Biopharmaceutics & Drug Disposition最新文献

Exploring the Potential of Nasal Drug Delivery for Brain Targeted Therapy: A Detailed Analysis.

IF 1.7 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-12-12 DOI: 10.1002/bdd.2400

Maitrayee Ghosh, Debajyoti Roy, Shubham Thakur, Amrinder Singh

{"title":"Exploring the Potential of Nasal Drug Delivery for Brain Targeted Therapy: A Detailed Analysis.","authors":"Maitrayee Ghosh, Debajyoti Roy, Shubham Thakur, Amrinder Singh","doi":"10.1002/bdd.2400","DOIUrl":"https://doi.org/10.1002/bdd.2400","url":null,"abstract":"The brain is a sensitive organ with numerous essential functions and complex mechanisms. It is secluded and safeguarded from the external environment as part of the central nervous system (CNS), serving as a sanctuary. By regulating their selective and specific absorption, efflux, and metabolism in the brain, the CNS controls brain homeostasis and the transit of endogenous and foreign substances. The mechanism which protects the brain from environmental chemicals, also prevent the entry of therapeutic chemicals to it. The delivery of molecules to the brain is hindered by several major barriers, such as the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and blood-tumor barrier. BBB is formed by the combination of cerebral endothelial cells, astrocytes, neurons, pericytes and microglia. It is a tight junction of capillary endothelial cells, preventing the diffusion of solute into the brain. BCSFB is the second barrier, located at the choroid plexus, separating the blood from cerebrospinal fluid (CSF). It is comparatively more permeable than BBB. An uneven distribution of microvasculature across the tumor interstitial compromises drug delivery to neoplastic cells of a solid tumor, resulting in spatially inconsistent drug administration. Nasal drug delivery to the brain is a method of drug delivery that tries to deliver therapeutic substances directly from the nasal cavity to the central nervous system including the brain. In this review, besides the role of barriers we have discussed in detail about approaches adapted to deliver drugs to the brain along with mechanisms through nasal route. Further, different commercial formulations, clinical trials and patents have been thoroughly elaborated to date. The findings suggest that the nose-to-brain drug delivery method holds promise as an evolving approach, potentially contributing to the specific and targeted delivery of drugs into the brain.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811719","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

A limited sampling model to estimate the area under the curve of mycophenolic acid in hematopoietic stem cell transplantation recipients. 用有限采样模型估算造血干细胞移植受者体内霉酚酸的曲线下面积。

IF 1.7 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-09-26 DOI: 10.1002/bdd.2399

Liangmo Lin, Mianhui Hong, Xiangjun Fu

{"title":"A limited sampling model to estimate the area under the curve of mycophenolic acid in hematopoietic stem cell transplantation recipients.","authors":"Liangmo Lin, Mianhui Hong, Xiangjun Fu","doi":"10.1002/bdd.2399","DOIUrl":"https://doi.org/10.1002/bdd.2399","url":null,"abstract":"Relationship between the areas under the curve (AUC) of mycophenolic acid (MPA) and the likelihood of rejection is well-established in solid organ transplantation recipients. In hematopoietic stem cell transplantation (HSCT), MPA AUC is also linked to graft versus host disease. This study aimed to develop a simplified method to estimate MPA AUC0-12 in Chinese patients undergoing allogeneic HSCT (allo-HSCT). Intensive sampling was conducted in 22 patients who were orally administered mycophenolate mofetil. Plasma concentrations of total MPA were measured, and a model predicting AUC0-12 using data from these 22 patients was constructed through regression analysis. The accuracy of the most suitable model was assessed in an additional 20 patients. None of the individual MPA concentrations showed a strong correlation with AUC0-12 (r2 < 0.7). Models utilizing 4 or more concentrations were found to effectively estimate MPA AUC0-12 (r2 > 0.87). The most operationally feasible model demonstrated good predictive performance with a mean absolute percentage error (APE%) < 20%. Single MPA concentrations showed poor correlation with MPA AUC0-12. A model utilizing 4 oral concentrations (0, 0.5, 1, and 4 h postdose) over a 12-h period could effectively estimate MPA AUC0-12 with precise results and minimal bias.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340466","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

Model-based interspecies interpretation of botulinum neurotoxin type A on muscle-contraction inhibition. 基于模型的 A 型肉毒杆菌神经毒素对肌肉收缩抑制作用的种间解释。

