Biopharmaceutics & Drug Disposition最新文献

{"title":"Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys","authors":"Teng Meng,&nbsp;Donald Jung,&nbsp;Xiao-Hong Cai,&nbsp;Zhao-Qiang Lu,&nbsp;Ji-Bing Yu,&nbsp;Tian-Yang Qi,&nbsp;Fan-Ying Meng,&nbsp;Mei-Zhen Ruan,&nbsp;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/m² 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}

{"title":"Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs","authors":"K. Sandy Pang,&nbsp;H. Benson Peng,&nbsp;Betty P. Li,&nbsp;Binyu Wen,&nbsp;Keumhan Noh,&nbsp;Runyu Xia,&nbsp;Anja Toscan,&nbsp;Sylvia Serson,&nbsp;Paul E. Fraser,&nbsp;Rommel G. Tirona,&nbsp;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 (Aβ₄₀ and Aβ₄₂) 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 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.</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}

{"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,&nbsp;Mohamed A. Osman,&nbsp;Sanaa A. El-Gizawy,&nbsp;Dimple Modi,&nbsp;Nitin B. Charbe,&nbsp;Ayman F. El-Kattan,&nbsp;Mohamed El-Tanani,&nbsp;Yusuf A. Haggag,&nbsp;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 &lt; jejunum &lt; duodenum &lt; 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}

{"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,&nbsp;Xuping Yang,&nbsp;Lulu Dong,&nbsp;Yan Jiang,&nbsp;Sulan Zou,&nbsp;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_cys-scr, CKD-EPI_scr, and CKD-EPI_cys) and two Berlin Initiative Study equations (BIS-1 and BIS-2). The CKD-EPI_cys-scr 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_cys-scr 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_cys-scr 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_cys-scr 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_cys-scr 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_cys-scr 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,&nbsp;Xinyi Wang,&nbsp;Xueyan Gou,&nbsp;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>_m. 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>_m 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>² &gt; 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}

{"title":"Computational exploration of microsomal cytochrome P450 3A1 enzyme modulation by phytochemicals of Cichorium intybus L.: Insights into drug metabolism","authors":"Abhishek Pathak,&nbsp;Satya Pal Singh,&nbsp;Dev Bukhsh Singh,&nbsp;Pranav Anjaria,&nbsp;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}

{"title":"Evidence for cytochrome P450 3A4-mediated metabolic activation of SCO-267","authors":"Cui Li,&nbsp;Xiaokun Li,&nbsp;Ali Fan,&nbsp;Ning He,&nbsp;Dongmei Wu,&nbsp;Hongyan Yu,&nbsp;Kun Wang,&nbsp;Weijie Jiao,&nbsp;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_I and <i>k</i>_inact values of 4.91 μM and 0.036 min⁻¹, 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}

