Drug Metabolism and Disposition最新文献

{"title":"Impact of sex and pregnancy on hepatic CYP3A4 expression and activity in a humanized mouse model.","authors":"Muluneh M Fashe, Taryn A Miner, Valeria Laboy Collazo, Joseph T Grieco, John K Fallon, Klarissa D Jackson, Craig R Lee","doi":"10.1016/j.dmd.2024.100025","DOIUrl":"10.1016/j.dmd.2024.100025","url":null,"abstract":"<p><p>Cytochrome P450 (CYP) 3A4 is an essential drug-metabolizing enzyme in humans, which shows substantial interindividual variation in response to various intrinsic and extrinsic factors such as sex and pregnancy. In humans, higher CYP3A4 metabolism has been observed in females compared with that in males and in pregnant compared with that in nonpregnant individuals, which has been linked to increased CYP3A4 expression in liver. However, sex differences and pregnancy-mediated changes in hepatic CYP3A4 expression and activity in vivo are not fully understood. In this study, we investigated the utility of a genetically engineered humanized mouse model that carries human CYP3A4/7, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) (huPXR/CAR/CYP3A4/7) to recapitulate sex-associated and pregnancy-associated differences in the hepatic CYP3A4 expression and metabolism observed in humans. We found that female huPXR/CAR/CYP3A4/7 mice exhibited higher basal CYP3A4 mRNA levels and CYP3A4 absolute protein concentrations in liver, and higher 1-hydroxymidazolam formation in liver microsomes, compared with male humanized mice. In contrast, pregnant huPXR/CAR/CYP3A4/7 mice exhibited lower CYP3A4 mRNA levels, CYP3A4 absolute protein concentrations, and 1-hydroxymidazolam formation compared with nonpregnant and postpartum humanized mice. Expression of CAR and Cyp2b10 (a CAR responsive gene) were also higher in females and decreased during pregnancy and were positively correlated with hepatic CYP3A4 mRNA levels. Overall, the huPXR/CAR/CYP3A4/7 mouse model demonstrated utility to study higher basal hepatic CYP3A4 metabolism in females compared with that in males in vivo; however, this humanized mouse model did not demonstrate utility to study pregnancy-mediated increases in CYP3A4 drug substrate metabolism and clearance observed in humans. SIGNIFICANCE STATEMENT: This study assessed the impact of sex and pregnancy on hepatic CYP3A4 protein concentrations and metabolism in humanized PXR/CAR/CYP3A4 mice. Consistent with humans, female mice demonstrated higher hepatic CYP3A4 expression and activity than male mice. In contrast, pregnant mice showed decreased CYP3A4 expression and metabolism compared with nonpregnant mice. The humanized mouse model appeared useful to evaluate sex differences in basal hepatic CYP3A4 metabolism in vivo, but not to study the pregnancy-mediated increase in CYP3A4 metabolism observed during human pregnancy.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100025"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536704","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":"Evaluation of reversible cytochrome P450 inhibition by Withania somnifera leaf and root extracts.","authors":"Zarna Raichura, Kabre Heck, Jaewoo Choi, Liping Yang, Mikah Brandes, Luke Marney, Armando Alcázar Mangaña, Cody Neff, Claudia S Maier, Amala Soumyanath, Richard B van Breemen, Robert D Arnold, Angela I Calderón","doi":"10.1016/j.dmd.2024.100024","DOIUrl":"https://doi.org/10.1016/j.dmd.2024.100024","url":null,"abstract":"<p><p>It is important to understand the potential of botanical-drug interactions to ensure the safe use of botanical dietary supplements (BDS). Cytochrome P450 (P450) is one of the most abundant phase 1 drug-metabolizing enzymes and is accountable for a great deal of pharmacokinetic botanical-drug interactions. This problem is particularly acute for older adults who often consume BDS with multiple prescription medicines. The consequences of botanical-drug interactions can lead to lack of prodrug efficacy or drug toxicity from reduced drug clearance through inhibition of P450 metabolizing enzymes. In this study, a 7-in-1 cocktail P450 inhibition assay with 7 Food and Drug Administration-recommended P450s (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4/5) including CYP2B6 recombinant enzyme was performed, minimizing substrate interactions with respect to specificity while maximizing assay sensitivity. High-performance liquid chromatography-mass spectrometry was used for quantitative determination of probe substrate metabolism. Withania somnifera L. Dunal (ashwagandha), a popular BDS in the United States with sales of ∼$16 million in 2021, is used to promote sleep and relieve stress and anxiety, especially in older adults. However, comprehensive studies of pharmacokinetic drug interactions with