IF 1.7 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-07-19 DOI: 10.1002/bdd.2398

Hyo-Jeong Ryu, Seongsung Kwak, Misun Park, Hwi-Yeol Yun

{"title":"Model-based interspecies interpretation of botulinum neurotoxin type A on muscle-contraction inhibition.","authors":"Hyo-Jeong Ryu, Seongsung Kwak, Misun Park, Hwi-Yeol Yun","doi":"10.1002/bdd.2398","DOIUrl":"https://doi.org/10.1002/bdd.2398","url":null,"abstract":"Botulinum neurotoxins (BoNTs) are commonly used in therapeutic and cosmetic applications. One such neurotoxin, BoNT type A (BoNT/A), has been studied widely for its effects on muscle function and contraction. Despite the importance of BoNT/A products, determining the blood concentrations of these toxins can be challenging. To address this, researchers have focused on pharmacodynamic (PD) markers, including compound muscle action potential (CMAP) and digit abduction scoring (DAS). In this study, we aimed to develop a probabilistic kinetic-pharmacodynamic (K-PD) model to interpret CMAP and DAS data obtained from mice and rats during the development of BoNT/A products. The researchers also wanted to gain a better understanding of how the estimated parameters from the model relate to the bridging of animal models to human responses. We used female Institute of Cancer Research mice and Sprague-Dawley (SD) rats to measure CMAP and DAS levels over 32 weeks after administering BoNT/A. We developed a muscle-contraction inhibition model using a virtual pharmacokinetic (PK) compartment combined with an indirect response model and performed model diagnostics using goodness-of-fit analysis, visual predictive checks (VPC), and bootstrap analysis. The CMAP and DAS profiles were dose-dependent, with recovery times varying depending on the administered dose. The final K-PD model effectively characterized the data and provided insights into species-specific differences in the PK and PD parameters. Overall, this study demonstrated the utility of PK-PD modeling in understanding the effects of BoNT/A and provides a foundation for future research on other BoNT/A products.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730962","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

Icaritin exhibits potential drug–drug interactions through the inhibition of human UDP-glucuronosyltransferase in vitro 淫羊藿苷通过在体外抑制人类 UDP-葡萄糖醛酸转移酶，表现出潜在的药物间相互作用。

IF 1.7 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-06-17 DOI: 10.1002/bdd.2397

Yi Rong, Nanxi Li, Xuan Qiao, Lei Yang, Peng Han, Zhiyun Meng, Hui Gan, Zhuona Wu, Xiaoxia Zhu, Yunbo Sun, Shuchen Liu, Guifang Dou, Ruolan Gu

{"title":"Icaritin exhibits potential drug–drug interactions through the inhibition of human UDP-glucuronosyltransferase in vitro","authors":"Yi Rong, Nanxi Li, Xuan Qiao, Lei Yang, Peng Han, Zhiyun Meng, Hui Gan, Zhuona Wu, Xiaoxia Zhu, Yunbo Sun, Shuchen Liu, Guifang Dou, Ruolan Gu","doi":"10.1002/bdd.2397","DOIUrl":"10.1002/bdd.2397","url":null,"abstract":"Icaritin is a prenylflavonoid derivative of the genus Epimedium (Berberidaceae) and has a variety of pharmacological actions. Icaritin is approved by the National Medical Products Administration as an anticancer drug that exhibits efficacy and safety advantages in patients with hepatocellular carcinoma cells. This study aimed to evaluate the inhibitory effects of icaritin on UDP-glucuronosyltransferase (UGT) isoforms. 4-Methylumbelliferone (4-MU) was employed as a probe drug for all the tested UGT isoforms using in vitro human liver microsomes (HLM). The inhibition potentials of UGT1A1 and 1A9 in HLM were further tested by employing 17β-estradiol (E2) and propofol (PRO) as probe substrates, respectively. The results showed that icaritin inhibits UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A10, 2B7, and 2B15. Furthermore, icaritin exhibited a mixed inhibition of UGT1A1, 1A3, and 1A9, and the inhibition kinetic parameters (Ki) were calculated to be 3.538, 2.117, and 0.306 (μM), respectively. The inhibition of human liver microsomal UGT1A1 and 1A9 both followed mixed mechanism, with Ki values of 2.694 and 1.431 (μM). This study provides supporting information for understanding the drug–drug interaction (DDI) potential of the flavonoid icaritin and other UGT-metabolized drugs in clinical settings. In addition, the findings provide safety evidence for DDI when liver cancer patients receive a combination therapy including icaritin.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 3","pages":"149-158"},"PeriodicalIF":1.7,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417543","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