{"title":"Quantitative analysis of the impact of membrane permeability on intestinal first-pass metabolism of CYP3A substrates","authors":"Yugo Yasugi,&nbsp;Yoshiyuki Shirasaka,&nbsp;Ikumi Tamai","doi":"10.1002/bdd.2379","DOIUrl":"10.1002/bdd.2379","url":null,"abstract":"<p>The aim of this study was firstly to investigate the effect of membrane permeability on the intestinal availability (<i>F</i>_g) of 10 cytochrome P450 3A4 substrates with differing permeability (<i>P</i>_app) and metabolic activity (<i>CL</i>_int) using Madin-Darby canine kidney II (MDCKII) cells expressing human CYP3A4 (MDCKII/CYP3A4 cells), and secondly to confirm the essential factors by simulations. A membrane permeation assay using MDCKII/CYP3A4 cells showed a significant correlation between human intestinal extraction ratio (ER) (<i>E</i>_g (=1 − <i>F</i>_g)) and <i>in vitro</i> cellular ER (<i>r</i> = 0.834). This relationship afforded better predictability of <i>E</i>_g values than the relationship between <i>E</i>_g and <i>CL</i>_int,HIM values obtained from human intestinal microsomes (<i>r</i> = 0.598). An even stronger correlation was observed between 1 − <i>F</i>_a·<i>F</i>_g and ER (<i>r</i> = 0.874). Simulation with a cellular kinetic model indicated that ER is sensitive to changes of <i>PS</i>_passive and <i>CL</i>_int values, but not to the intracellular unbound fraction (<i>f</i>_u,cell) or P-gp-mediated efflux (<i>PS</i>_P − gp). It may be concluded that, based on the concentration–time profile of drugs in epithelial cells, transmembrane permeability influences <i>F</i>_g (or ER) and drug exposure time to metabolizing enzymes for P450 substrate.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"45 1","pages":"3-14"},"PeriodicalIF":2.1,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138629572","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":"Metabolism of testosterone and progesterone by cytochrome P450 2C19 allelic variants","authors":"Shiori Takeji,&nbsp;Mai Okada,&nbsp;Shu Hayashi,&nbsp;Kengo Kanamaru,&nbsp;Yuichi Uno,&nbsp;Hiromasa Imaishi,&nbsp;Tomohide Uno","doi":"10.1002/bdd.2378","DOIUrl":"10.1002/bdd.2378","url":null,"abstract":"<p>CYP2C19 is a member of the human microsomal cytochrome P450 (CYP). Significant variation in CYP2C19 levels and activity can be attributed to polymorphisms in this gene. Wildtype CYP2C19 and 13 mutants (CYP2C19.1B, CYP2C19.5A, CYP2C19.5B, CYP2C19.6, CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.11, CYP2C19.13, CYP2C19.16, CYP2C19.19, CYP2C19.23, CYP2C19.30, and CYP2C19.33) were coexpressed with NADPH-cytochrome P450 reductase in <i>Escherichia coli</i>. Hydroxylase activity toward testosterone and progesterone was also examined. Ten CYP2C19 variants showed Soret peaks (450 nm) typical of P450 in the reduced CO-difference spectra. CYP2C19.11 and CYP2C19.23 showed higher testosterone 11α, 16α-/17- and progesterone 6β-,21-,16α-/17α-hydroxylase activities than CYP2C19.1B. CYP2C19.6, CYP2C19.16, CYP2C19.19, and CYP2C19.30 showed lower activity than CYP2C19.1B. CYP2C19.9, CYP2C19.10. CYP2C19.13, and CYP2C19.33 showed different hydroxylation activities than CYP2C19.1B. These results indicated that CYP2C19 variants have very different substrate specificities for testosterone and progesterone.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 6","pages":"420-430"},"PeriodicalIF":2.1,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41189939","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":"Pharmacokinetic–pharmacodynamic modeling of the active components of Shenkang injection in rats with chronic renal failure and its protective effect on damaged renal cells","authors":"Lin Zhou,&nbsp;Xiaohui Wang,&nbsp;Jinlan Xia,&nbsp;Liyuan Zhang,&nbsp;Lianping Xue,&nbsp;Qingquan Jia,&nbsp;Zhihui Fu,&nbsp;Zhi Sun","doi":"10.1002/bdd.2377","DOIUrl":"10.1002/bdd.2377","url":null,"abstract":"&lt;p&gt;The study aimed to explore the pharmacokinetic and pharmacodynamic alterations of the active components of Shenkang injection (i.e. hydroxy saffron yellow pigment A [HSYA], tanshinol, rheum emodin, and astragaloside IV) in rats with chronic renal failure (CRF), and establish a pharmacokinetic–pharmacodynamic model (PK-PD model) in order to provide a scientific and theoretical basis for the rational clinical use of Shenkang injection. Sprague–Dawley (SD) rats were randomly divided into a normal group, model group, and Shenkang injection group. A rat model of CRF was induced by adenine gavage and then followed by drug administration via tail vein injection. Orbital blood was collected at different timepoints and the blood concentrations of the four active components were measured by UHPLC-Q-Orbitrap HRMS. Serum levels of creatinine (Scr), urea nitrogen (BUN), and uric acid (UA) were determined using an automatic biochemical analyzer. A PK-PD model was established, and DAS 3.2.6 software was used for model fitting as well as statistical analysis. TGF-β1 was utilized to induce normal rat kidney cells to construct a renal fibrosis model to investigate the protective effect of the pharmacological components on renal fibrosis. The pharmacokinetic analysis of hydroxy saffron yellow pigment A, tanshinol, rheum emodin, and astragaloside IV based on UHPLC-Q-Orbitrap HRMS was stable. The linear regression equations for the four active components were as follows: &lt;i&gt;Y&lt;/i&gt; = 0.031X + 0.0091 (&lt;i&gt;R&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt; = 0.9986) for hydroxy saffron yellow pigment A, &lt;i&gt;Y&lt;/i&gt; = 0.0389X + 0.164 (&lt;i&gt;R&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt; = 0.9979) for tanshinol, &lt;i&gt;Y&lt;/i&gt; = 0.0257X + 0.0146 (&lt;i&gt;R&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt; = 0.9973) for rheum emodin, and &lt;i&gt;Y&lt;/i&gt; = 0.0763X + 0.0139 (&lt;i&gt;R&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt; = 0.9993) for astragaloside IV, which indicated good linear relationships. The methodological investigation was stable, with the interday and intraday precision RSD &lt;10%. Meanwhile, the recoveries ranged between 90% and 120%, in accordance with the requirements for in vivo analysis of drugs. Compared with the model group, the levels of Scr, BUN, and UA were significantly decreased after 20 min in the Shenkang injection group (&lt;i&gt;p&lt;/i&gt; &lt; 0.01). The PK-PD model showed that the four active components in the Shenkang injection group could fit well with the three effect measures (i.e. Scr, BUN, and UA), with the measured values similar to the predicted values. The cell model of renal fibrosis showed that the connective tissue growth factor and FN1 protein expression levels were significantly lower in the Shenkang injection group than those in the model group, and the cell fibrosis was improved. The established method for in vivo analysis of Shenkang injection was highly specific, with good separation of the components and simple operation. The total statistical moment could well integrate the pharmacokinetic parameters of the four active components. After treatment with Shenkang injection, all index","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 6","pages":"406-419"},"PeriodicalIF":2.1,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10535240","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}