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":"<p>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.</p>","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}
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":"<p>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(<i>N,N</i>-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 <i>ζ</i>-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 (<i>T</i><sub>max</sub>) of 3.4 h, maximum plasma concentration (<i>C</i><sub>max</sub>) of 0.12 μg/mL, and bioavailability of 0.7%. Compared with amorphous CsA powder, MP/CsA shortened <i>T</i><sub>max</sub> by 1.1 to 2.3 h and increased the bioavailability by 43-fold to 30.1%, while MA/CsA prolonged <i>T</i><sub>max</sub> by 3.4 to 6.8 h with <i>C</i><sub>max</sub> 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.</p>","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}
{"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":"<p>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 (AUC<sub>0−<i>t</i></sub>) 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 AUC<sub>0−<i>t</i></sub> 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.</p>","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}
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":"<p>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/m<sup>2</sup> in the first-in-human dose escalation study.</p>","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}
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":"<p>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 (Aβ<sub>40</sub> and Aβ<sub>42</sub>) peptides, <i>Mdr1</i> 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 (<i>Abcb1</i>) and Cyp46a1 (24(S)-hydroxylase) for Aβ<sub>40</sub>, and Aβ<sub>42</sub> 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.</p>","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}
Ahmed M. Elmeniar, Mohamed A. Osman, Sanaa A. El-Gizawy, Dimple Modi, Nitin B. Charbe, Ayman F. El-Kattan, Mohamed El-Tanani, Yusuf A. Haggag, Murtaza M. Tambuwala
{"title":"In situ evaluation of the impact of metformin or verapamil coadministration with vildagliptin on its regional absorption from the rabbit’s intestine","authors":"Ahmed M. Elmeniar, Mohamed A. Osman, Sanaa A. El-Gizawy, Dimple Modi, Nitin B. Charbe, Ayman F. El-Kattan, Mohamed El-Tanani, Yusuf A. Haggag, Murtaza M. Tambuwala","doi":"10.1002/bdd.2384","DOIUrl":"10.1002/bdd.2384","url":null,"abstract":"<p>This research aims to identify regional differences in vildagliptin absorption across the intestinal membrane. Furthermore, it was to investigate the effect of verapamil or metformin on vildagliptin absorptive clearance. The study utilized an <i>in situ</i> rabbit intestinal perfusion technique to determine vildagliptin oral absorption from duodenum, jejunum, ileum, and ascending colon. This was conducted both with and without perfusion of metformin or verapamil. The findings revealed that the vildagliptin absorptive clearance per unit length varied by site and was in the order as follows: ileum < jejunum < duodenum < ascending colon, implying that P-gp is significant in the reduction of vildagliptin absorption. Also, the arrangement cannot reverse intestinal P-gp, but the observations suggest that P-gp is significant in reducing vildagliptin absorption. Verapamil co-perfusion significantly increased the vildagliptin absorptive clearance by 2.4 and 3.2 fold through the jejunum and ileum, respectively. Metformin co-administration showed a non-significant decrease in vildagliptin absorptive clearance through all tested segments. Vildagliptin absorption was site-dependent and may be related to the intestinal P-glycoprotein content. This may aid in understanding the important elements that influence vildagliptin absorption, besides drug–drug interactions that can occur in type 2 diabetic patients taking vildagliptin in conjunction with other drugs that can modify the P-glycoprotein level.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 2","pages":"71-82"},"PeriodicalIF":2.1,"publicationDate":"2024-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2384","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139943858","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}
Jing Ling, Xuping Yang, Lulu Dong, Yan Jiang, Sulan Zou, Nan Hu
