Biopharmaceutics & Drug Disposition最新文献_第8页

Effects of aged garlic and ginkgo biloba extracts on the pharmacokinetics of sofosbuvir in rats 陈年大蒜和银杏叶提取物对索非布韦大鼠药动学的影响

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-08-17 DOI: 10.1002/bdd.2326

Abanoub K. Wasef, Sara A. Wahdan, Noha M. Saeed, Ebtehal El-Demerdash

{"title":"Effects of aged garlic and ginkgo biloba extracts on the pharmacokinetics of sofosbuvir in rats","authors":"Abanoub K. Wasef, Sara A. Wahdan, Noha M. Saeed, Ebtehal El-Demerdash","doi":"10.1002/bdd.2326","DOIUrl":"10.1002/bdd.2326","url":null,"abstract":"Sofosbuvir is a direct acting antiviral (DAA) approved for the treatment of hepatitis C virus (HCV). Sofosbuvir is a substrate of P-glycoprotein (P-gp). For this reason, inhibitors, or inducers of intestinal P-gp may alter the plasma concentration of sofosbuvir and increase or decrease its efficacy causing a significant change in its pharmacokinetic parameters. The purpose of the study was to evaluate the pharmacokinetic interaction between either aged garlic or ginkgo biloba extracts with sofosbuvir through targeting P-gp as well as possible toxicities in rats. Rats were divided into four groups and treated for 14 days with saline, verapamil (15 mg/kg, PO), aged garlic extract (120 mg/kg, PO), or ginkgo biloba extract (25 mg/kg, PO) followed by a single oral dose of sofosbuvir (40 mg/kg). Validated LC-MS/MS was used to determine sofosbuvir and its metabolite GS-331007 in rat plasma. Aged garlic extract caused a significant decrease of sofosbuvir AUC(0−t) by 36%, while ginkgo biloba extract caused a significant increase of sofosbuvir AUC(0−t) by 11%. Ginkgo biloba extract exhibited a significant increase of the sofosbuvir t1/2 by 60%, while aged garlic extract significantly increased the clearance of sofosbuvir by 63%. The pharmacokinetic parameters of GS-331007 were not affected. The inhibitory action of ginkgo biloba on P-gp and the subsequent increase in the sofosbuvir plasma concentration did not show a significant risk of renal or hepatic toxicity. Conversely, although aged garlic extracts increased intestinal P-gp expression, they did not alter the Cmax and Tmax of sofosbuvir and did not induce significant hepatic or renal toxicities.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 4","pages":"152-162"},"PeriodicalIF":2.1,"publicationDate":"2022-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40619639","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

Effect of ABCB1 gene variants on rivaroxaban pharmacokinetic and hemorrhage events occurring in patients with non-valvular atrial fibrillation ABCB1基因变异对非瓣膜性房颤患者利伐沙班药代动力学和出血事件的影响

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-08-08 DOI: 10.1002/bdd.2327