ashwagandha, especially with leaf extracts, have not been reported. Four extracts from ashwagandha root or leaf were evaluated for P450 inhibition, and no reversible inhibition was detected at IC₅₀ > 100 μg/mL extract. SIGNIFICANCE STATEMENT: Ashwagandha is often consumed by older adults, who also often use multiple prescribed medications concomitantly. Polypharmacy, combined with age-related decline of drug metabolism and other changes in drug disposition in this population, increases the risk of adverse events due to botanical inhibition of drug metabolism, indicating the significance of evaluating ashwagandha for potential pharmacokinetic drug interactions. This study will support our understanding for the safe use of ashwagandha.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100024"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536683","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 metabolism of targeted covalent inhibitors and their thiol conjugates by gut microbiome from rats, mice, and humans.","authors":"Ting-Jia Gu, Jingwei Cai, Alexis Auster, Elizabeth Torres, Donglu Zhang, S Cyrus Khojasteh, Shuai Wang","doi":"10.1016/j.dmd.2024.100027","DOIUrl":"https://doi.org/10.1016/j.dmd.2024.100027","url":null,"abstract":"<p><p>Targeted covalent inhibitor (TCI) represents a noncanonical class of small molecules that function via \"inactivating\" the target protein through the formation of drug-protein adducts. The electrophilic groups (warheads) embedded in the TCIs are essential for their activity while also being recognized as sites susceptible to metabolism by various enzymes and endogenous nucleophiles. Given the growing knowledge of gut microbiome-mediated drug metabolism and its impact on drug absorption, distribution, metabolism, and excretion, the fate of the reactive warhead-containing TCIs in the gut warrants further understanding. In this study, we selected unsubstituted terminal acrylamides (ibrutinib, sotorasib, and divarasib), β-substituted acrylamides (afatinib, neratinib, and dacomitinib), an α-substituted acrylamide (adagrasib), an alkynamide (acalabrutinib), and a salicylaldehyde (voxelotor) to investigate. An anaerobic in vitro approach was utilized using both fecal slurry and feces-outgrown bacteria from rats, mice, and humans. The results showed that double bond reduction was the major metabolism captured for terminal acrylamides, but the activity decreases significantly when α or β substitutions are present; acalabrutinib was stable; and voxelotor was efficiently reduced to a benzyl alcohol metabolite. Synthesized TCI-GSH adducts can be efficiently hydrolyzed sequentially to cysteine adducts, which are rather stable from further microbiome modifications. There were no apparent species differences between rats, mice, and humans qualitatively, while the reductase activity observed was generally higher in the human gut microbiome. This study provides insights into both enzymatic and nonenzymatic reactions of TCIs and their thiol conjugates in the gut environment, which can be translated to the understanding of their absorption, distribution, metabolism, and excretion behavior during drug development. SIGNIFICANCE STATEMENT: Understanding the gut microbiome metabolism of targeted covalent inhibitors and their thiol conjugates will help interpret absorption, distribution, metabolism, and excretion studies for new targeted covalent inhibitors in delineating that from human metabolism, predicting clearance pathways, and assessing the impact on absorption/reabsorption. The species difference information can inform proper preclinical species for better human translation in overall drug behavior. The experimental conditions developed from this work can also be adapted to study gut microbiome metabolism in general across different species.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100027"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536717","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":"Rat PermQ: A permeability- and perfusion-based physiologically based pharmacokinetic model for improved prediction of drug concentration-time profiles in rat.","authors":"Yifan Gong, Ken Korzekwa, Swati Nagar","doi":"10.1016/j.dmd.2024.100033","DOIUrl":"https://doi.org/10.1016/j.dmd.2024.100033","url":null,"abstract":"<p><p>A new rat permeability- and perfusion-limited physiologically based pharmacokinetic model, \"rat PermQ,\" was developed with the goal of improving concentration-time (C-t) predictions of drugs. Similar to the previously published human PermQ, drugs can reversibly distribute between capillaries and interstitial fluid by fenestra or discontinuities in capillaries or by transcellular diffusion through endothelial cells. Drugs also can