Biopharmaceutics & Drug Disposition最新文献_第7页

Predicting transporter mediated drug–drug interactions via static and dynamic physiologically based pharmacokinetic modeling: A comprehensive insight on where we are now and the way forward 通过基于静态和动态生理的药代动力学模型预测转运蛋白介导的药物-药物相互作用:对我们现在和未来发展方向的全面洞察

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-11-22 DOI: 10.1002/bdd.2339

Gautam Vijaywargi, Sivacharan Kollipara, Tausif Ahmed, Siddharth Chachad

{"title":"Predicting transporter mediated drug–drug interactions via static and dynamic physiologically based pharmacokinetic modeling: A comprehensive insight on where we are now and the way forward","authors":"Gautam Vijaywargi, Sivacharan Kollipara, Tausif Ahmed, Siddharth Chachad","doi":"10.1002/bdd.2339","DOIUrl":"10.1002/bdd.2339","url":null,"abstract":"The greater utilization and acceptance of physiologically-based pharmacokinetic (PBPK) modeling to evaluate the potential metabolic drug–drug interactions is evident by the plethora of literature, guidance's, and regulatory dossiers available in the literature. In contrast, it is not widely used to predict transporter-mediated DDI (tDDI). This is attributed to the unavailability of accurate transporter tissue expression levels, the absence of accurate in vitro to in vivo extrapolations (IVIVE), enzyme-transporter interplay, and a lack of specific probe substrates. Additionally, poor understanding of the inhibition/induction mechanisms coupled with the inability to determine unbound concentrations at the interaction site made tDDI assessment challenging. Despite these challenges, continuous improvements in IVIVE approaches enabled accurate tDDI predictions. Furthermore, the necessity of extrapolating tDDI's to special (pediatrics, pregnant, geriatrics) and diseased (renal, hepatic impaired) populations is gaining impetus and is encouraged by regulatory authorities. This review aims to visit the current state-of-the-art and summarizes contemporary knowledge on tDDI predictions. The current understanding and ability of static and dynamic PBPK models to predict tDDI are portrayed in detail. Peer-reviewed transporter abundance data in special and diseased populations from recent publications were compiled, enabling direct input into modeling tools for accurate tDDI predictions. A compilation of regulatory guidance's for tDDI's assessment and success stories from regulatory submissions are presented. Future perspectives and challenges of predicting tDDI in terms of in vitro system considerations, endogenous biomarkers, the use of empirical scaling factors, enzyme-transporter interplay, and acceptance criteria for model validation to meet the regulatory expectations were discussed.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 3","pages":"195-220"},"PeriodicalIF":2.1,"publicationDate":"2022-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9732420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: Advances, challenges, and future perspectives 寡核苷酸治疗药物在中枢神经系统的生物分布和递送:进展、挑战和未来展望

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-11-05 DOI: 10.1002/bdd.2338

Akihiko Goto, Syunsuke Yamamoto, Shinji Iwasaki

{"title":"Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: Advances, challenges, and future perspectives","authors":"Akihiko Goto, Syunsuke Yamamoto, Shinji Iwasaki","doi":"10.1002/bdd.2338","DOIUrl":"10.1002/bdd.2338","url":null,"abstract":"Considerable advances have been made in the research and development of oligonucleotide therapeutics (OTs) for treating central nervous system (CNS) diseases, such as psychiatric and neurodegenerative disorders, because of their promising mode of action. However, due to the tight barrier function and complex physiological structure of the CNS, the efficient delivery of OTs to target the brain has been a major challenge, and intensive efforts have been made to overcome this limitation. In this review, we summarize the representative methodologies and current knowledge of biodistribution, along with the pharmacokinetic/pharmacodynamic (PK/PD) relationship of OTs in the CNS, which are critical elements for the successful development of OTs for CNS diseases. First, quantitative bioanalysis methods and imaging-based approaches for the evaluation of OT biodistribution are summarized. Next, information available on the biodistribution profile, distribution pathways, quantitative PK/PD modeling, and simulation of OTs following intrathecal or intracerebroventricular administration are reviewed. Finally, the latest knowledge on the drug delivery systems to the brain via intranasal or systemic administration as noninvasive routes for improved patient quality of life is reviewed. The aim of this review is to enrich research on the successful development of OTs by clarifying OT distribution profiles and pathways to the target brain regions or cells, and by identifying points that need further investigation for a mechanistic approach to generate efficient OTs.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"26-47"},"PeriodicalIF":2.1,"publicationDate":"2022-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9135496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