Heterogeneous brain distribution of bumetanide following systemic administration in rats 大鼠全身用药后布美他尼在大脑中的分布不均。

IF 1.7 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-06-01 DOI: 10.1002/bdd.2390

Wolfgang Löscher, Martina Gramer, Kerstin Römermann

{"title":"Heterogeneous brain distribution of bumetanide following systemic administration in rats","authors":"Wolfgang Löscher, Martina Gramer, Kerstin Römermann","doi":"10.1002/bdd.2390","DOIUrl":"10.1002/bdd.2390","url":null,"abstract":"Bumetanide is used widely as a tool and off-label treatment to inhibit the Na-K-2Cl cotransporter NKCC1 in the brain and thereby to normalize intra-neuronal chloride levels in several brain disorders. However, following systemic administration, bumetanide only poorly penetrates into the brain parenchyma and does not reach levels sufficient to inhibit NKCC1. The low brain penetration is a consequence of both the high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, and of brain efflux transport. In previous studies, bumetanide was determined in the whole brain or a few brain regions, such as the hippocampus. However, the blood–brain barrier and its efflux transporters are heterogeneous across brain regions, so it cannot be excluded that bumetanide reaches sufficiently high brain levels for NKCC1 inhibition in some discrete brain areas. Here, bumetanide was determined in 14 brain regions following i.v. administration of 10 mg/kg in rats. Because bumetanide is much more rapidly eliminated by rats than humans, its metabolism was reduced by pretreatment with piperonyl butoxide. Significant, up to 5-fold differences in regional bumetanide levels were determined with the highest levels in the midbrain and olfactory bulb and the lowest levels in the striatum and amygdala. Brain:plasma ratios ranged between 0.004 (amygdala) and 0.022 (olfactory bulb). Regional brain levels were significantly correlated with local cerebral blood flow. However, regional bumetanide levels were far below the IC50 (2.4 μM) determined previously for rat NKCC1. Thus, these data further substantiate that the reported effects of bumetanide in rodent models of brain disorders are not related to NKCC1 inhibition in the brain.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 3","pages":"138-148"},"PeriodicalIF":1.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2390","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186079","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

Evaluating gender effect in the generic bioequivalence studies by physiologically based pharmacokinetic modeling – A case study of dextromethorphan modified release tablets 通过基于生理的药代动力学模型评估非专利药生物等效性研究中的性别效应--右美沙芬改良释放片的案例研究。

IF 1.7 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-05-22 DOI: 10.1002/bdd.2389

Manoj Gundeti, Aditya Murthy, Shubham Jamdade, Tausif Ahmed

{"title":"Evaluating gender effect in the generic bioequivalence studies by physiologically based pharmacokinetic modeling – A case study of dextromethorphan modified release tablets","authors":"Manoj Gundeti, Aditya Murthy, Shubham Jamdade, Tausif Ahmed","doi":"10.1002/bdd.2389","DOIUrl":"10.1002/bdd.2389","url":null,"abstract":"The United States Food and Drug Administration guidelines for the bioequivalence (BE) testing of the generic drug products suggests that there should be an equal proportion of male and female population in the BE study. Despite this requirement, many generic drug companies do not maintain the suggested proportion of female population in their studies. Several socio-economic and cultural factors lead to lower participation of the females in the BE studies. More recently, the regulatory agencies across the globe are requesting the generic drug companies to demonstrate the performance of their drug products in the under-represented sex via additional studies. In this work, we describe the case of Dextromethorphan modified release tablets where the gender effect on the product performance was evaluated by physiologically based pharmacokinetic (PBPK) modeling approach. We have compared the drug product's performance by population simulations considering four different scenarios. The data from all-male population (from in house Pharmacokinetic [PK] BE studies) was considered as a reference and other scenarios were compared against the all-male population data. In the first scenario, we made a comparison between all-male (100% male) vs all-female (100% female) population. Second scenario was as per agency’s requirements—equal proportion of male and female in the BE study. As an extreme scenario, 100% male vs 30:70 male:female was considered (higher females than males in the BE studies). Finally, as a more realistic scenario, 100% male versus 70:30 male:female was considered (lower females than males in the BE studies). Population PK followed by virtual BE was employed to demonstrate the similarity/differences in the drug product performance between the sexes. This approach can be potentially utilized to seek BE study waivers thus saving cost and accelerating the entry of the generic products to the market.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 3","pages":"127-137"},"PeriodicalIF":1.7,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080413","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