Dan Zhang, Wei Qin, Wenwen Du, Xiaoxing Wang, Wenqian Chen, Pengmei Li

{"title":"Effect of ABCB1 gene variants on rivaroxaban pharmacokinetic and hemorrhage events occurring in patients with non-valvular atrial fibrillation","authors":"Dan Zhang, Wei Qin, Wenwen Du, Xiaoxing Wang, Wenqian Chen, Pengmei Li","doi":"10.1002/bdd.2327","DOIUrl":"10.1002/bdd.2327","url":null,"abstract":"Hemorrhage events occur most frequently in anticoagulant therapy for non-valvular atrial fibrillation (NVAF). Rivaroxaban is used widely for routine anticoagulation care. Genetic polymorphisms are thought to contribute to the wide intraindividual variability seen in rivaroxaban metabolism and the anticoagulant response. The aim of this study was to evaluate the effect of drug transport related single-nucleotide polymorphisms (SNPs) on rivaroxaban metabolism and on the risk of a hemorrhage event. A total of 216 Chinese patients with NVAF were enrolled in the study. Rivaroxaban was used for anticoagulation therapy. Rivaroxaban plasma concentrations were detected using a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Seven SNPs in four genes were genotyped using the Sanger dideoxy DNA sequencing method. Associations between genotype variants, the incidence of hemorrhage events, and the time of bleeding were analyzed. ABCB1 2677G (rs2032582) variation was highly associated with the dose-adjusted rivaroxaban peak concentration in plasma (Cmax/D) (p = 0.025, FDR = 0.042). The ABCB1 G allele carriers had a higher rivaroxaban Cmax/D than non-carriers. Logistic regression showed that rivaroxaban Cmax/D and ABCB1 genotype variants were associated with a higher incidence of hemorrhage events. No statistically significant difference was found between ABCB1 genotypes and the time of bleeding after anticoagulant therapy in 30 days. These results indicated that ABCB1 2677G (rs2032582) genetic variant affects the rivaroxaban Cmax/Dose and the incidence of hemorrhage events significantly.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 4","pages":"163-171"},"PeriodicalIF":2.1,"publicationDate":"2022-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40680160","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

Mouse Cyp2c expression and zonation structure in the liver begins in the early neonatal stage 小鼠肝脏中Cyp2c的表达和分带结构始于新生儿早期

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-06-24 DOI: 10.1002/bdd.2324

Taisuke Kawamura, Mako Ichikawa, Jo Hatogai, Yuya Koyama, Misa Tachibana, Misaki Kuwahara, Keita Negishi, Miyu Matsumoto, Masafumi Miyazaki, Wataru Ochiai

{"title":"Mouse Cyp2c expression and zonation structure in the liver begins in the early neonatal stage","authors":"Taisuke Kawamura, Mako Ichikawa, Jo Hatogai, Yuya Koyama, Misa Tachibana, Misaki Kuwahara, Keita Negishi, Miyu Matsumoto, Masafumi Miyazaki, Wataru Ochiai","doi":"10.1002/bdd.2324","DOIUrl":"10.1002/bdd.2324","url":null,"abstract":"In the adult liver, drug-metabolizing enzymes such as cytochrome P450 (CYP) efficiently metabolize drugs by forming an expression pattern called “zonation” structure around the central veins (CV). However, most previous studies on CYPs have focused on the expression levels of CYP mRNA and proteins in the whole liver. In this study, we analyzed not only the expression levels of Cyp2c family mRNAs and proteins in mice during fetal liver development, but also the relationship with their localization. In the whole fetal liver, Cyp2c mRNA and protein were hardly expressed. On the other hand, zonation analysis results showed that only some cells around the CV of the fetal liver expressed Cyp2c. In addition, the protein expression level of Cyp2c in the whole liver during the neonatal period started from postnatal day (P) 7 in both males and females, while the zonation was weakly formed from P5. This study suggested that fetal liver cannot metabolize Cyp2c substrate drugs transferred from mother to fetus due to the low expression of Cyp2c and unformed zonation. The expression level of Cyp2c protein in neonates was lower than that in adult liver, and the zonation structure was not clear, suggesting that drug metabolism was not sufficient. Furthermore, this study revealed that the expression level of Cyp2c does not correlate with the formation of zonation structures, because Cyp2c expression is found in hepatocytes near the CV even in the fetal and neonatal stages, when Cyp2c protein expression is hardly detectable in the whole liver.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 4","pages":"130-139"},"PeriodicalIF":2.1,"publicationDate":"2022-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40395115","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

Simulation of febuxostat pharmacokinetics in healthy subjects and patients with impaired kidney function using physiologically based pharmacokinetic modeling 利用基于生理的药代动力学模型模拟非布司他在健康受试者和肾功能受损患者中的药代动力学

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-06-24 DOI: 10.1002/bdd.2325

Yichao Xu, Jinliang Chen, Zourong Ruan, Bo Jiang, Dandan Yang, Yin Hu, Honggang Lou

