Biopharmaceutics & Drug Disposition最新文献

{"title":"Investigating CNS distribution of PF-05212377, a P-glycoprotein substrate, by translation of 5-HT6 receptor occupancy from non-human primates to humans","authors":"Aarti Sawant-Basak,&nbsp;Laigao Chen,&nbsp;Peter Lockwood,&nbsp;Tracey Boyden,&nbsp;Angela C. Doran,&nbsp;Jessica Mancuso,&nbsp;Kenneth Zasadny,&nbsp;Timothy McCarthy,&nbsp;Evan D. Morris,&nbsp;Richard E. Carson,&nbsp;Irina Esterlis,&nbsp;Yiyun Huang,&nbsp;Nabeel Nabulsi,&nbsp;Beata Planeta,&nbsp;Terence Fullerton","doi":"10.1002/bdd.2351","DOIUrl":"https://doi.org/10.1002/bdd.2351","url":null,"abstract":"<p>PF-05212377 (SAM760) is a potent and selective 5-HT₆ antagonist, previously under development for the treatment of Alzheimer’s disease. <i>In vitro</i>, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the <i>in vivo</i> brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (C_bu/C_pu) of 0.05 in rat and 0.64 in non-human primates (NHP). Based on pre-clinical evidence, brain penetration and target engagement of PF-05212377 was confirmed in NHP using positron emission tomography (PET) measured 5-HT₆ receptor occupancy (%RO). The NHP C_pu EC₅₀ of PF-05212377 was 0.31 nM (consistent with the <i>in vitro</i> human 5HT6 K_i: 0.32 nM). P-gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non-human primates and human; brain penetration of PF-05212377 in humans was postulated to be similar to that in non-human primates. In humans, PF-05212377 demonstrated dose and concentration dependent increases in 5-HT₆ RO; maximal 5-HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC₅₀ of 0.37 nM (which was similar to the <i>in vitro</i> human 5HT6 binding K_i 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF-05212377, a P-gp/non-BCRP substrate.</p><p>Clinical trial number: NCT01258751.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"48-59"},"PeriodicalIF":2.1,"publicationDate":"2023-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50142731","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}

{"title":"In vitro and ex vivo experimental models for evaluation of intranasal systemic drug delivery as well as direct nose-to-brain drug delivery","authors":"Anja Haasbroek-Pheiffer,&nbsp;Suzanne Van Niekerk,&nbsp;Frank Van der Kooy,&nbsp;Theunis Cloete,&nbsp;Jan Steenekamp,&nbsp;Josias Hamman","doi":"10.1002/bdd.2348","DOIUrl":"10.1002/bdd.2348","url":null,"abstract":"<p>The intranasal route of administration provides a noninvasive method to deliver drugs into the systemic circulation and/or directly into the brain. Direct nose-to-brain drug delivery offers the possibility to treat central nervous system diseases more effectively, as it can evade the blood–brain barrier. <i>In vitro</i> and <i>ex vivo</i> intranasal models provide a means to investigate physiological and pharmaceutical factors that could play a role in drug delivery across the nasal epithelium as well as to determine the mechanisms involved in drug absorption from the nose. The development and implementation of cost-effective pharmacokinetic models for intranasal drug delivery with good <i>in vitro</i>-<i>in vivo</i> correlation can accelerate pharmaceutical drug product development and improve economic and ecological aspects by reducing the time and costs spent on animal studies. Special considerations should be made with regard to the purpose of the <i>in vitro</i>/<i>ex vivo</i> study, namely, whether it is intended to predict systemic or brain delivery, source and site of tissue or cell sampling, viability window of selected model, and the experimental setup of diffusion chambers. The type of model implemented should suit the relevant needs and requirements of the project, researcher, and interlaboratory. This review aims to provide an overview of <i>in vitro</i> and <i>ex vivo</i> models that have been developed to study intranasal and direct nose-to-brain drug delivery.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"94-112"},"PeriodicalIF":2.1,"publicationDate":"2023-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9149994","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}