Pharmacokinetic control of orally dosed cyclosporine A with mucosal drug delivery system 利用粘膜给药系统控制口服环孢素 A 的药代动力学。

IF 1.7 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-04-22 DOI: 10.1002/bdd.2388

Kohei Yamada, Kurt D. Ristroph, Yuuki Kaneko, Hoang D. Lu, Robert K. Prud’homme, Hideyuki Sato, Satomi Onoue

{"title":"Pharmacokinetic control of orally dosed cyclosporine A with mucosal drug delivery system","authors":"Kohei Yamada, Kurt D. Ristroph, Yuuki Kaneko, Hoang D. Lu, Robert K. Prud’homme, Hideyuki Sato, Satomi Onoue","doi":"10.1002/bdd.2388","DOIUrl":"10.1002/bdd.2388","url":null,"abstract":"This study aimed to control the oral absorption of cyclosporine A (CsA) with the use of a mucosal drug delivery system (mDDS). Mucopenetrating nanocarriers (MP/NCs) and mucoadhesive nanocarriers (MA/NCs) were prepared by flash nanoprecipitation employing polystyrene-block-poly(ethylene glycol) and polystyrene-block-poly(N,N-dimethyl aminoethyl methacrylate), respectively. Their particle distribution in the rat gastrointestinal tract were visualized by fluorescent imaging. Plasma concentrations were monitored after oral administration of CsA-loaded MP/NCs (MP/CsA) and MA/NCs (MA/CsA) to rats. MP/NCs and MA/NCs had a particle size below 200 nm and ζ-potentials of 4 and 40 mV, respectively. The results from in vitro experiments demonstrated mucopenetration of MP/NCs and mucoadhesion of MA/NCs. Confocal laser scanning microscopic images showed diffusion of MP/NCs in the gastrointestinal mucus towards epithelial cells and localization of MA/NCs on the surface of the gastrointestinal mucus layer. In a pH 6.8 solution, rapid and sustained release of CsA were observed for MP/CsA and MA/CsA, respectively. After oral dosing (10 mg-CsA/kg) to rats, amorphous CsA powder exhibited a time to maximum plasma concentration (Tmax) of 3.4 h, maximum plasma concentration (Cmax) of 0.12 μg/mL, and bioavailability of 0.7%. Compared with amorphous CsA powder, MP/CsA shortened Tmax by 1.1 to 2.3 h and increased the bioavailability by 43-fold to 30.1%, while MA/CsA prolonged Tmax by 3.4 to 6.8 h with Cmax and bioavailability of 0.65 μg/mL and 11.7%, respectively. These pharmacokinetic behaviors would be explained by their diffusion and release properties modulated by polymeric surface modification. The mDDS approach is a promising strategy for the pharmacokinetic control of orally administered CsA.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 3","pages":"117-126"},"PeriodicalIF":1.7,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140676763","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

Gender difference in the pharmacokinetics and metabolism of VX-548 in rats 大鼠体内 VX-548 药代动力学和代谢的性别差异

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-04-04 DOI: 10.1002/bdd.2387

