Drug Metabolism and Disposition最新文献

{"title":"Decreased expression of P-glycoprotein in the placenta of women with autoimmune disease.","authors":"Angela Pollinzi, Kamelia Mirdamadi, Navaz Karimian Pour, Rashi Asthana-Nijjar, Dennis Lee, Ori Nevo, Micheline Piquette-Miller","doi":"10.1016/j.dmd.2024.100031","DOIUrl":"10.1016/j.dmd.2024.100031","url":null,"abstract":"<p><p>Autoimmune diseases (ADs), such as systemic lupus erythematosus (SLE), require multiple medications to ensure maternal-fetal health during pregnancy. These medications are often substrates for placental transporters that could cross over to the fetal compartment. However, the effects of ADs on placental transporters remain poorly understood. This study aimed to investigate the impact of ADs on placental transporters and key inflammatory cytokines. Human preterm and term placentas from AD-affected women (n = 28) and gestational age-matched controls (n = 38) were collected. The placentas were examined for transporter expression via quantitative real-time PCR and immunodetection. Subgroup analysis and untargeted proteomic analysis of samples from patients with SLE were performed. P-glycoprotein (P-gp/ABCB1) and organic anion transporter 4 (OAT4/SLC22A11) mRNA expression were significantly decreased and expression of T helper 17- associated cytokines were increased in preterm and term AD placenta relative to controls. P-gp protein expression was also downregulated in preterm, but not in term AD placenta. Subgroup analysis of SLE also detected downregulation of P-gp and OAT4 at the mRNA level in preterm samples. Proteomic analysis of SLE and control samples indicated global changes in proteins related to processes like inflammation, oxidative stress, angiogenesis, and hemostasis. These findings elucidate that ADs such as SLE are associated with the downregulation of the ABC transporter P-gp in the placenta as well as global changes to the placenta proteome. Dysregulation of cytokines and associated pathways was also observed and postulated to cause changes in placental transporters. Future studies that validate these mechanisms could offer potential strategies to mitigate inflammation-mediated alterations in placental transporters, ultimately improving fetal and neonatal health. SIGNIFICANCE STATEMENT: Autoimmune diseases have significant effects on the placenta, influencing pregnancy outcomes and the effectiveness of prescribed medications. The study revealed that autoimmune diseases induce inflammatory cytokines in the placenta and were associated with a significant downregulation of P-glycoprotein. Additionally, in patients affected by lupus, proteomics uncovered the enrichment of pathways associated with placental damage and dysfunction. This work will help inform care plans for these patients by identifying clinically relevant proteins that are affected by the disease, improving maternal-fetal outcomes.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100031"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536513","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":"Cannabidiol and Δ9-tetrahydrocannabinol induce drug-metabolizing enzymes, but not transporters, in human hepatocytes: Implications for predicting complex cannabinoid-drug interactions.","authors":"Ankit Balhara, Yik Pui Tsang, Jashvant D Unadkat","doi":"10.1016/j.dmd.2025.100037","DOIUrl":"10.1016/j.dmd.2025.100037","url":null,"abstract":"<p><p>Cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC) can inhibit multiple CYPs and UGTs in vivo and/or in vitro. CBD, but not THC, is also a time-dependent inhibitor of CYP3A, CYP1A2, and CYP2C19. We showed that a single 640 mg oral dose of CBD inhibits oral midazolam plasma clearance by 56%, whereas others found no interaction of chronic CBD with midazolam. These data can be explained if chronic CBD induces CYP3A enzymes. To investigate if CBD or THC induces CYP enzymes or transporters, we treated 4 lots of human hepatocytes for 72 hours with in vivo relevant concentrations of CBD (42 nM, 420 nM) or THC (250 nM, 700 nM). Then, mRNA expression and CYP activity were measured using quantitative polymerase chain reaction and liquid chromatography-tandem mass spectrometry, respectively. CYP3A4 mRNA was significantly induced to 7.3-, 11.1-, and 3.3-fold by CBD (420 nM) and 14.8-, 5.9-, and 3.1-fold by THC (700 nM) in 3 of the 4 lots. CYP3A activity was significantly induced 3.39- and 3.28-fold by low (42 nM) and 2.4- and 2.3-fold by high (420 nM) CBD concentrations, respectively, in 2 lots, and 2.3-fold by THC (700 nM) in 1 lot. Rifampin (10 μM) significantly induced CYP3A mRNA and activity across all lots. CBD (420 nM) significantly induced CYP1A2 and CYP2B6 mRNA (but not activity) in 2 lots. No significant induction of other CYPs, UGTs, or transporters was observed. Incorporation of CBD E_max and EC₅₀ of CYP3A4 mRNA induction (without scaling by rifampin mRNA induction) into a CBD physiologically-based pharmacokinetic model successfully captured the lack of the observed chronic CBD-midazolam drug interaction. SIGNIFICANCE STATEMENT: Time-dependent inhibition and induction of CYP3A enzymes by cannabidiol (CBD) is a plausible explanation for the significant CBD-midazolam pharmacokinetic interaction after single-dose CBD administration and the absence of such an interaction after multiple-dose CBD administration.