SIGNIFICANCE STATEMENT: Incorporating renal uptake transport is essential for mechanistically describing edoxaban renal clearance in physiologically based pharmacokinetic (PK) modeling. The model identifies intestinal P-glycoprotein saturation as the primary driver of nonlinear PK and renal P-glycoprotein inhibition as the major mechanism of the intraveous edoxaban-quinidine drug-drug interaction. These findings offer mechanistic insight into transporter contributions to edoxaban disposition and drug-drug interactions and emphasize the role of tissue-specific transport processes in nonlinear PK.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100333"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301307","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":"Population pharmacokinetics and resistance patterns of vancomycin and amikacin in pediatric oncology patients.","authors":"Khalid M Alkharfy, Ajaz Ahmad, Mitab Alenazi, Azzam Neyaz, Abdullah Almousa, Manar Eid Alshammari, Rakan Jamal Alanazi","doi":"10.1016/j.dmd.2026.100336","DOIUrl":"10.1016/j.dmd.2026.100336","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Febrile episodes in pediatric oncology patients, particularly those with neutropenia, pose major clinical challenges and require prompt empiric antimicrobial therapy. The current study evaluated the pharmacokinetics (PK) and pharmacodynamics of vancomycin and amikacin in pediatric oncology patients. A retrospective review was conducted in 105 pediatric oncology patients admitted between January 2020 and January 2024. Data collected included demographic characteristics, vital signs, laboratory findings, neutropenic status, malignancy type, microbial cultures, resistance profiles, and total serum concentrations of vancomycin and amikacin obtained during routine therapeutic drug monitoring (TDM). Blood cultures were positive in ∼39% of cases, with Staphylococcus epidermidis (∼24%) and methicillin-resistant Staphylococcus aureus (∼16%) being the predominant isolates. Vancomycin peak and trough concentrations were 18.37 ± 7.42 μg/mL and 8.63 ± 3.81 μg/mL, respectively. Amikacin peak and trough concentrations were 26.27 ± 12.11 μg/mL and 1.09 ± 0.67 μg/mL, respectively. Population PK analyses identified body weight and bilirubin level as key covariates for vancomycin (CL = 0.169 L/h/kg; V = 1.519 L/kg), and body weight and tumor type for amikacin (CL = 0.182 L/h/kg; V = 0.505 L/kg). Solid tumors were associated with a lower amikacin volume of distribution (∼0.32 L/kg). The calculated area under the curve (AUC) of vancomycin exposure over one dosing interval was estimated as AUC&lt;sub&gt;0-6&lt;/sub&gt; = 62.76 ± 22.25 μg·h/mL; assuming steady-state every 6 hours dosing, the corresponding daily exposure was AUC&lt;sub&gt;0-24&lt;/sub&gt; = 251.04 ± 89.00 μg·h/mL. Using a reference minimum inhibitory concentration (MIC) of 1 μg/mL, the mean vancomycin AUC&lt;sub&gt;0-24&lt;/sub&gt;/MIC remained well beneath the therapeutic target of ≥400. Similarly, the calculated Cpeak/MIC of amikacin was 6.57 ± 3.03, which was below the optimal PK/pharmacodynamics target (ie, 8-10), with only ∼30% accomplished therapeutic goals, highlighting the need for personalized dosing and TDM in this cohort. Analytical target attainment projections derived from the final population PK models confirmed that standard dosing regimens achieved suboptimal probability of target attainment for both drugs, and indicated that dose escalation to at least 20 mg/kg every 6 hours for vancomycin and 22.5 mg/kg every 24 hours for amikacin would be required to meaningfully improve exposure adequacy across this population. These outcomes emphasize the need for individualized dosing strategies and TDM in pediatric oncology patients receiving antimicrobial therapy. SIGNIFICANCE STATEMENT: Vancomycin and amikacin display pharmacokinetic variability in pediatric oncology patients, with body weight identified as determinant for both drugs, bilirubin level for vancomycin, and tumor type for amikacin. standard dosing was associated with lower-than-target exposure in a proportion of patients. Analytical target attainment projections","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100336"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337931","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":"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}