Guilan Yu, Xueying Zhou

{"title":"Gender difference in the pharmacokinetics and metabolism of VX-548 in rats","authors":"Guilan Yu, Xueying Zhou","doi":"10.1002/bdd.2387","DOIUrl":"10.1002/bdd.2387","url":null,"abstract":"VX-548 is a sodium channel blocker, which acts as an analgesic. This study aims to investigate the gender differences in the pharmacokinetics and metabolism of VX-548 in rats. After intravenous administration, the area under the curve (AUC0−t) of VX-548 was much higher in female rats (1505.8 ± 47.3 ng·h/mL) than in male rats (253.8 ± 6.3 ng·h/mL), and the clearance in female rats (12.5 ± 0.8 mL/min/kg) was much lower than in male rats (65.1 ± 1.7 mL/min/kg). After oral administration, the AUC0−t in female rats was about 50-fold higher than that in male rats. The oral bioavailability in male rats was 11% while it was 96% in female rats. An in vitro metabolism study revealed that the metabolism of VX-548 in female rat liver microsomes was much slower than in male rats. Further metabolite identification suggested that the significant gender difference in pharmacokinetics was attributed to demethylation. The female rat liver microsomes showed a limited ability to convert VX-548 into desmethyl VX-548. Phenotyping experiments indicated that the formation of desmethyl VX-548 was mainly catalyzed by CYP3A2 and CYP2C11 using rat recombinant CYPs. Overall, we revealed that the pharmacokinetics and metabolism of VX-548 in male and female rats showed significant gender differences.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 2","pages":"107-114"},"PeriodicalIF":2.1,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140576364","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

Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys AST-001 非临床药代动力学特征：一种新型选择性 AKR1C3 激活原药在小鼠、大鼠和猕猴体内的作用。

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-03-16 DOI: 10.1002/bdd.2385

Teng Meng, Donald Jung, Xiao-Hong Cai, Zhao-Qiang Lu, Ji-Bing Yu, Tian-Yang Qi, Fan-Ying Meng, Mei-Zhen Ruan, Jian-Xin Duan

{"title":"Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys","authors":"Teng Meng, Donald Jung, Xiao-Hong Cai, Zhao-Qiang Lu, Ji-Bing Yu, Tian-Yang Qi, Fan-Ying Meng, Mei-Zhen Ruan, Jian-Xin Duan","doi":"10.1002/bdd.2385","DOIUrl":"10.1002/bdd.2385","url":null,"abstract":"AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 2","pages":"83-92"},"PeriodicalIF":2.1,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2385","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140139798","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

Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs 衰老和脑游离胆固醇浓度对豚鼠淀粉样β肽积累的影响

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2024-03-15 DOI: 10.1002/bdd.2386

K. Sandy Pang, H. Benson Peng, Betty P. Li, Binyu Wen, Keumhan Noh, Runyu Xia, Anja Toscan, Sylvia Serson, Paul E. Fraser, Rommel G. Tirona, Inès A. M. de Lannoy

{"title":"Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs","authors":"K. Sandy Pang, H. Benson Peng, Betty P. Li, Binyu Wen, Keumhan Noh, Runyu Xia, Anja Toscan, Sylvia Serson, Paul E. Fraser, Rommel G. Tirona, Inès A. M. de Lannoy","doi":"10.1002/bdd.2386","DOIUrl":"10.1002/bdd.2386","url":null,"abstract":"Alzheimer’s disease is a complex multifactorial neurodegenerative disorder wherein age is a major risk factor. The appropriateness of the Hartley guinea pig (GP), which displays high sequence homologies of its amyloid-β (Aβ40 and Aβ42) peptides, Mdr1 and APP (amyloid precursor protein) and similarity in lipid handling to humans, was appraised among 9–40 weeks old guinea pigs. Protein expression levels of P-gp (Abcb1) and Cyp46a1 (24(S)-hydroxylase) for Aβ40, and Aβ42 efflux and cholesterol metabolism, respectively, were decreased with age, whereas those for Lrp1 (low-density lipoprotein receptor related protein 1), Rage (receptor for advanced glycation endproducts) for Aβ efflux and influx, respectively, and Abca1 (the ATP binding cassette subfamily A member 1) for cholesterol efflux, were unchanged among the ages examined. There was a strong, negative correlation of the brain Aβ peptide concentrations and Abca1 protein expression levels with free cholesterol. The correlation of Aβ peptide concentrations with Cyp46a1 was, however, not significant, and concentrations of the 24(S)-hydroxycholesterol metabolite revealed a decreasing trend from 20 weeks old toward 40 weeks old guinea pigs. The composite data suggest a role for free cholesterol on brain Aβ accumulation. The decreases in P-gp and Lrp1 protein levels should further exacerbate the accumulation of Aβ peptides in guinea pig brain.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 2","pages":"93-106"},"PeriodicalIF":2.1,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130660","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