be partitioned into intracellular phospholipids and neutral lipids in the cytosol. For acidic drugs, active uptake transport and an empirical protein binding correction factor were considered. A shallow distribution compartment was added for basic drugs to account for early distribution. In vitro and in vivo experimental inputs were collected in-house or from the literature. C-t profiles were predicted for 7 drugs (2 acidic, 2 neutral, and 3 basic) with 3 models: Rodgers and Rowland (RR), a perfusion-limited membrane-based model, and rat PermQ. Results indicate the importance of consistent, species-specific in vitro inputs. In general, rat PermQ predicted C-t profiles at least as well as the other models. For acidic drugs, rat PermQ predictions improved with incorporation of uptake transport and the empirical protein binding factor. For neutral drugs, RR predicted digoxin C-t profiles better compared with rat PermQ, while midazolam predictions with rat PermQ were improved with the use of in-house in vitro experimental inputs. Rat PermQ predicted C-t profiles for all 3 bases better than RR and perfusion-limited membrane-based model, and addition of a shallow compartment greatly improved the predictions. Rat and human PermQ allowed several hypotheses to be simulated for putative uptake mechanisms for atenolol and glyburide. SIGNIFICANCE STATEMENT: A new physiologically based pharmacokinetic framework, rat PermQ, was developed. This model predicted plasma concentration-time profiles of the tested drugs as well as or better than published physiologically based pharmacokinetic models. PermQ allowed several hypotheses to be simulated for uptake mechanisms in rats and humans. The work highlights the importance of accurate in vitro parameters such as drug plasma protein binding and blood-to-plasma ratio. The model can aid in testing new hypotheses to explain poorly understood observations in distribution and elimination of drugs.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100033"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536767","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":"Clearance prediction with three novel plated human hepatocyte models compared to conventional suspension assays: Assessment with 50 compounds and multiple donors.","authors":"David A Kukla, Julia A Schulz Pauly, Paul R Lesniak, Elizabeth Sande, Yue-Ting Wang, John Cory Kalvass, David M Stresser","doi":"10.1016/j.dmd.2024.100032","DOIUrl":"https://doi.org/10.1016/j.dmd.2024.100032","url":null,"abstract":"<p><p>Incubation of drugs with suspension hepatocytes (SH) to determine intrinsic clearance is common in drug discovery. However, the limited duration of SH assays hampers clearance assessment of metabolically stable compounds. In turn, this has driven the development of alternative in vitro approaches to generate intrinsic clearance estimates. Culturing primary hepatocytes with supportive cells as co/tricultures has been shown to maintain morphology, viability, and drug-metabolizing enzyme function for weeks, permitting extended incubations. Another assay from our laboratory is the preloaded hepatocyte assay (preload assay), which involves preloading plated monoculture hepatocytes with compounds and measuring the loss from cells in drug-free media. This approach increases analytical sensitivity compared to assays that measure bulk compound loss in the cells plus medium. We conducted a systematic evaluation of the ability of coculture, triculture, and preload assay models to predict human in vivo clearance for 50 predominantly low-clearance compounds with a range of physicochemical properties, including equal numbers of compounds following or violating Lipinski's rule of 5, across 3 hepatocyte donors. The results were compared with SH. Co/tricultures exhibited lower inter-donor differences compared to the preload and SH assays, likely due to the blunting of environmental cues after 5 days in culture prior to compound introduction. All 3 plated models significantly reduced the number of compounds with insufficient turnover to calculate CL_int,u compared to SH (SH: 40%; preload: 18%; cocultures: 8%; tricultures: 4%), exhibited strong interexperimental reproducibility and robust predictions of blood clearance (preload: 26/41; cocultures: 31/46; tricultures: 30/48 within 3-fold of observed). SIGNIFICANCE STATEMENT: Preloading plated hepatocytes with compounds and measuring the loss in drug-free media, or culturing hepatocytes with supportive cells as co/tricultures, facilitate quantitation of metabolically stable compounds in substrate depletion assays compared to suspension hepatocytes (SH). All 4 models exhibit robust estimates of CL_int,u and CL_b, but plated models allowed assessment of several compounds found to be too stable to evaluate in SH.