{"title":"Recent advances in the in vitro and in vivo methods to assess impact of P-glycoprotein and breast cancer resistance protein transporters in central nervous system drug disposition","authors":"Sagnik Chatterjee,&nbsp;Anup Arunrao Deshpande,&nbsp;Hong Shen","doi":"10.1002/bdd.2345","DOIUrl":"10.1002/bdd.2345","url":null,"abstract":"<p>One challenge in central nervous system (CNS) drug discovery has been ensuring the blood–brain barrier (BBB) penetration of compounds at an efficacious concentration that provides suitable safety margins for clinical investigation. Research providing for the accurate prediction of brain penetration of compounds during preclinical discovery is important to a CNS program. In the BBB, P-glycoprotein (P-gp) (<i>ABCB1</i>) and breast cancer resistance protein (BCRP) (<i>ABCG2</i>) transporters have been demonstrated to play a major role in the active efflux of endogenous compounds and xenobiotics out of the brain microvessel cells and back to the systemic circulation. In the past 10 years, there has been significant technological improvement in the sensitivity of quantitative proteomics methods, <i>in vivo</i> imaging, <i>in vitro</i> methods of organoid and microphysiological systems, as well as <i>in silico</i> quantitative physiological based pharmacokinetic and systems pharmacology models. Scientists continually leverage these advancements to interrogate the distribution of compounds in the CNS which may also show signals of substrate specificity of P-gp and/or BCRP. These methods have shown promise toward predicting and quantifying the unbound concentration(s) within the brain relevant for efficacy or safety. In this review, the authors have summarized the <i>in vivo</i>, <i>in vitro</i>, and proteomics advancements toward understanding the contribution of P-gp and/or BCRP in restricting the entry of compounds to the CNS of either healthy or special populations. Special emphasis has been provided on recent investigations on the application of a proteomics-informed approach to predict steady-state drug concentrations in the brain. Moreover, future perspectives regarding the role of these transporters in newer modalities are discussed.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"7-25"},"PeriodicalIF":2.1,"publicationDate":"2023-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9140543","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}

{"title":"Metabolism and pharmacokinetic study of deuterated osimertinib","authors":"Xuyi Zhan,&nbsp;Shaoyin Bao,&nbsp;Xumei Li,&nbsp;Shaojun Zhou,&nbsp;Maha Raja Dahar,&nbsp;Nengming Lin,&nbsp;Xiugui Chen,&nbsp;Chengshan Niu,&nbsp;Kaige Ji,&nbsp;Yusheng Wu,&nbsp;Kui Zeng,&nbsp;Zhihua Tang,&nbsp;Lushan Yu","doi":"10.1002/bdd.2347","DOIUrl":"10.1002/bdd.2347","url":null,"abstract":"<p>Osimertinib is a highly selective third-generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non-small cell lung cancer. As the substrate of cytochrome P450 enzyme, it is mainly metabolized by the CYP3A enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib-d3) in liver microsomes and human recombinant cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib-d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib-d3 had higher systemic exposure (AUC) and peak concentration (C_max) compared with the osimertinib in rats and human body.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 2","pages":"165-174"},"PeriodicalIF":2.1,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9339547","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}

