Biopharmaceutics & Drug Disposition最新文献_第5页

Attenuation of phenobarbital-induced cytochrome P450 expression in carbon tetrachloride-induced hepatitis in mice models 苯巴比妥诱导的细胞色素P450在四氯化碳诱导的小鼠肝炎模型中表达的减弱。

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-04-09 DOI: 10.1002/bdd.2356

Chieri Fujino, Taiki Kuzu, Yukine Kubo, Kurumi Hayashi, Satoshi Ueshima, Toshiya Katsura

{"title":"Attenuation of phenobarbital-induced cytochrome P450 expression in carbon tetrachloride-induced hepatitis in mice models","authors":"Chieri Fujino, Taiki Kuzu, Yukine Kubo, Kurumi Hayashi, Satoshi Ueshima, Toshiya Katsura","doi":"10.1002/bdd.2356","DOIUrl":"10.1002/bdd.2356","url":null,"abstract":"Certain pathological conditions, such as inflammation, are known to affect basal cytochrome P450 (CYP) expression by modulating transcriptional regulation, and the pharmacokinetics of drugs can vary among patients. However, changes in drug-induced CYP expression under pathological conditions have not been elucidated in detail. Here, we investigated the effects of hepatic inflammation and injury on phenobarbital-induced expression of CYP isoforms in mice. Phenobarbital was administered once as a CYP inducer in the carbon tetrachloride-induced hepatitis model mice. The mRNA expression levels of Cyp3a11 and Cyp2b10 in the liver and small intestine were measured using reverse transcription polymerase chain reaction. The enzymatic activity of CYP3A in liver S9 was evaluated using midazolam as the substrate. Phenobarbital increased the mRNA expression of Cyp3a11 and Cyp2b10 in the liver of healthy mice, but not in the small intestine. Increased mRNA expression of hepatic Cyp3a11 and Cyp2b10 by phenobarbital was significantly suppressed in the hepatitis model mice. Hepatitis also suppressed the increased CYP3A enzymatic activity induced by phenobarbital in liver S9, consistent with the results of Cyp3a11 mRNA expression. These results suggest that the inducibility of CYP by phenobarbital may vary in patients with hepatitis, indicating that pharmacokinetic drug–drug interactions can be altered under certain pathological conditions.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 5","pages":"351-357"},"PeriodicalIF":2.1,"publicationDate":"2023-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9264061","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

Enhanced oral bioavailability of capsaicin-loaded microencapsulation complex via electrospray technology: Preparation, in vitro and in vivo evaluation 通过电喷雾技术提高辣椒素微胶囊复合物的口服生物利用度:制备、体外和体内评价

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-03-31 DOI: 10.1002/bdd.2355

Yuan Zhu, Shuang Li, Haiqiao Wang, Michael Adu-Frimpong, Yuanyuan Xue, Zhengqing Gu, Jiangnan Yu, Ximing Xu

{"title":"Enhanced oral bioavailability of capsaicin-loaded microencapsulation complex via electrospray technology: Preparation, in vitro and in vivo evaluation","authors":"Yuan Zhu, Shuang Li, Haiqiao Wang, Michael Adu-Frimpong, Yuanyuan Xue, Zhengqing Gu, Jiangnan Yu, Ximing Xu","doi":"10.1002/bdd.2355","DOIUrl":"10.1002/bdd.2355","url":null,"abstract":"The purpose of this work was to fabricate the microencapsulation of capsaicin using electrospray technology and polyvinylpyrrolidone (PVP) K30 as a carrier. The morphological characteristics of capsaicin-PVP electrosprayed microencapsulation complex under different processing parameters were observed by scanning electron microscope (SEM), while the best process was determined, wherein it comprised of 10 KV (voltage), 0.8 ml·h−1 (solution flow rate), 0.9 mm (the inner diameter of the needle), and 10 cm (receiving distance). The X-ray diffraction results of the electrosprayed complex showed that capsaicin was present in the carrier in an amorphous form. The drug release properties of capsaicin powder and electrosprayed complex in different media were investigated. The results showed that in vitro release rates of the capsaicin complex in different media were much higher than that of capsaicin powder, with correspondingly improved bioavailability, defined by intravenous and oral dosing in rats in vivo, for the electrosprayed complex compared to that of capsacin powder. The dose absorbed of the electrosprayed complex was 2.2-fold that of the capsaicin powder. In short, electrospray technology can be used to prepare capsaicin-loaded electrosprayed microencapsulation complex. This technique can improve the solubility and bioavailability of capsaicin, and provide a new idea for the solubilization of other insoluble drugs.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 2","pages":"137-146"},"PeriodicalIF":2.1,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9341036","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