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100032"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536814","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":"Development of an OATP1-humanized transchromosomic mouse model for prediction of hepatic drug uptake in humans.","authors":"Tomoki Koishikawa, Kanako Kazuki, Rina Ohnishi, Koki Okita, Tadahaya Mizuno, Satoshi Abe, Isamu Nanchi, Yusaku Masago, Kyotaro Yamazaki, Jun-Ichiro Ohzeki, Hiroyuki Kusuhara, Yasuhiro Kazuki","doi":"10.1016/j.dmd.2024.100028","DOIUrl":"https://doi.org/10.1016/j.dmd.2024.100028","url":null,"abstract":"<p><p>Transchromosomic technology using mouse artificial chromosomes (MACs) offers a promising approach for transferring gene clusters into host organisms. This study focused on the multispecific organic anion-transporting polypeptides (OATPs) in the liver, which exhibit significant species differences between mice (Oatp1a1/Slco1a1, Oatp1a4/Slco1a4, Oatp1b2/Slco1b2) and humans (OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3). We generated an OATP1-humanized transchromosomic mouse model using a MAC vector (hOATP1-MAC mice) by transferring the human OATP1 gene cluster (SLCO1C1-SLCO1B3-SLCO1B7-SLCO1B1-SLCO1A2, 700 kbp) via an MAC into Slco1a/1b cluster knockout (KO) mice (Oatp1-KO). The human OATP1 genes were expressed in a tissue-specific manner. Plasma concentrations of the OATP1B biomarkers, coproporphyrin I and III, which were 7.2- and 23.3-fold higher in Oatp1-KO mice than in wild-type mice, were decreased by 68% and 96% in hOATP1-MAC mice, respectively. A pharmacokinetics study using pitavastatin revealed greater total body clearance (168 mL/min/kg) in hOATP1-MAC mice than in Oatp1-KO mice (100 mL/min/kg) but lower clearance than in wild-type mice (484 mL/min/kg), with bioavailability ranging from 0.66 to 0.77. In addition, drug-drug interactions were investigated using rifampicin, an OATP1B inhibitor. Rifampicin (60 mg/kg orally) increased the area under the plasma concentration-time curves of orally administered pitavastatin and grazoprevir in hOATP1-MAC mice, but not of asunaprevir. These findings demonstrated the functional expression of OATP1B1 and OATP1B3 in the mouse liver and their significant role in the systemic elimination of substrates. This is the first study to introduce multiple solute carrier drug transporter genes using artificial chromosome technology, highlighting its potential to overcome species differences in drug transport. SIGNIFICANCE STATEMENT: Transchromosomic technology holds promise for addressing species differences by introducing multiple solute carrier drug transporter genes such as OATP1. Mice OATP1-humanized using a mouse artificial chromosome vector demonstrated enhanced clearance of endogenous OATP1B biomarkers and probe drugs.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100028"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536673","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":"Investigating the sexual dimorphism in isoproterenol-induced cardiac hypertrophy in Sprague Dawley rats.","authors":"Sara A Helal, Samar H Gerges, Sareh Panahi, Jason R B Dyck, Ayman O S El-Kadi","doi":"10.1016/j.dmd.2025.100035","DOIUrl":"10.1016/j.dmd.2025.100035","url":null,"abstract":"<p><p>Distinct differences between sexes exist in various cardiovascular diseases. Moreover, there is a significant correlation between the pathogenesis of cardiac hypertrophy (CH) and the metabolites of arachidonic acid (AA) mediated by cytochrome P450 (CYP) enzymes. The potential link between these sex differences, the levels and the activity of CYP enzymes, and their AA-mediated metabolites remains to be elucidated. Male and female Sprague Dawley rats were injected with 1 mg/kg isoproterenol for 7 days to induce CH. Echocardiography was performed before and after the induction of CH. The hypertrophic markers and CYP enzyme levels were analyzed at the gene and protein levels using real-time polymerase chain reaction and Western blot, respectively. Heart microsomal proteins were incubated with AA, and the resulting metabolites were quantified using liquid chromatography-tandem mass spectrometry. Both sexes showed a significant degree of CH, albeit to varying extents, as the echocardiograph, heart weight/tibial length, and left ventricular parameters proved. In addition, the β/α-myosin heavy chain was 2-fold higher in male compared with female rats. Albeit the 20-hydroxyeicosatetraenoic acid (20-HETE) metabolite formation showed no increase in both sexes, the mid-chain HETEs (5- and 15-HETE) were higher in male rats, which paralleled the increase in the gene and protein levels of CYP1B1. The formation rate of