In vitro–in vivo extrapolation of bexarotene metabolism in the presence of chronic kidney disease and acute kidney injury in rat using physiologically based pharmacokinetic modeling and extrapolation to human 利用基于生理的药代动力学模型和外推法对慢性肾脏疾病和急性肾损伤大鼠贝沙罗汀代谢进行体内外推

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-11-01 DOI: 10.1002/bdd.2337

Mo'tasem M. Alsmadi, Saja B. Alzughoul

{"title":"In vitro–in vivo extrapolation of bexarotene metabolism in the presence of chronic kidney disease and acute kidney injury in rat using physiologically based pharmacokinetic modeling and extrapolation to human","authors":"Mo'tasem M. Alsmadi, Saja B. Alzughoul","doi":"10.1002/bdd.2337","DOIUrl":"10.1002/bdd.2337","url":null,"abstract":"Renal impairment can affect the elimination of hepatically metabolized drugs. Bexarotene (BXT) used for cutaneous T-cell lymphoma is highly bound in plasma and metabolized by CYP3A4. The BXT European Medicine Agency and Food and Drug Administration packages recommended the evaluation of renal impairment on BXT metabolism. The plasma protein binding of BXT can be changed in patients with renal dysfunction due to hypoalbuminemia and accumulation of uremic toxins. In vitro, microsomal stability and plasma protein binding studies were pursued. A preclinical pharmacokinetic study was pursued in control, chronic kidney disease (CKD), and acute kidney injury (AKI) rats. A BXT physiologically based pharmacokinetic (PBPK) model that utilized in vitro–in vivo extrapolation of metabolism was established and verified in healthy rats, customized to CKD and AKI rats, and extrapolated to healthy human subjects and those with CKD stages 3, 4, and 5. In vitro studies showed that AKI and CKD significantly increased the BXT fraction unbound in plasma (from 0.011 to 0.018 and 0.022, respectively) and decreased intrinsic clearance (from 4.1 to 2.5, and 2.2 mL/min/g liver, respectively). This could explain the reduced in vivo clearance observed in CKD rats (from 0.4 to 0.28 L/h/kg) and the 1.3-fold increase in BXT exposure. Changes in BXT disposition in AKI rats were not straightforward due to simultaneous changes in BXT distribution. The human PBPK model predicted an increased BXT exposure by 2-fold in CKD patients, suggesting the need for dose reduction and drug monitoring. The reduced BXT metabolism due to renal impairment is especially relevant in cancer patients with CKD.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 3","pages":"221-244"},"PeriodicalIF":2.1,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10091795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Intestinal absorption pathways of lisinopril: Mechanistic investigations 赖诺普利的肠道吸收途径:机理研究

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-26 DOI: 10.1002/bdd.2336

Sarah H. Elewa, Mohamed A. Osman, Ebtessam A. Essa, Amal A. Sultan

{"title":"Intestinal absorption pathways of lisinopril: Mechanistic investigations","authors":"Sarah H. Elewa, Mohamed A. Osman, Ebtessam A. Essa, Amal A. Sultan","doi":"10.1002/bdd.2336","DOIUrl":"10.1002/bdd.2336","url":null,"abstract":"Lisinopril is an antihypertensive drug with poor intestinal permeability. Enhancement of intestinal absorption depends on a clear understanding of the permeation pathways and absorption mechanisms. Unfortunately, these are not fully elucidated for lisinopril. Accordingly, the aim was to determine lisinopril permeation pathways and obstacles limiting membrane transport with subsequent nomination of appropriate permeation enhancers. This employed an in situ rabbit intestinal perfusion technique, which revealed site-dependent absorptive clearance (PeA/L) from a lisinopril simple solution (5 μg/ml), with paracellular absorption playing a role. Regional drug permeability ranked as colon> duodenum> jejunum> ileum opposing intestinal expression rank of P-glycoprotein (P-gp) efflux transporters. Duodenal and jejunal perfusion of a higher lisinopril concentration (50 μg/ml) reflected saturable absorption, suggesting carrier-mediated transport. The effect of piperine and verapamil as P-gp inhibitors on intestinal absorption of lisinopril was investigated. Coperfusion with either piperine or verapamil significantly enhanced lisinopril absorption, with enhancement being dominant in the ileum segment. This supported the contribution of P-gp transporters to poor lisinopril permeability. On the other hand, coperfusion of lisinopril with zinc acetate dihydrate significantly multiplied lisinopril PeA/L by 2.3- and 6.6-fold in duodenum and ileum segments, respectively, through magnifying intestinal water flux. The study explored the barriers limiting lisinopril intestinal absorption. Moreover, the study exposed clinically relevant lisinopril interactions with common coadministered cargos that should be considered for an appropriate lisinopril regimen. However, this requires further in vivo verification.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 6","pages":"233-246"},"PeriodicalIF":2.1,"publicationDate":"2022-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10441082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiologically based pharmacokinetic model to predict drug concentrations of breast cancer resistance protein substrates in milk 基于生理的药代动力学模型预测乳中乳腺癌耐药蛋白底物的药物浓度