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100037"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515055","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":"Improvement in static and dynamic projections of drug-drug interactions caused by cytochrome P4503A time-dependent inhibitors through in vitro allosteric modulation by progesterone.","authors":"Pooja Hegde, Brianna Rodriguez, Alec Bell, Stephen D Hall, Luc R A Rougée","doi":"10.1016/j.dmd.2024.100030","DOIUrl":"10.1016/j.dmd.2024.100030","url":null,"abstract":"<p><p>Current drug discovery screens to assess the drug-drug interaction (DDI) risk caused by time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 are known to overpredict or produce false positives that do not translate in vivo. Recent work identified that inclusion of the allosteric modulator progesterone (PGS), at a concentration of 45 μM to human liver microsomal incubations, generated in vitro TDI values that replicated clinical DDI predictions for 2 well established mechanism-based inhibitors. Further application of this approach across a diverse set of compounds was undertaken in this study, with 56 molecules reported in literature as time-dependent inhibitors in vitro tested in the human liver microsomal TDI kinetic assay in the absence and presence of 45 μM PGS. No TDI signal was observed for 15 molecules under control conditions despite literature reports. For the remaining compounds observed to have a TDI signal under control conditions, presence of PGS modified the inactivation efficiency for 36 compounds and eliminated the TDI signal for 5 compounds that were false positives. In vitro kinetic values were incorporated into mechanistic static and dynamic physiologically based pharmacokinetic models to project DDIs. TDI parameters established in the presence of PGS decreased the magnitude of overprediction while maintaining a high sensitivity (96% and 100%) for the detection of TDI with improved specificity (69% and 89%) when using mechanistic static and dynamic models, respectively. Inclusion of PGS into in vitro TDI assays provides a simple, rapid, and cost-effective solution for identifying true CYP3A4 TDIs and improving TDI-related DDI predictions. SIGNIFICANCE STATEMENT: The impact of the previously determined optimal concentration of the allosteric modulator progesterone (45 μM) was evaluated across a set of 56 compounds reported to be time-dependent inhibitors in vitro. In vitro generated values were incorporated into mechanistic static and physiologically based pharmacokinetic models to predict extent of drug-drug interactions and compared to clinical reports. Inclusion of progesterone into the assay identified in vitro false positives and improved risk predictions.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100030"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536715","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":"Exploring cytochrome P450 under hypoxia: potential pharmacological significance in drug metabolism and protection against high-altitude diseases.","authors":"Qian Wang, Guiqin Liu, Yabin Duan, Delong Duo, Junbo Zhu, Xiangyang Li","doi":"10.1016/j.dmd.2024.100026","DOIUrl":"10.1016/j.dmd.2024.100026","url":null,"abstract":"<p><p>High-altitude hypoxia affects the human respiratory, central nervous, cardiovascular, and endocrine systems. These outcomes affect the expression of cytochrome P450 (CYP), the most important family of metabolic enzymes in the body that is involved in the metabolism of both exogenous and endogenous substances (such as arachidonic acid, vitamins, and steroids). Hypoxia influences CYP expression and activity, mediating changes in drug and endogenous substance metabolism, with endogenous metabolites playing a significant role in controlling high-altitude diseases. However, the mechanisms regulating CYP changes under hypoxic conditions and the effects of CYP changes on drug and endogenous metabolism remain unclear. We explored how changes in CYP expression and activity during hypoxia affect the metabolism of drugs and endogenous substances, such as arachidonic acid, vitamins, and steroid hormones, and how CYPs are controlled by nuclear receptors, epigenetic modifications, cytokines, and gut microbiota during hypoxia. Special attention will also be given to the complex role of CYP and its metabolites in the pathophysiology of high-altitude diseases to provide valuable insights for plateau medicine research. SIGNIFICANCE STATEMENT: Cytochrome P450 is a class of monooxygenases that metabolize xenobiotics and endogenous substances. Hypoxia affects the expression and activity of cytochrome P450, and this in turn affects the metabolism of drugs and endogenous substances, leading to altered clinical efficacy and the development of hypoxia-associated diseases. A comprehensive understanding of the changes and regulatory mechanisms of cytochrome P450 under hypoxic conditions can improve therapeutic protocols in hypoxic environments and provide new ideas for the targeted treatment of hypoxic diseases.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"53 2","pages":"100026"},"PeriodicalIF":4.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536694","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":"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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12105745/pdf/","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":"OA","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":"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":"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":"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":"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":"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}