Norvancomycin plasma concentration monitoring in hemodialysis patients with end stage kidney disease: A retrospective cohort study 终末期肾病血液透析患者去甲万古霉素血药浓度监测:一项回顾性队列研究

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-03-28 DOI: 10.1002/bdd.2354

Liying Du, Liman Huo, Juan Hou, Xiajin Zhou, Mingfeng Liu, Teng Guo, Wei Wang, Huihui Chen, Xinran Chen

{"title":"Norvancomycin plasma concentration monitoring in hemodialysis patients with end stage kidney disease: A retrospective cohort study","authors":"Liying Du, Liman Huo, Juan Hou, Xiajin Zhou, Mingfeng Liu, Teng Guo, Wei Wang, Huihui Chen, Xinran Chen","doi":"10.1002/bdd.2354","DOIUrl":"10.1002/bdd.2354","url":null,"abstract":"Blood concentration monitoring plays an important role in the rational use of norvancomycin. However, the reference interval for the norvancomycin plasma concentration in the treatment of infections in hemodialysis patients with end stage kidney disease is undefined. To determine the safe and effective interval for the norvancomycin plasma trough concentration, 39 patients treated with hemodialysis and norvancomycin were analyzed retrospectively. The norvancomycin plasma concentration before hemodialysis was tested as the trough concentration. The associations of the norvancomycin trough concentration with efficacy and adverse reactions were evaluated. No norvancomycin concentration above 20 μg/mL was detected. The trough concentration, but not the dose, had a significant effect on the anti-infectious efficacy. Compared with the low norvancomycin trough concentration group (<9.30 μg/mL), the high concentration group (9.30–20.0 μg/mL) had improved efficacy (OR = 15.45, p < 0.01) with similar side effects (OR = 0.5417, p = 0.4069). It is beneficial to maintain the norvancomycin trough concentration at 9.30–20.0 μg/mL to achieve a good anti-infectious effect in hemodialysis patients with end stage kidney disease. Plasma concentration monitoring provides a data basis for the individual treatment of infections with norvancomycin in hemodialysis patients.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 2","pages":"175-182"},"PeriodicalIF":2.1,"publicationDate":"2023-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9717469","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

Exploring in vitro solubility of lamotrigine in physiologically mimetic conditions to prospect the in vivo dissolution in pediatric population 探索拉莫三嗪在生理模拟条件下的体外溶解度，以预测其在儿童体内的溶出度

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-03-23 DOI: 10.1002/bdd.2353

Edilainy Rizzieri Caleffi-Marchesini, Fernanda Belincanta Borghi-Pangoni, Julia Macente, Priscila Chiamulera-Mantovani, Josmar Mazucheli, Rodrigo Cristofoletti, Andréa Diniz

{"title":"Exploring in vitro solubility of lamotrigine in physiologically mimetic conditions to prospect the in vivo dissolution in pediatric population","authors":"Edilainy Rizzieri Caleffi-Marchesini, Fernanda Belincanta Borghi-Pangoni, Julia Macente, Priscila Chiamulera-Mantovani, Josmar Mazucheli, Rodrigo Cristofoletti, Andréa Diniz","doi":"10.1002/bdd.2353","DOIUrl":"10.1002/bdd.2353","url":null,"abstract":"Pediatric drugs knowledge still leaves several gaps to be filled, all the while many biopharmaceutic properties applied to adults do not work in pediatrics. The solubility in many cases is extrapolated to pediatrics; however, sometimes it may not represent the real scenario. In this context, the aim of this study was to assess the possibility of the extrapolation of the solubility data assumed for adults to children aged 2–12 years using lamotrigine (LTG) as a model. LTG showed that its solubility is dependent on the pH of the medium, no precipitate formation was seen, and biomimetic media showed a greater capacity to solubilize it. Based on the dose number (D0) in adults, the LTG was soluble in acidic pH media and poorly soluble in neutral to basic. Similar behavior was found in conditions which mimic children aged 10–12 years at a dose of 5 and 15 mg/kg. The D0 for 5-year-old children at a dose of 15 mg/kg showed different behaviors between biorelevant and pharmacopeial buffers media. For children aged 2–3 years, LTG appeared to be poorly soluble under both gastric and intestinal conditions. Solubility was dependent on the volume of fluid calculated for each age group, and this may impact the development of better pharmaceutical formulations for this population, better pharmacokinetic predictions in tools as PBPK, and physiologically-based biopharmaceutics modeling, greater accuracy in the justifications for biowaiver, and many other possibilities.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 2","pages":"147-156"},"PeriodicalIF":2.1,"publicationDate":"2023-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9347907","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