the epoxyeicosatrienoic acids was almost unchanged in female-treated rats, while it was significantly decreased in male-treated rats. Our results suggest sexual dimorphism in the isoproterenol-induced CH in rats, specifically on the level of CYP enzymes and their AA-mediated metabolites. SIGNIFICANCE STATEMENT: Sexual dimorphism was observed in rats following isoproterenol-induced cardiac hypertrophy, with males showing a stronger hypertrophic response. This was linked to higher CYP1B1 gene and protein expression in males, along with sex-related differences in many cytochrome P450 enzyme activities and their mediated arachidonic acid metabolites. These findings emphasized the need for targeted, sex-specific therapeutic strategies for the management and treatment of cardiac hypertrophy and other cardiovascular disorders.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100035"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074333","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":"Pharmacokinetics and absorption, distribution, metabolism and excretion profiling of tanimilast following an intravenous ¹⁴C-microtracer coadministered with an inhaled dose in healthy male individuals.","authors":"Michele Bassi, Veronica Puviani, Debora Santoro, Sonia Biondaro, Aida Emirova, Mirco Govoni","doi":"10.1124/dmd.124.001895","DOIUrl":"https://doi.org/10.1124/dmd.124.001895","url":null,"abstract":"<p><p>Tanimilast is an inhaled phosphodiesterase-4 inhibitor currently in phase III clinical development for treating chronic obstructive pulmonary disease and asthma. This trial aimed to characterize the pharmacokinetics, mass balance, and metabolite profiling of tanimilast. Eight healthy male volunteers received a single dose of nonradiolabeled tanimilast via powder inhaler (Chiesi NEXThaler [3200 μg]), followed by a concomitant intravenous infusion of a microtracer ([¹⁴C]-tanimilast: 18.5 μg and 500 nCi). Plasma, whole blood, urine, and feces samples were collected up to 240 hours after dose to quantify nonradiolabeled tanimilast, [¹⁴C]-tanimilast, and total-[¹⁴C]. The inhaled absolute bioavailability of tanimilast was found to be approximately 50%. Following intravenous administration of [¹⁴C]-tanimilast, plasma clearance was 22 L/h, the steady-state volume of distribution was 201 L, and the half-life was shorter compared to inhaled administration (14 vs 39 hours, respectively), suggesting that plasma elimination is limited by the absorption rate from the lungs. Seventy-nine percent (71% in feces; 8% in urine) of the intravenous dose was recovered in excreta as total-[¹⁴C]. [¹⁴C]-tanimilast was the major radioactive compound in plasma, whereas no recovery was observed in urine and only 0.3% was recovered in feces, indicating predominant elimination through metabolic route. Importantly, as far as no metabolites accounting for more than 10% of the circulating drug-related exposure in plasma or the administered dose in excreta were detected, no further qualification is required according to regulatory guidelines. This study design successfully characterized the absorption, distribution, and elimination of tanimilast, providing key pharmacokinetic parameters to support its clinical development and regulatory application. SIGNIFICANCE STATEMENT: This trial investigates pharmacokinetic and absorption, distribution, metabolism and excretion profile of tanimilast, an inhaled phosphodiesterase-4 inhibitor for chronic obstructive pulmonary disease and asthma. Eight male volunteers received a dose of nonradiolabeled tanimilast via Chiesi NEXThaler and a microtracer intravenous dose. Results show pivotal pharmacokinetic results for the characterization of tanimilast, excretion route and quantification of significant metabolites, facilitating streamlined clinical development and regulatory approval.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100009"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064375","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 pharmacokinetic modeling of small molecules: How much progress have we made?","authors":"Nina Isoherranen","doi":"10.1124/dmd.123.000960","DOIUrl":"10.1124/dmd.123.000960","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic (PBPK) models of small molecules have become mainstream in drug development and in academic research. The use of PBPK models is continuously expanding, with the majority of work now focusing on predictions of drug-drug interactions, drug-disease interactions, and changes in drug disposition across lifespan. Recently, publications that use PBPK modeling to predict drug disposition during pregnancy and in organ impairment have increased reflecting the advances in incorporating diverse physiologic changes into