{"title":"Simulation of febuxostat pharmacokinetics in healthy subjects and patients with impaired kidney function using physiologically based pharmacokinetic modeling","authors":"Yichao Xu, Jinliang Chen, Zourong Ruan, Bo Jiang, Dandan Yang, Yin Hu, Honggang Lou","doi":"10.1002/bdd.2325","DOIUrl":"10.1002/bdd.2325","url":null,"abstract":"Febuxostat is recommended by the American College of Rheumatology Gout Management Guidelines as a first-line therapy for lowering the level of urate in patients with gout. At present, this drug is being prescribed mainly based on the clinical experience of doctors. The potential effects of clinical and demographic variables on the bioavailability and therapeutic effectiveness of febuxostat are not being considered. In this study a physiologically based pharmacokinetic (PBPK) model of febuxostat was developed, thereby providing a theoretical basis for the individualized dosing of this drug in gout patients. The plasma concentration–time profiles corresponding to healthy subjects and gout patients with normal kidney function were simulated and validated; then, the model was used to predict the pharmacokinetic (PK) data of the drug in gout patients suffering from varying degrees of impaired kidney function. The error values (the predicted value/observed value) were used to validate the simulated PK parameters predicted by the PBPK model, including the area under the plasma concentration–time curve, the maximum plasma concentration, and time to maximum plasma concentration. Considering that to all error fold changes were smaller than 2, the PBPK model was. In subjects suffering from mild kidney impairment, moderate kidney impairment, severe kidney impairment, and endstage kidney disease (ESRD), the predicted AUC0-24h values increased by 1.62, 1.74, 2.27, and 2.65-fold, respectively, compared to gout patients with normal kidney function. Overall, the results showed that the PBPK model constructed in this study predict the pharmacokinetic changes in gout patients suffering from varying degrees of impaired kidney function.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 4","pages":"140-151"},"PeriodicalIF":2.1,"publicationDate":"2022-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40392052","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

Optimizing transcardial perfusion of small molecules and biologics for brain penetration and biodistribution studies in rodents 优化小分子和生物制剂经心脏灌注用于啮齿动物脑渗透和生物分布研究

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-05-04 DOI: 10.1002/bdd.2317

Keumhan Noh, Xingrong Liu, Cong Wei

{"title":"Optimizing transcardial perfusion of small molecules and biologics for brain penetration and biodistribution studies in rodents","authors":"Keumhan Noh, Xingrong Liu, Cong Wei","doi":"10.1002/bdd.2317","DOIUrl":"10.1002/bdd.2317","url":null,"abstract":"Efficiently removing blood from the brain vasculature is critical to evaluate accurately the brain penetration and biodistribution of drug candidates, especially for biologics as their blood concentrations are substantially higher than the brain concentrations. Transcardial perfusion has been used widely to remove residual blood in the brain; however, the perfusion conditions (such as the perfusion rate and time) reported in the literature are quite varied, and the performance of these methods on blood removal has not been investigated thoroughly. In this study, the effectiveness of the perfusion conditions was assessed by measuring brain hemoglobin levels. Sodium nitrite (NaNO2) as an additive in the perfusate was evaluated at different concentrations. Blood removal was significantly improved with 2% NaNO2 over a 20 min perfusion in mouse without disrupting the integrity of the blood-brain barrier (BBB). In mice, the optimized perfusion method significantly lowered the measured brain-to-plasma ratio (Kp,brain) for monoclonal antibodies due to the removal of blood contamination and small molecules with a moderate-to-high BBB permeability and with a high brain-unbound-fraction (fu,brain) presumably due to flux out of the brain during perfusion. Perfusion with or without NaNO2 clearly removed the residual blood in rat brain but with no difference observed in Kp,brain between the perfusion groups with or without 2% NaNO2. In conclusion, a perfusion method was successfully developed to evaluate the brain penetration of small molecules and biologics in rodents for the first time. The transcardial perfusion with 2% NaNO2 effectively removed the residual blood in the brain and significantly improved the assessment of brain penetration of biologics. For small molecules, however, transcardial perfusion may not be performed, as small molecule compounds could be washed away from the brain by the perfusion procedure.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"71-83"},"PeriodicalIF":2.1,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9134438","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 acetaminophen glucuronide/acetaminophen concentration ratio warns the onset of acetaminophen‐induced liver injury 血浆对乙酰氨基酚葡萄糖醛酸/对乙酰氨基酚浓度比降低提示对乙酰氨基酚诱导的肝损伤的发生