Decreased plasma exposure of clopidogrel active metabolite in rats after long-term treatment with clopidogrel 氯吡格雷长期治疗后大鼠血浆氯吡格雷活性代谢物暴露减少

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-02-27 DOI: 10.1002/bdd.2349

Yani Wang, Yingrui Liu, Hongwei Yao, Xue Chen, Yantong Sun, Yingjie Guo

{"title":"Decreased plasma exposure of clopidogrel active metabolite in rats after long-term treatment with clopidogrel","authors":"Yani Wang, Yingrui Liu, Hongwei Yao, Xue Chen, Yantong Sun, Yingjie Guo","doi":"10.1002/bdd.2349","DOIUrl":"10.1002/bdd.2349","url":null,"abstract":"Clopidogrel (Clop) is oxidized by cytochrome P450s (CYPs) to an active thiol metabolite, Clop-AM, to inhibit platelet activation and aggregation. As an irreversible inhibitor of CYP2B6 and CYP2C19, clopidogrel may inhibit its own metabolism after long-term administration. The study compared the pharmacokinetic profiles of clopidogrel and its metabolites in rats receiving a single or a 2 week administration of Clop. The mRNA and protein levels of hepatic clopidogrel-metabolizing enzymes and their enzymatic activities were analyzed to explore their contribution to any altered plasma exposure of Clop and its metabolites. The results showed that long-term treatment with clopidogrel significantly decreased the AUC(0-t) and Cmax values of Clop-AM in rats, accompanied with markedly impaired catalytic activities of Clop-metabolizing CYPs including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4. It suggests that consecutive administration of Clop to rats decreases hepatic CYPs activities, which may, in turn, inhibit clopidogrel metabolism and then reduce Clop-AM plasma exposure. Therefore, long-term treatment with clopidogrel has the potential to reduce its anti-platelet activity and to increase the risk of drug–drug interaction.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 2","pages":"129-136"},"PeriodicalIF":2.1,"publicationDate":"2023-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9717429","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

Metabolic interaction between biflavonoids in Ginkgo biloba leaves and tacrolimus 银杏叶中生物黄酮与他克莫司的代谢相互作用

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-02-25 DOI: 10.1002/bdd.2350

Jie Bai, Chao Zhang

{"title":"Metabolic interaction between biflavonoids in Ginkgo biloba leaves and tacrolimus","authors":"Jie Bai, Chao Zhang","doi":"10.1002/bdd.2350","DOIUrl":"10.1002/bdd.2350","url":null,"abstract":"The aim of this study was to investigate the effect of biflavonoids in Ginkgo biloba leaves on tacrolimus metabolism. First, the inhibitory effects of five main biflavonoids (amentoflavone, sciadopitysin, ginkgetin, isoginkgetin, bilobetin) in G. biloba leaves on tacrolimus metabolism were investigated in vitro in human liver microsomes (HLM), and the concentration-dependent inhibition was further calculated. Then the time-dependent inhibition activities of five biflavonoids were studied and the drug interaction was studied in Sprague–Dawley (SD) rats. Finally, the molecular mechanism of inhibition was explored by molecular docking. The results of in vitro incubation in HLM showed tacrolimus metabolism was strongly inhibited by amentoflavone, ginkgetin, and bilobetin, whose IC50 value was 5.57, 3.16, and 5.03 μM, respectively. The time-dependent inhibition of the three above biflavonoids at 50 μM was 33.47%–50.89%. In the in vivo study in rats, the AUC0−t and Cmax of tacrolimus increased 3.8-fold and 2.5-fold after oral preadministration with amentoflavone. The molecular docking results showed that the inhibitory effect may be related to the formation of hydrogen bonds. The results showed that long-term combination of G. biloba leaves and tacrolimus may cause drug–drug interactions. This study provided theoretical and experimental basis for rational drug use in clinical practice.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 2","pages":"157-164"},"PeriodicalIF":2.1,"publicationDate":"2023-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9346573","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