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-20 DOI: 10.1002/bdd.2335

Tao Zhang, Peng Zou, Yingsi Fang, Yanyan Li

{"title":"Physiologically based pharmacokinetic model to predict drug concentrations of breast cancer resistance protein substrates in milk","authors":"Tao Zhang, Peng Zou, Yingsi Fang, Yanyan Li","doi":"10.1002/bdd.2335","DOIUrl":"10.1002/bdd.2335","url":null,"abstract":"Many mothers need to take some medications during breastfeeding, which may carry a risk to breastfed infants. Thus, determining the amount of a drug transferred into breast milk is critical for risk–benefit analysis of breastfeeding. Breast cancer resistance protein (BCRP), an efflux transporter which usually protects the body from environmental and dietary toxins, was reported to be highly expressed in lactating mammary glands. In this study, we developed a mechanistic lactation physiologically based pharmacokinetic (PBPK) modeling approach incorporating BCRP mediated transport kinetics to simulate the concentration–time profiles of five BCRP drug substrates (acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin) in nursing women’s plasma and milk. Due to the lack of certain physiological parameters and scaling factors in nursing women, we combine the bottom up and top down PBPK modeling approaches together with literature reported data to optimize and determine a set of parameters that are applicable for all five drugs. The predictive performance of the PBPK models was assessed by comparing predicted pharmacokinetic profiles and the milk-to-plasma (M/P) ratio with clinically reported data. The predicted M/P ratios for acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin were 2.48, 3.70, 3.55, 1.21, and 5.78, which were all within 1.5-fold of the observed values. These PBPK models are useful to predict the PK profiles of those five drugs in the milk for different dosing regimens. Furthermore, the approach proposed in this study will be applicable to predict pharmacokinetics of other transporter substrates in the milk.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 6","pages":"221-232"},"PeriodicalIF":2.1,"publicationDate":"2022-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10487429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Prediction of basic drug exposure in milk using a lactation model algorithm integrated within a physiologically based pharmacokinetic model 利用基于生理的药代动力学模型集成的哺乳模型算法预测牛奶中的基本药物暴露

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-09 DOI: 10.1002/bdd.2334

Amita Pansari, Muhammad Faisal, Masoud Jamei, Khaled Abduljalil

{"title":"Prediction of basic drug exposure in milk using a lactation model algorithm integrated within a physiologically based pharmacokinetic model","authors":"Amita Pansari, Muhammad Faisal, Masoud Jamei, Khaled Abduljalil","doi":"10.1002/bdd.2334","DOIUrl":"10.1002/bdd.2334","url":null,"abstract":"Medication use during breastfeeding can be a matter of concern due to unintended infant exposure to drugs through breast milk. The available information relating to the safety of most medications is limited and may vary. More precise information is needed regarding the safety to the newborn or infants of the medications taken by the mother during breastfeeding. Physiologically based Pharmacokinetic Model (PBPK) approaches can be utilized to predict the drug exposure in the milk of breastfeeding women and can act as a supporting tool in the risk assessment of feeding infants. This study aims to assess the predictive performance of an integrated ‘log transformed phase-distribution’ lactation model within a PBPK platform. The model utilizes the physicochemical properties of four basic drugs, namely tramadol, venlafaxine, fluoxetine, and paroxetine, and analyses the milk compositions to predict the milk-to-plasma (M/P) ratio. The M/P prediction model was incorporated within the Simcyp Simulator V20 to predict the milk exposure and to estimate the likely infant dose for these drugs. The PBPK models adequately predicted the maternal plasma exposure, M/P ratio, and the infant daily dose to within two-fold of the clinically observed values for all four compounds. Integration of the lactation model within PBPK models facilitates the prediction of drug exposure in breast milk. The developed model can inform the design of lactation studies and assist with the neonatal risk assessment after maternal exposure to such environmental chemicals or basic drugs which diffuse passively into the milk.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 5","pages":"201-212"},"PeriodicalIF":2.1,"publicationDate":"2022-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33493629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