{"title":"In vivo monitoring of brain pharmacokinetics and pharmacodynamics with cerebral open flow microperfusion","authors":"Thomas Altendorfer-Kroath,&nbsp;Joanna Hummer,&nbsp;Thomas Birngruber","doi":"10.1002/bdd.2343","DOIUrl":"10.1002/bdd.2343","url":null,"abstract":"<p>In vivo investigation of brain pharmacokinetics and pharmacodynamics (PK/PD) is an integral part of neurological drug development. However, drugs intended to act in the brain may reach it at very low concentrations due to the protective effect of the blood–brain barrier (BBB). Consequently, very sensitive measurement methods are required to investigate PK/PD of drugs in the brain. Also, these methods must be capable of continuously assessing cerebral drug concentrations with verifiable intact BBB, as disrupted BBB may lead to compound efflux from blood into brain and to biased results. To date, only a few techniques are available that can sensitively measure drug concentrations in the brain over time; one of which is cerebral open flow microperfusion (cOFM). cOFM's key features are that it enables measurement of cerebral compound concentrations with intact BBB, induces only minor tissue reactions, and that no scar formation occurs around the probe. The membrane-free cOFM probes collect diluted cerebral interstitial fluid (ISF) samples that are containing the whole molecule spectrum of the ISF. Further, combining cOFM with an in vivo calibration protocol (e.g. Zero Flow Rate) enables absolute quantification of compounds in cerebral ISF. In general, three critical aspects have to be considered when measuring cerebral drug concentrations and recording PK/PD profiles with cOFM: (a) the BBB integrity during sampling, (b) the status of the brain tissue next to the cOFM probe during sampling, and (c) the strategy to absolutely quantify drugs in cerebral ISF. This work aims to review recent applications of cOFM for PK/PD assessment with a special focus on these critical aspects.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"84-93"},"PeriodicalIF":2.1,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2343","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9196460","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}

{"title":"Regional distributions of curcumin and tetrahydrocurcumin in the liver and small intestine of rats when orally co-administered with quercetin and paeoniflorin","authors":"Weilan Yu,&nbsp;Xiaolin Liu,&nbsp;Dake Cai,&nbsp;Juntao Zheng,&nbsp;Biaochang Lao,&nbsp;Min Huang,&nbsp;Guoping Zhong","doi":"10.1002/bdd.2346","DOIUrl":"10.1002/bdd.2346","url":null,"abstract":"<p>Curcumin (CUR), derived from the dietary spice turmeric, is a polyphenolic compound with various biological and pharmacological activities. Tetrahydrocurcumin (THC) is one of the major reductive metabolites of curcumin. A pharmacokinetic study using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) for the simultaneous determination of curcumin, THC, quercetin (QR), and paeoniflorin (PF) in rat plasma had been performed. In this study, the regional distributions of curcumin and tetrahydrocurcumin in the liver and the three segments of small intestine (duodenum, jejunum, and ileum) of rats when orally co-administered with quercetin and paeoniflorin were carried out. Drug concentrations were determined using UHPLC-MS/MS. The results showed that curcumin was well distributed in the small intestine, while the distributions of tetrahydrocurcumin in the liver, duodenum, jejunum were similar, but much more abundant in the ileum. When orally co-administered with quercetin and paeoniflorin, the tissue to plasma concentration ratios (K_p values) of curcumin in the three segments of the small intestine were increased, indicating that the presence of quercetin and paeoniflorin increases the distribution of curcumin in these regions. Moreover, the half-life (t_1/2) of THC in the liver was significantly prolonged, and the K_p value of THC in the liver was increased and the K_p values in the small intestine were decreased, suggesting that the combination of quercetin and paeoniflorin might suppress the metabolism of curcumin in the small intestine. In brief, the combination had an effect on the distributions of curcumin and tetrahydrocurcumin in the liver and small intestine of rats.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 2","pages":"183-191"},"PeriodicalIF":2.1,"publicationDate":"2023-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9346846","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}

{"title":"Evaluation of bottom-up modeling of the blood–brain barrier to improve brain penetration prediction via physiologically based pharmacokinetic modeling","authors":"Christine Bowman,&nbsp;Fang Ma,&nbsp;Jialin Mao,&nbsp;Emile Plise,&nbsp;Eugene Chen,&nbsp;Liling Liu,&nbsp;Shu Zhang,&nbsp;Yuan Chen","doi":"10.1002/bdd.2344","DOIUrl":"10.1002/bdd.2344","url":null,"abstract":"<p>Predicting the brain penetration of drugs has been notoriously difficult; however, recently, permeability-limited brain models have been constructed. Lead optimization for central nervous system compounds often focuses on compounds that have low transporter efflux, where passive permeability could be a main driver in determining cerebrospinal fluid (CSF)/brain concentrations. The main objective of this study was to evaluate the translatability of passive permeability data generated from different in vitro systems and its impact on the prediction of human CSF/brain concentrations using physiologically-based pharmacokinetic (PBPK) modeling. In vitro data were generated using gMDCK and parallel artificial membrane permeability assay-blood–brain barrier for comparison and predictions using a quantitative structure-activity relationship model were also evaluated. PBPK modeling was then performed for seven compounds with moderate-high permeability and a range of efflux in vitro, and the CSF/brain mass concentrations and Kpuu were reasonably predicted. This work provides the first step of a promising approach using bottom-up PBPK modeling for CSF/brain penetration prediction to support lead optimization and clinical candidate selection.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"60-70"},"PeriodicalIF":2.1,"publicationDate":"2023-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9142812","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}