{"title":"Utility of cystatin C and serum creatinine-based glomerular filtration rate equations in predicting vancomycin clearance: A population pharmacokinetics analysis in elderly Chinese patients","authors":"Jing Ling, Xuping Yang, Lulu Dong, Yan Jiang, Sulan Zou, Nan Hu","doi":"10.1002/bdd.2383","DOIUrl":"10.1002/bdd.2383","url":null,"abstract":"<p>Renal function is an important factor affecting the pharmacokinetics of vancomycin. The renal function in elderly patients gradually decreases with age. An accurate estimated glomerular filtration rate (GFR) is essential in drug dosing. The study aimed to determine the most appropriate renal function estimation equations to describe vancomycin pharmacokinetics in elderly patients using population pharmacokinetic analysis. Data were obtained retrospectively from elderly patients aged ≥65 years who received vancomycin for infection from September 2016 to January 2022. Renal function was estimated using the Cockcroft-Gault equation (CG), Modification of Diet in Renal Disease equation (MDRD), three Chronic Kidney Disease Epidemiology Collaboration equations (CKD-EPI<sub>cys-scr</sub>, CKD-EPI<sub>scr</sub>, and CKD-EPI<sub>cys</sub>) and two Berlin Initiative Study equations (BIS-1 and BIS-2). The CKD-EPI<sub>cys-scr</sub> and BIS-2 equations were based on cystatin C (Cys C) and serum creatinine (Scr). The others were based on Cys C or Scr. A nonlinear mixed effects model (NONMEM) was used to develop the population pharmacokinetic model. A total of 471 serum concentrations from 313 elderly patients were used to develop the population pharmacokinetic model. Weight and GFR were identified as significant covariates affecting the pharmacokinetics of vancomycin. Cys C and Scr-based GFR (CKD-EPI<sub>cys-scr</sub> and BIS-2) yielded significant improvement performance compared with the other equations in model building. The interindividual variability of CL was reduced from 49.4% to 23.6% and 49.4% to 23.7% in CKD-EPI<sub>cys-scr</sub> and BIS-2 based models, respectively. However, greater interindividual variabilities of CL (from 26.6% to 29.0%) were represented in the other five models which were based on either Cys C or Scr. The GFR estimated by EPI<sub>cys-scr</sub> and BIS-2 equations and vancomycin CL exhibited a good correlation (r = 0.834 and 0.833). In the external validation with 124 serum concentrations, the predictive performances of the CKD-EPI<sub>cys-scr</sub> and BIS-2 based models (the mean relative prediction errors were less than 1%, the mean relative absolute prediction errors were about 23%) were also superior to the other five models (the mean relative prediction errors were about 2%, the mean relative absolute prediction errors were greater than 25%) which are based on either Cys C or Scr. In this study, we determined that the equation used to estimate GFR can affect the population pharmacokinetic model fitting result. Population pharmacokinetics model with CKD-EPI<sub>cys-scr</sub> or BIS-2 can be used to optimize vancomycin dosage in elderly Chinese patients.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 1","pages":"58-68"},"PeriodicalIF":2.1,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691116","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":"Identification and characterization of an endogenous biomarker of the renal vectorial transport (OCT2-MATE1)","authors":"Yanrong Ma, Xinyi Wang, Xueyan Gou, Xinan Wu","doi":"10.1002/bdd.2382","DOIUrl":"10.1002/bdd.2382","url":null,"abstract":"<p>The renal tubular organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the vectorial elimination of many drugs and toxins from the kidney, and endogenous biomarkers for vectorial transport (OCT2-MATE1) would allow more accurate drug dosing and help to characterize drug–drug interactions and toxicity. Human serum uptake in OCT2-overexpressing cells and metabolomics analysis were carried out. Potential biomarkers were verified <i>in vitro</i> and <i>in vivo</i>. The specificity of biomarkers was validated in renal transporter overexpressing cells and the sensitivity was investigated by <i>K</i><sub>m</sub>. The results showed that the uptake of thiamine, histamine, and 5-hydroxytryptamine was significantly increased in OCT2-overexpressing cells. <i>In vitro</i> assays confirmed that thiamine, histamine, and 5-hydroxytryptamine were substrates of both OCT2 and MATE1. <i>In vivo</i> measurements indicated that the serum thiamine level was increased significantly in the presence of the rOCT2 inhibitor cimetidine, and the level in renal tissue was increased significantly by the rMATE1 inhibitor pyrimethamine. There were no significant changes in the uptake or efflux of thiamine in cell lines overexpressed OAT1, OAT2, OAT3, MRP4, organic anion transporting polypeptide 4C1, P-gp, peptide transporter 2, urate transporter 1, and OAT4. The <i>K</i><sub>m</sub> for thiamine with OCT2 and MATE1 were 71.2 and 10.8 μM, respectively. In addition, the cumulative excretion of thiamine at 2 and 4 h was strongly correlated with metformin excretion (<i>R</i><sup>2</sup> > 0.6). Thus, thiamine is preferentially secreted by the OCT2 and MATE1 in renal tubules and can provide a reference value for evaluating the function of the renal tubular OCT2-MATE1.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 1","pages":"43-57"},"PeriodicalIF":2.1,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139665487","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}
Abhishek Pathak, Satya Pal Singh, Dev Bukhsh Singh, Pranav Anjaria, Apoorv Tiwari