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-05-04 DOI: 10.1002/bdd.2316

T. Noda, R. Kato, Yasuyuki Ozato, Y. Kawai, M. Yamamoto, Yuya Kagawa, Misa Azuma, Kojiro Yamamoto, Mika Kusanagi, Kiyoaki Uryu, Hiromasa Harada, Y. Ijiri, T. Hayashi, Kazuhiko Tanaka

{"title":"Decreased plasma acetaminophen glucuronide/acetaminophen concentration ratio warns the onset of acetaminophen‐induced liver injury","authors":"T. Noda, R. Kato, Yasuyuki Ozato, Y. Kawai, M. Yamamoto, Yuya Kagawa, Misa Azuma, Kojiro Yamamoto, Mika Kusanagi, Kiyoaki Uryu, Hiromasa Harada, Y. Ijiri, T. Hayashi, Kazuhiko Tanaka","doi":"10.1002/bdd.2316","DOIUrl":"https://doi.org/10.1002/bdd.2316","url":null,"abstract":"Acetaminophen (APAP)‐induced liver injury (AILI) is the most common cause of acute liver failure. Although the mechanisms that trigger AILI are well known, it is less understood how to halt AILI progression and facilitate liver recovery. Therefore, it is necessary to understand the pathophysiology of APAP hepatotoxicity in patients and to examine predictive/preventive markers. In a clinical study, we had a case in which aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels increased in a patient with a low ratio of APAP glucuronide concentration (AP‐G)/APAP plasma concentration. Then a reverse translational study was conducted for clarifying this clinical question. The relationship between plasma AP‐G/APAP concentration ratio and the levels of AST and ALT was examined by in vivo and in vitro experiments. In in vivo experiments, 10‐week‐old rats showed lower UGT activity, lower AP‐G/APAP concentration ratios, and higher AST and ALT levels than 5‐week‐old rats. This suggests an inverse correlation between the AP‐G/APAP concentration ratio and the AST, ALT levels in APAP‐treated rats. Furthermore, as a result of the in vitro experiment, it was confirmed that the cell viability decreased when the AP‐G/APAP concentration ratio in the culture medium decreased. Since the decrease in the plasma AP‐G/APAP concentration ratio appears earlier than the increase of AST and ALT levels, the ratio might be a presymptomatic marker of AILI. When APAP is used for a long time, it is recommended to perform therapeutic drug monitoring of the AP‐G/APAP concentration ratio, which is a predictive/preventive marker of AILI.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 1","pages":"108 - 116"},"PeriodicalIF":2.1,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43991090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Physiologically based pharmacokinetic modeling and simulations to inform dissolution specifications and clinical relevance of release rates on elagolix exposure 基于生理学的药代动力学建模和模拟，以告知依拉哥利暴露的溶出规格和释放率的临床相关性

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-04-11 DOI: 10.1002/bdd.2315