the models. Because of the expanding computational power and diversity of modeling platforms available, the complexity of PBPK models has also increased. Academic efforts have provided clear advances in better capturing human physiology in PBPK models and incorporating more complex mathematical concepts into PBPK models. Examples of such advances include the segregated gut model with a series of gut compartments allowing modeling of physiologic blood flow distribution within an organ and zonation of metabolic enzymes and series compartment liver models allowing simulations of hepatic clearance for high extraction drugs. Despite these advances in academic research, the progress in assessing model quality and defining model acceptance criteria based on the intended use of the models has not kept pace. This Minireview suggests that awareness of the need for predefined criteria for model acceptance has increased, but many manuscripts still lack description of scientific justification and/or rationale for chosen acceptance criteria. As artificial intelligence and machine learning approaches become more broadly accepted, these tools offer promise for development of comprehensive assessment for existing observed data and analysis of model performance. SIGNIFICANCE STATEMENT: Physiologically based pharmacokinetic (PBPK) modeling has become a mainstream application in academic literature and is broadly used for predictions, analysis, and evaluation of pharmacokinetic data. Significant progress has been made in developing advanced PBPK models that better capture human physiology, but oftentimes sufficient justification for the chosen model acceptance criterion and model structure is still missing. This Minireview provides a summary of the current landscape of PBPK applications used and highlights the need for advancing PBPK modeling science and training in academia.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100013"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064348","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":"Heterotropic allosteric modulation of CYP3A4 in vitro by progesterone: Evidence for improvement in prediction of time-dependent inhibition for macrolides.","authors":"Luc R A Rougée, Pooja V Hegde, Kaitlin Shin, Trent L Abraham, Alec Bell, Stephen D Hall","doi":"10.1124/dmd.124.001820","DOIUrl":"https://doi.org/10.1124/dmd.124.001820","url":null,"abstract":"<p><p>Predictions of drug-drug interactions resulting from time-dependent inhibition (TDI) of CYP3A4 have consistently overestimated or mispredicted (ie, false positives) the interaction that is observed in vivo. Recent findings demonstrated that the presence of the allosteric modulator progesterone (PGS) in the in vitro assay could alter the in vitro kinetics of CYP3A4 TDI with inhibitors that interact with the heme moiety, such as metabolic-intermediate complex forming inhibitors. The impact of the presence of 100 μM PGS on the TDI of molecules in the class of macrolides typically associated with metabolic-intermediate complex formation was investigated. The presence of PGS resulted in varied responses across the inhibitors tested. The TDI signal was eliminated for 5 inhibitors, and unaltered in the case of 1, fidaxomicin. The remaining molecules erythromycin, clarithromycin, and troleandomycin were observed to have a decrease in both potency and maximum inactivation rate ranging from 1.7- to 6.7-fold. These changes in TDI kinetics led to a >90% decrease in inactivation efficiency. To determine in vitro conditions that could reproduce in vivo inhibition, varied concentrations of PGS were incubated with clarithromycin and erythromycin. The resulting in vitro TDI kinetics were incorporated into dynamic physiologically based pharmacokinetic models to predict clinically observed interactions. The results suggested that a concentration of ∼45 μM PGS would result in TDI kinetic values that could reproduce in vivo observations and could potentially improve predictions for CYP3A4 TDI. SIGNIFICANCE STATEMENT: The impact of the allosteric heterotropic modulator progesterone on the CYP3A4 time-dependent inhibition kinetics was quantified for a set of metabolic-intermediate complex forming mechanism-based inhibitors. We identify the in vitro conditions that optimally predict time-dependent inhibition for in vivo drug-drug interactions through dynamic physiologically based pharmacokinetic modeling. The optimized assay conditions improve in vitro to in vivo translation and prediction of time-dependent inhibition.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 1","pages":"100006"},"PeriodicalIF":4.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064359","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}