Biopharmaceutics & Drug Disposition最新文献

{"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}

{"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,&nbsp;Sivacharan Kollipara,&nbsp;Tausif Ahmed,&nbsp;Siddharth Chachad","doi":"10.1002/bdd.2339","DOIUrl":"10.1002/bdd.2339","url":null,"abstract":"<p>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.</p>","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}

{"title":"Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: Advances, challenges, and future perspectives","authors":"Akihiko Goto,&nbsp;Syunsuke Yamamoto,&nbsp;Shinji Iwasaki","doi":"10.1002/bdd.2338","DOIUrl":"10.1002/bdd.2338","url":null,"abstract":"<p>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.</p>","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}

{"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,&nbsp;Saja B. Alzughoul","doi":"10.1002/bdd.2337","DOIUrl":"10.1002/bdd.2337","url":null,"abstract":"<p>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. <i>In vitro</i>, 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 <i>in vitro–in vivo</i> 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. <i>In vitro</i> 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 <i>in vivo</i> 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.</p>","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}

{"title":"Intestinal absorption pathways of lisinopril: Mechanistic investigations","authors":"Sarah H. Elewa,&nbsp;Mohamed A. Osman,&nbsp;Ebtessam A. Essa,&nbsp;Amal A. Sultan","doi":"10.1002/bdd.2336","DOIUrl":"10.1002/bdd.2336","url":null,"abstract":"<p>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&gt; duodenum&gt; jejunum&gt; 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.</p>","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}