Dwaipayan Mukherjee, M. Chiney, Xi Shao, T. Ju, M. Shebley, P. Marroum

{"title":"Physiologically based pharmacokinetic modeling and simulations to inform dissolution specifications and clinical relevance of release rates on elagolix exposure","authors":"Dwaipayan Mukherjee, M. Chiney, Xi Shao, T. Ju, M. Shebley, P. Marroum","doi":"10.1002/bdd.2315","DOIUrl":"https://doi.org/10.1002/bdd.2315","url":null,"abstract":"The aim of this analysis was to use a physiologically based pharmacokinetic (PBPK) model to predict the impact of changes in dissolution rates on elagolix exposures and define clinically relevant acceptance criteria for dissolution. Varying in vitro dissolution profiles were utilized in a PBPK model to describe the absorption profiles of elagolix formulations used in Phase 3 clinical trials and for the to be marketed commercial formulations. Single dose studies of 200 mg elagolix formulations were used for model verification under fasted conditions. Additional dissolution scenarios were evaluated to assess the impact of dissolution rates on elagolix exposures. Compared to the Phase 3 clinical trial formulation, sensitivity analysis on dissolution rates suggested that a hypothetical scenario of ∼75% slower dissolution rate would result in 14% lower predicted elagolix plasma exposures, however, the predicted exposures are still within the bioequivalence boundaries of 0.8–1.25 for both Cmax and AUC. A clinically verified PBPK model of elagolix was utilized to evaluate the impact of wider dissolution specifications on elagolix plasma exposures. The simulation results indicated that a slower in vitro dissolution profile, would not have a clinically significant impact on elagolix exposures. These model results informed the setting of wider dissolution specifications without requiring in vivo studies.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 1","pages":"98 - 107"},"PeriodicalIF":2.1,"publicationDate":"2022-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42825095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients 他克莫司在中国成人肝移植患者中的群体药代动力学

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-02-26 DOI: 10.1002/bdd.2311

Fei Teng, Weiyue Zhang, Wei Wang, Jiani Chen, Shiyi Liu, Mingming Li, Lujin Li, Wenyuan Guo, Hua Wei

{"title":"Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients","authors":"Fei Teng, Weiyue Zhang, Wei Wang, Jiani Chen, Shiyi Liu, Mingming Li, Lujin Li, Wenyuan Guo, Hua Wei","doi":"10.1002/bdd.2311","DOIUrl":"10.1002/bdd.2311","url":null,"abstract":"Tacrolimus is widely used in organ transplantation to prevent rejection. However, the narrow therapeutic window and the large inter-and intra-individual variability in the pharmacokinetics (PK) of tacrolimus make it difficult for individualization of dosing. This study aimed at developing a population pharmacokinetic model for estimating the oral clearance of tacrolimus in Chinese liver transplant patients, and identifying factors that contribute to the PK variability of tacrolimus. Data of 151 liver transplant patients who received tacrolimus were analyzed in this study. The population PK model was analyzed and the covariates including population demographic and biochemical characteristics, drug combination, and genetic polymorphism were explored using non-linear mixed-effects modeling approach. A single-compartment population PK model was developed, and the final model was CL/F = (14.6–2.38 × cytochrome P450 (CYP) 3A5−3.72 × WZC+1.04 × (POD/9)+2.48 × COR) × Exp(ηi), where CYP3A5 was 1 for CYP3A5*3/*3, Wuzhi Capsule (WZC) was 1 when patients took tacrolimus combined with WZC, otherwise it was 0, corticosteroids (COR) was 1 when patients take tacrolimus combined with COR, otherwise, it was 0, POD was the post-operative day. Visual inspection and bootstrap indicated that the final model was stable and robust. In this study, we developed the first tacrolimus population PK model in Chinese adult liver transplant patients. We first determined the influence of WZC on tacrolimus in these people, which could provide useful PK information for the drug combination of tacrolimus and WZC. We also revealed the influence of genetic polymorphism of CYP3A5, POD, and a combination of COR on tacrolimus PK. Therefore, these significant factors should be taken into consideration in optimizing dosage regimens.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 2","pages":"76-85"},"PeriodicalIF":2.1,"publicationDate":"2022-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46136799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81 α2/3选择性GABAkine KRM-II-81的代谢、药代动力学和抗惊厥活性

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-02-22 DOI: 10.1002/bdd.2313

Lalit K. Golani, Branka Divović, Dishary Sharmin, Kamal P. Pandey, Md Yeunus Mian, Rok Cerne, Nicolas M. Zahn, Michelle J. Meyer, Veera V. N. P. B. Tiruveedhula, Jodi L. Smith, Xingjie Ping, Xiaoming Jin, Arnold Lippa, Jeffrey M. Schkeryantz, Leggy A. Arnold, James M. Cook, Miroslav M. Savić, Jeffrey M. Witkin