The role of the efflux transporter, P-glycoprotein, at the blood–brain barrier in drug discovery 血脑屏障外排转运蛋白p -糖蛋白在药物发现中的作用

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-05 DOI: 10.1002/bdd.2331

Benoit Cox, Johan Nicolaï, Beth Williamson

{"title":"The role of the efflux transporter, P-glycoprotein, at the blood–brain barrier in drug discovery","authors":"Benoit Cox, Johan Nicolaï, Beth Williamson","doi":"10.1002/bdd.2331","DOIUrl":"10.1002/bdd.2331","url":null,"abstract":"The blood–brain barrier (BBB) expresses a high abundance of transporters, particularly P-glycoprotein (P-gp), that regulate endogenous and exogenous molecule uptake and removal of waste. This review discusses key drug metabolism and pharmacokinetic considerations for the efflux transporter P-gp at the BBB in drug discovery and development. We highlight the differences in P-gp expression and protein levels across species but the limited observations of species-specific substrates. Given the impact of age and disease on BBB biology, we summarise the modulation of P-gp for several neurological disorders and ageing and exemplify several disease-specific hurdles or opportunities for drug exposure in the brain. Furthermore, the review includes observations of CNS-related drug-drug interactions due to the inhibition or induction of P-gp at the BBB in animal studies and humans and the need for continued evaluation especially for compounds with a narrow therapeutic window. This review focusses primarily on small molecules but also considers the impact of new chemical entities, particularly beyond Ro5 molecules and their potential to be recognised as P-gp substrates as well as advanced drug delivery systems which offer an alternative approach to achieve and sustain central nervous system exposure.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"113-126"},"PeriodicalIF":2.1,"publicationDate":"2022-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9494138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Evaluation of bleeding and anticoagulation markers by edoxaban and low-dose cyclosporine: A case series study 依多沙班和低剂量环孢素对出血和抗凝指标的评价:一个病例系列研究

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-04 DOI: 10.1002/bdd.2332

Toshinori Hirai, Yuri Shinogi, Makoto Ikejiri, Tomohiro Murata, Takuya Iwamoto

{"title":"Evaluation of bleeding and anticoagulation markers by edoxaban and low-dose cyclosporine: A case series study","authors":"Toshinori Hirai, Yuri Shinogi, Makoto Ikejiri, Tomohiro Murata, Takuya Iwamoto","doi":"10.1002/bdd.2332","DOIUrl":"10.1002/bdd.2332","url":null,"abstract":"It was reported that high-dose cyclosporine at 500 mg daily increases edoxaban exposure. We investigated whether cyclosporine <500 mg daily leads to edoxaban-induced bleeding in the clinical setting. This case series study included patients receiving edoxaban and cyclosporine at Mie University Hospital. The outcomes were bleeding and anticoagulant markers, including activated partial thromboplastin time (APTT), prothrombin time (PT), and the international normalized ratio of prothrombin time (PT-INR). We examined the genotypes of cytochrome P450 3A5 (CYP3A5), multidrug resistance 1 (ABCB1), and solute carrier organic anion transporter 1B1 (SLCO1B1). Trends in anticoagulant markers were analyzed. Thirteen patients received edoxaban (standard dose; n = 3 and reduced dose; n = 10) and cyclosporine (1.94 ± 1.42 mg/kg). A bleeding event occurred in one patient receiving a standard dose of edoxaban plus cyclosporine of 25 mg daily (HAS-BLED score of 2 and genotypes; CYP3A5*3/*3, ABCB1 3435CT, and SLCO1B1*1a/*1b). After edoxaban treatment, anticoagulant markers were prolonged (APTT; 27.95 ± 3.64 s vs. 31.11 ± 3.90 s, p < 0.001, PT; 11.53 ± 1.01 s vs. 13.03 ± 0.98 s, p = 0.002, PT-INR; 0.98 ± 0.09 vs. 1.11 ± 0.11, p = 0.007). In summary, the genotypes of CYP3A5, ABCB1, and SLCO1B1 and the dosage of edoxaban may affect the risk of bleeding by edoxaban when co-administered with cyclosporine, even at low doses.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 5","pages":"192-200"},"PeriodicalIF":2.1,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33487342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of canalicular and sinusoidal taurocholate efflux by cholestatic drugs in human hepatoma HepaRG cells 抑胆药对人肝癌HepaRG细胞小管和窦型牛磺胆酸外排的抑制作用