{"title":"Computational exploration of microsomal cytochrome P450 3A1 enzyme modulation by phytochemicals of Cichorium intybus L.: Insights into drug metabolism","authors":"Abhishek Pathak, Satya Pal Singh, Dev Bukhsh Singh, Pranav Anjaria, Apoorv Tiwari","doi":"10.1002/bdd.2380","DOIUrl":"10.1002/bdd.2380","url":null,"abstract":"<p>Drug metabolism plays a crucial role in drug fate, including therapeutic inactivation or activation, as well as the formation of toxic compounds. This underscores the importance of understanding drug metabolism in drug discovery and development. Considering the substantial costs associated with traditional drug development methods, computational approaches have emerged as valuable tools for predicting the metabolic fate of drug candidates. With this in mind, the present study aimed to investigate the potential mechanisms underlying the modulation of microsomal cytochrome P450 3A1 (CYP3A1) enzyme activity by various phytochemicals found in <i>Cichorium intybus</i> L., commonly known as chicory. To achieve this goal, several <i>in silico</i> methods, including molecular docking and molecular dynamics (MD) simulation, were employed to explore computationally the microsomal CYP3A1 enzyme. Schrodinger software was utilized for the molecular docking study, which involved the interaction analysis between CYP3A1 and 28 phytoconstituents of <i>Cichorium intybus</i>. Virtual screening of 28 compounds from chicory led to the identification of the top five ranked compounds. These compounds were evaluated for drug-likeness properties, pharmacokinetic profiles, and predicted binding affinities to CYP3A1. Caffeoylshikimic acid and cichoric acid emerged as promising candidates due to their favorable characteristics, including good oral bioavailability and high binding affinities to CYP3A1. Molecular dynamics simulations were conducted to assess the stability of caffeoylshikimic acid within the CYP3A1 binding pocket. The results demonstrated that caffeoylshikimic acid maintained stable interactions with the enzyme throughout the simulation, suggesting its potential as an effective modulator of CYP3A1 activity. The findings of this study have the potential to provide valuable insights into the complex molecular mechanisms by which <i>Cichorium intybus</i> L. acts on hepatocytes and modulates CYP3A1 enzyme expression or activity. By elucidating the impact of these phytochemicals on drug metabolism, this research contributes to our understanding of how chicory may interact with drugs and influence their efficacy and safety profiles.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 1","pages":"15-29"},"PeriodicalIF":2.1,"publicationDate":"2024-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139511610","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}
Cui Li, Xiaokun Li, Ali Fan, Ning He, Dongmei Wu, Hongyan Yu, Kun Wang, Weijie Jiao, Xu Zhao
{"title":"Evidence for cytochrome P450 3A4-mediated metabolic activation of SCO-267","authors":"Cui Li, Xiaokun Li, Ali Fan, Ning He, Dongmei Wu, Hongyan Yu, Kun Wang, Weijie Jiao, Xu Zhao","doi":"10.1002/bdd.2381","DOIUrl":"10.1002/bdd.2381","url":null,"abstract":"<p>SCO-267 is a potent G-protein-coupled receptor 40 agonist that is undergoing clinical development for the treatment of type 2 diabetes mellitus. The current work was undertaken to investigate the bioactivation potential of SCO-267 <i>in vitro</i> and <i>in vivo</i>. Three SCO-267-derived glutathione (GSH) conjugates (M1–M3) were found both in rat and human liver microsomal incubations supplemented with GSH and nicotinamide adenine dinucleotide phosphate. Two GSH conjugates (M1–M2) together with two <i>N-</i>acetyl-cysteine conjugates (M4–M5) were detected in the bile of rats receiving SCO-267 at 10 mg/kg. The identified conjugates suggested the generation of quinone-imine and <i>ortho</i>-quinone intermediates. CYP3A4 was demonstrated to primarily catalyze the bioactivation of SCO-267. In addition, SCO-267 concentration-, time-, and NADPH-dependently inactivated CYP3A in human liver microsomes using testosterone as a probe substrate, along with K<sub>I</sub> and <i>k</i><sub>inact</sub> values of 4.91 μM and 0.036 min<sup>−1</sup>, respectively. Ketoconazole (a competitive inhibitor of CYP3A) displayed no significant protective effect on SCO-267-induced CYP3A inactivation. However, inclusion of GSH showed significant protection. These findings revealed that SCO-267 undergoes a facile CYP3A4-catalyzed bioactivation with the generation of quinone-imine and <i>ortho</i>-quinone intermediates, which were assumed to be involved in SCO-267 induced CYP3A inactivation. These findings provide further insight into the bioactivation pathways involved in the generation of reactive, potentially toxic metabolites of SCO-267. Further studies are needed to evaluate the influence of SCO-267 metabolism on the safety of this drug <i>in vivo</i>.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 1","pages":"30-42"},"PeriodicalIF":2.1,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139490329","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}