Investigating CNS distribution of PF-05212377, a P-glycoprotein substrate, by translation of 5-HT6 receptor occupancy from non-human primates to humans 通过将5-HT6受体占据从非人灵长类动物转化为人类来研究P-糖蛋白底物PF-05212377的中枢神经系统分布

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-02-24 DOI: 10.1002/bdd.2351

Aarti Sawant-Basak, Laigao Chen, Peter Lockwood, Tracey Boyden, Angela C. Doran, Jessica Mancuso, Kenneth Zasadny, Timothy McCarthy, Evan D. Morris, Richard E. Carson, Irina Esterlis, Yiyun Huang, Nabeel Nabulsi, Beata Planeta, Terence Fullerton

{"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, Laigao Chen, Peter Lockwood, Tracey Boyden, Angela C. Doran, Jessica Mancuso, Kenneth Zasadny, Timothy McCarthy, Evan D. Morris, Richard E. Carson, Irina Esterlis, Yiyun Huang, Nabeel Nabulsi, Beata Planeta, Terence Fullerton","doi":"10.1002/bdd.2351","DOIUrl":"https://doi.org/10.1002/bdd.2351","url":null,"abstract":"PF-05212377 (SAM760) is a potent and selective 5-HT6 antagonist, previously under development for the treatment of Alzheimer’s disease. In vitro, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (Cbu/Cpu) 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 Cpu EC50 of PF-05212377 was 0.31 nM (consistent with the in vitro human 5HT6 Ki: 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 in vitro human 5HT6 binding Ki 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.Clinical trial number: NCT01258751.","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}

引用次数: 0

In vitro and ex vivo experimental models for evaluation of intranasal systemic drug delivery as well as direct nose-to-brain drug delivery 体外和离体实验模型用于评估经鼻全身给药和直接经鼻至脑给药

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-02-03 DOI: 10.1002/bdd.2348

Anja Haasbroek-Pheiffer, Suzanne Van Niekerk, Frank Van der Kooy, Theunis Cloete, Jan Steenekamp, Josias Hamman

{"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, Suzanne Van Niekerk, Frank Van der Kooy, Theunis Cloete, Jan Steenekamp, Josias Hamman","doi":"10.1002/bdd.2348","DOIUrl":"10.1002/bdd.2348","url":null,"abstract":"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. In vitro and ex vivo 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 in vitro-in vivo 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 in vitro/ex vivo 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 in vitro and ex vivo models that have been developed to study intranasal and direct nose-to-brain drug delivery.","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}

引用次数: 2

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 p -糖蛋白和乳腺癌耐药蛋白转运体对中枢神经系统药物处置影响的体内外研究进展

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-01-24 DOI: 10.1002/bdd.2345

Sagnik Chatterjee, Anup Arunrao Deshpande, Hong Shen

{"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, Anup Arunrao Deshpande, Hong Shen","doi":"10.1002/bdd.2345","DOIUrl":"10.1002/bdd.2345","url":null,"abstract":"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) (ABCB1) and breast cancer resistance protein (BCRP) (ABCG2) 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, in vivo imaging, in vitro methods of organoid and microphysiological systems, as well as in silico 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 in vivo, in vitro, 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.","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}

引用次数: 4

Metabolism and pharmacokinetic study of deuterated osimertinib 氘化奥希替尼的代谢及药代动力学研究

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2023-01-17 DOI: 10.1002/bdd.2347

Xuyi Zhan, Shaoyin Bao, Xumei Li, Shaojun Zhou, Maha Raja Dahar, Nengming Lin, Xiugui Chen, Chengshan Niu, Kaige Ji, Yusheng Wu, Kui Zeng, Zhihua Tang, Lushan Yu

{"title":"Metabolism and pharmacokinetic study of deuterated osimertinib","authors":"Xuyi Zhan, Shaoyin Bao, Xumei Li, Shaojun Zhou, Maha Raja Dahar, Nengming Lin, Xiugui Chen, Chengshan Niu, Kaige Ji, Yusheng Wu, Kui Zeng, Zhihua Tang, Lushan Yu","doi":"10.1002/bdd.2347","DOIUrl":"10.1002/bdd.2347","url":null,"abstract":"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 (Cmax) compared with the osimertinib in rats and human body.","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}

引用次数: 0