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-04 DOI: 10.1002/bdd.2333

Marc Le Vée, Amélie Moreau, Elodie Jouan, Claire Denizot, Yannick Parmentier, Olivier Fardel

{"title":"Inhibition of canalicular and sinusoidal taurocholate efflux by cholestatic drugs in human hepatoma HepaRG cells","authors":"Marc Le Vée, Amélie Moreau, Elodie Jouan, Claire Denizot, Yannick Parmentier, Olivier Fardel","doi":"10.1002/bdd.2333","DOIUrl":"10.1002/bdd.2333","url":null,"abstract":"HepaRG cells are highly-differentiated human hepatoma cells, which are increasingly recognized as a convenient cellular model for in vitro evaluation of hepatic metabolism, transport, and/or toxicity of drugs. The present study was designed to evaluate whether HepaRG cells can also be useful for studying drug-mediated inhibition of canalicular and/or sinusoidal hepatic efflux of bile acids, which constitutes a major mechanism of drug-induced liver toxicity. For this purpose, HepaRG cells, initially loaded with the bile acid taurocholate (TC), were reincubated in TC-free transport assay medium, in the presence or absence of calcium or drugs, before analysis of TC retention. This method allowed us to objectivize and quantitatively measure biliary and sinusoidal efflux of TC from HepaRG cells, through distinguishing cellular and canalicular compartments. In particular, time-course analysis of the TC-free reincubation period of HepaRG cells, that is, the efflux period, indicated that a 20 min-efflux period allowed reaching biliary and sinusoidal excretion indexes for TC around 80% and 60%, respectively. Addition of the prototypical cholestatic drugs bosentan, cyclosporin A, glibenclamide, or troglitazone during the TC-free efflux phase period was demonstrated to markedly inhibit canalicular and sinusoidal secretion of TC, whereas, by contrast, incubation with the noncholestatic compounds salicylic acid or flumazenil was without effect. Such data therefore support the use of human HepaRG cells for in vitro predicting drug-induced liver toxicity (DILI) due to the inhibition of hepatic bile acid secretion, using a biphasic TC loading/efflux assay.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 6","pages":"265-271"},"PeriodicalIF":2.1,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/18/ae/BDD-43-265.PMC10092305.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9650970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Estimation of fraction of drug metabolism by a single UDP-glucuronosyl transferase enzyme using relative expression factor 用相对表达因子估计单udp -葡萄糖醛基转移酶的药物代谢分数

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-09-23 DOI: 10.1002/bdd.2330

Tomoyo Honda, Wataru Obuchi, Yumi Nishiya, Takahiro Shibayama, Kengo Watanabe, Nobuaki Watanabe

{"title":"Estimation of fraction of drug metabolism by a single UDP-glucuronosyl transferase enzyme using relative expression factor","authors":"Tomoyo Honda, Wataru Obuchi, Yumi Nishiya, Takahiro Shibayama, Kengo Watanabe, Nobuaki Watanabe","doi":"10.1002/bdd.2330","DOIUrl":"10.1002/bdd.2330","url":null,"abstract":"The estimation of the contributions of UDP-glucuronosyl transferase (UGT) isoforms to the overall metabolism still suffers from technical difficulties due to limited information on enzyme levels in recombinant systems and specific inhibitors, unlike the case for cytochrome P450s (CYPs). The protein expression levels of UGT in both recombinant system microsomes (RM) and human liver microsomes (HLM) were quantified using liquid chromatography-tandem mass spectrometry, and the relative expression factor (REF) value of HLM to recombinant microsomes was estimated to evaluate the fractions of drug metabolism by a single UGT enzyme (fmUGT) of UGT substrates. The REF values of UGT1A1, UGT1A3, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 were 0.228, 0.0714, 0.0665, 0.420, 0.118, and 0.0442, respectively. fmUGTs in HLM were estimated for several typical UGT substrates utilizing these values and metabolic clearances in RM. These values were comparable to the reported values estimated by various methods. This study provided useful information on REF values, which promote a robust estimation of fmUGT values for UGT substrates when evaluating the contribution of UGT isoforms to total metabolic clearance.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 5","pages":"213-217"},"PeriodicalIF":2.1,"publicationDate":"2022-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33479253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0