{"title":"Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81","authors":"Lalit K. Golani, Branka Divović, Dishary Sharmin, Kamal P. Pandey, Md Yeunus Mian, Rok Cerne, Nicolas M. Zahn, Michelle J. Meyer, Veera V. N. P. B. Tiruveedhula, Jodi L. Smith, Xingjie Ping, Xiaoming Jin, Arnold Lippa, Jeffrey M. Schkeryantz, Leggy A. Arnold, James M. Cook, Miroslav M. Savić, Jeffrey M. Witkin","doi":"10.1002/bdd.2313","DOIUrl":"10.1002/bdd.2313","url":null,"abstract":"The imidazodiazepine, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo [f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a new α2/3-selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half-life of KRM-II-81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM-II-81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5-KRM-II-81) that could be evaluated as a potentially longer-acting analog. In contrast to computer predictions, peak plasma concentrations of D5-KRM-II-81 in rats were not significantly greater than those produced by KRM-II-81 after oral administration. Furthermore, brain disposition of KRM-II-81 was higher than that of D5-KRM-II-81. The half-life of the two compounds in either plasma or brain did not statistically differ from one another but the tmax for D5-KRM-II-81 occurred slightly earlier than for KRM-II-81. Non-metabolic considerations might be relevant to the lack of increases in exposure by D5-KRM-II-81. Alternative sites of metabolism on KRM-II-81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5-KRM-II-81, like KRM-II-81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5-KRM-II-81.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 2","pages":"66-75"},"PeriodicalIF":2.1,"publicationDate":"2022-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39945099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Effect of hepar-protecting Wuzhi capsule on pharmacokinetics and dose-effect character of tacrolimus in healthy volunteers 保肝五脂胶囊对他克莫司在健康人体药动学及量效特性的影响

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-02-18 DOI: 10.1002/bdd.2312

Fei Teng, Wei Wang, Weiyue Zhang, Jinlong Qu, Binguo Liu, Jiani Chen, Shiyi Liu, Mingming Li, Wansheng Chen, Hua Wei

{"title":"Effect of hepar-protecting Wuzhi capsule on pharmacokinetics and dose-effect character of tacrolimus in healthy volunteers","authors":"Fei Teng, Wei Wang, Weiyue Zhang, Jinlong Qu, Binguo Liu, Jiani Chen, Shiyi Liu, Mingming Li, Wansheng Chen, Hua Wei","doi":"10.1002/bdd.2312","DOIUrl":"10.1002/bdd.2312","url":null,"abstract":"Wuzhi capsule (WZC), a preparation of Fructus Schisandra sphenanthera extract, has been used widely for the treatment of viral and drug-induced hepatitis in China. This study aimed to determine the pharmacokinetic parameters of tacrolimus (TAC) when co-administered with WZC and the dose-effect of WZC on tacrolimus in healthy volunteers. The effect of an increased dosage of WZC (1, 2, 6, and 8 capsules once daily) on the relative oral exposure of tacrolimus was assessed to explore the dose–response relationship between WZC and tacrolimus using bioanalysis, pharmacokinetic, and genotypical analyses. The influence of CYP3A5 and MDR1 genetic polymorphisms on the WZC dose was elucidated by maintaining the Ctrough of tacrolimus in Chinese healthy volunteers. When co-administered with WZC, the Tmax of tacrolimus was increased significantly while the apparent oral clearance was decreased. The plasma tacrolimus level in volunteers with high CYP3A5 expression was much lower than that in those with mutant CYP3A5. However, polymorphisms of MDR1 exon26 C3435T, exon21 G2677T/A, and exon12 C1236T were not associated with plasma tacrolimus levels. Our findings provide important information on interactions between modern medications and herbal products, thus facilitating a better usage of tacrolimus in patients receiving WZC.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 4","pages":"119-129"},"PeriodicalIF":2.1,"publicationDate":"2022-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39935506","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