{"title":"Special issue on applications of in vitro, in vivo, and modeling and simulation tools for central nervous system drug disposition","authors":"Li Di","doi":"10.1002/bdd.2342","DOIUrl":"10.1002/bdd.2342","url":null,"abstract":"This special issue of Biopharmaceutics and Drug Disposition is a collection of articles intended to provide new insights into recent developments of in silico, in vitro, and in vivo tools to advance our understanding of CNS (central nervous system) drug disposition. Over the last decades, great progress has been made in the field to enable effective CNS drug design and delivery. Here, a few areas of the advances are highlighted. Unbound drug concentration in the brain, rather than the total brain drug concentration, has been widely recognized as the driver for in vivo efficacy (Liu et al., 2014; Smith et al., 2010). Critical factors influencing the rate and extent of brain penetration have been identified (Di & Kerns, 2015; Di et al., 2013; Hammarlund‐Udenaes et al., 2008). Passive permeability across the blood–brain barrier and plasma protein binding are key parameters that control the rate of brain uptake (Di et al., 2020; Trapa et al., 2016). On the other hand, P‐gp (P‐glycoprotein) and BCRP (breast cancer resistance protein) are the most important efflux transporters limiting the extent of brain exposure (Di et al., 2013; Loryan et al., 2022; Trapa et al., 2016). These insights help to develop effective design strategies to enhance or limit brain exposure in order to maximize CNS efficacy or minimize central toxicity. P‐gp and BCRP efflux transporters at the blood–brain barrier play critical roles in limiting brain penetration of many drug candidates. Quantification of transporter proteins at the blood–brain barrier has been a major breakthrough in the past decade (Al Feteisi et al., 2018; Al‐Majdoub et al., 2019; Bao et al., 2020; Billington et al., 2019; Gomez‐Zepeda et al., 2019; Hoshi et al., 2013; Ohtsuki et al., 2013; Sato et al., 2021; Shawahna et al., 2011; Storelli et al., 2021; Uchida et al., 2011, 2020). P‐gp and BCRP protein expression data at the blood–brain barrier have been well‐ documented. This information enables development of PBPK (physiologically‐based pharmacokinetic) models to simulate drug concentration–time profiles in the brain (Murata et al., 2022). PBPK modeling is becoming a valuable tool in preclinical and clinical study design and regulatory review (Grimstein et al., 2019; Zhang et al., 2020). High‐throughput screening assays using P‐gp and BCRP transfected cell lines (e.g. MDR1‐MDCK [multidrug resistance 1— Madin‐Darby canine kidney cell line], BCRP‐MDCK) have been broadly implemented in the pharmaceutical industry to measure efflux ratios of drug candidates. These data are widely applied by medicinal chemists to guide drug design in order to minimize efflux transport and enhance brain penetration. Quality cell lines with high transport expression levels are key to assay sensitivity for identification of efflux transporter substrates (Feng et al., 2019). In practice, brain endothelial cell culture systems are not commonly used in drug discovery to evaluate CNS drug disposition, as they are less robust, more var","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"3-6"},"PeriodicalIF":2.1,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9147244","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}

{"title":"Vicagrel is hydrolyzed by Raf kinase inhibitor protein in human intestine","authors":"Ting Zhu,&nbsp;Yu Wu,&nbsp;Xue-Mei Li,&nbsp;Yu-Meng Jia,&nbsp;Huan Zhou,&nbsp;Li-Ping Jiang,&nbsp;Ting Tai,&nbsp;Qiong-Yu Mi,&nbsp;Jin-Zi Ji,&nbsp;Hong-Guang Xie","doi":"10.1002/bdd.2340","DOIUrl":"10.1002/bdd.2340","url":null,"abstract":"<p>As an analog of clopidogrel and prasugrel, vicagrel is completely hydrolyzed to intermediate thiolactone metabolite 2-oxo-clopidogrel (also the precursor of active thiol metabolite H4) in human intestine, predominantly by AADAC and CES2; however, other unknown vicagrel hydrolases remain to be identified. In this study, recombinant human Raf kinase inhibitor protein (rhRKIP) and pooled human intestinal S9 (HIS9) fractions and microsome (HIM) preparations were used as the different enzyme sources; prasugrel as a probe drug for RKIP (a positive control), vicagrel as a substrate drug of interest, and the rate of the formation of thiolactone metabolites 2-oxo-clopidogrel and R95913 as metrics of hydrolase activity examined, respectively. In addition, an IC₅₀ value of inhibition of rhRKIP-catalyzed vicagrel hydrolysis by locostatin was measured, and five classical esterase inhibitors with distinct esterase selectivity were used to dissect the involvement of multiple hydrolases in vicagrel hydrolysis. The results showed that rhRKIP hydrolyzed vicagrel in vitro, with the values of K_m, V_max, and CL_int measured as 20.04 ± 1.99 μM, 434.60 ± 12.46 nM/min/mg protein, and 21.69 ± 0.28 ml/min/mg protein, respectively, and that an IC₅₀ value of locostatin was estimated as 1.24 ± 0.04 mM for rhRKIP. In addition to locostatin, eserine and vinblastine strongly suppressed vicagrel hydrolysis in HIM. It is concluded that RKIP can catalyze the hydrolysis of vicagrel in the human intestine, and that vicagrel can be hydrolyzed by multiple hydrolases, such as RKIP, AADAC, and CES2, concomitantly.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 6","pages":"247-254"},"PeriodicalIF":2.1,"publicationDate":"2022-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10441674","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}

{"title":"Enalapril increases the urinary excretion of metformin in rats by inducing multidrug and toxin excretion protein 1 in the kidney","authors":"Xue-yan Gou,&nbsp;Yan-fang Wu,&nbsp;Feng-lin Ran,&nbsp;Yan-rong Ma,&nbsp;Xin-an Wu","doi":"10.1002/bdd.2341","DOIUrl":"10.1002/bdd.2341","url":null,"abstract":"<p>Two-thirds of patients with type 2 diabetes mellitus have hypertension, and thus the combination of two or more drugs to treat these diseases is common. It has been shown that the combination of metformin and enalapril has beneficial effects, but few studies have evaluated the interactions between these two drugs. This study investigated the effects of enalapril on the pharmacokinetics and urinary excretion of metformin in rats, with a focus on transporter-mediated drug interactions. Rats were dosed orally with metformin alone (100 mg/kg) or in combination with enalapril (4 mg/kg). The concentration of metformin was measured by high performance liquid chromatography and the level of organic cation transporters (rOCTs) and multidrug and toxin excretion protein 1 (rMATE1), which mediate the uptake and efflux of metformin, respectively, were evaluated by immunoblotting. After single and 7-day dosing, the plasma concentration of metformin in the co-administration group was significantly lower than that in the metformin-only group, and the CL/F and urinary excretion were increased in the co-administration group. Enalapril did not affect the K_p of metformin but reduced renal slice-uptake of metformin. The expression of rMATE1 was increased, whereas rOCT2 expression was decreased in rat kidney. Importantly, long-term co-administration of metformin and enalapril markedly decreased the level of lactic acid and uric acid in the blood. Enalapril increases the urinary excretion of metformin through the up-regulation of rMATE1. This reveals a new mechanism of drug interactions and provides a basis for drug dosage adjustment when these drugs are co-administered.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 6","pages":"255-264"},"PeriodicalIF":2.1,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10433017","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}