Shiori Takeji, Mai Okada, Shu Hayashi, Kengo Kanamaru, Yuichi Uno, Hiromasa Imaishi, Tomohide Uno
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 Escherichia coli. 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.
{"title":"Metabolism of testosterone and progesterone by cytochrome P450 2C19 allelic variants","authors":"Shiori Takeji, Mai Okada, Shu Hayashi, Kengo Kanamaru, Yuichi Uno, Hiromasa Imaishi, 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}
Lin Zhou, Xiaohui Wang, Jinlan Xia, Liyuan Zhang, Lianping Xue, Qingquan Jia, Zhihui Fu, Zhi Sun
<p>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: <i>Y</i> = 0.031X + 0.0091 (<i>R</i><sup>2</sup> = 0.9986) for hydroxy saffron yellow pigment A, <i>Y</i> = 0.0389X + 0.164 (<i>R</i><sup>2</sup> = 0.9979) for tanshinol, <i>Y</i> = 0.0257X + 0.0146 (<i>R</i><sup>2</sup> = 0.9973) for rheum emodin, and <i>Y</i> = 0.0763X + 0.0139 (<i>R</i><sup>2</sup> = 0.9993) for astragaloside IV, which indicated good linear relationships. The methodological investigation was stable, with the interday and intraday precision RSD <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 (<i>p</i> < 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
{"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, Xiaohui Wang, Jinlan Xia, Liyuan Zhang, Lianping Xue, Qingquan Jia, Zhihui Fu, Zhi Sun","doi":"10.1002/bdd.2377","DOIUrl":"10.1002/bdd.2377","url":null,"abstract":"<p>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: <i>Y</i> = 0.031X + 0.0091 (<i>R</i><sup>2</sup> = 0.9986) for hydroxy saffron yellow pigment A, <i>Y</i> = 0.0389X + 0.164 (<i>R</i><sup>2</sup> = 0.9979) for tanshinol, <i>Y</i> = 0.0257X + 0.0146 (<i>R</i><sup>2</sup> = 0.9973) for rheum emodin, and <i>Y</i> = 0.0763X + 0.0139 (<i>R</i><sup>2</sup> = 0.9993) for astragaloside IV, which indicated good linear relationships. The methodological investigation was stable, with the interday and intraday precision RSD <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 (<i>p</i> < 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}
Frederico Severino Martins, Luiza Borges, Rene Oliveira do Couto, Stephan Schaller, Osvaldo de Freitas
Model-informed drug development is an important area recognized by regulatory authorities and is gaining increasing interest from the generic drug industry. Physiologically based biopharmaceutics modeling (PBBM) is a valuable tool to support drug development and bioequivalence assessments. This study aimed to utilize an artificial neural network (ANN) with a multilayer perceptron (MLP) model to develop a sustained-release matrix tablet of metformin HCl 500 mg, and to test the likelihood of the prototype formulation being bioequivalent to Glucophage® XR, using PBBM modeling and virtual bioequivalence (vBE). The ANN with MLP model was used to simultaneously optimize 735 formulations to determine the optimal formulation for Glucophage® XR release. The optimized formulation was evaluated and compared to Glucophage® XR using PBBM modeling and vBE. The optimized formulation consisted of 228 mg of hydroxypropyl methylcellulose (HPMC) and 151 mg of PVP, and exhibited an observed release rate of 42% at 1 h, 47% at 2 h, 55% at 4 h, and 58% at 8 h. The PBBM modeling was effective in assessing the bioequivalence of two formulations of metformin, and the vBE evaluation demonstrated the utility and relevance of translational modeling for bioequivalence assessments. The study demonstrated the effectiveness of using PBBM modeling and model-informed drug development methodologies, such as ANN and MLP, to optimize drug formulations and evaluate bioequivalence. These tools can be utilized by the generic drug industry to support drug development and biopharmaceutics assessments.
{"title":"Integration of artificial neural network and physiologically based biopharmaceutic models in the development of sustained-release formulations","authors":"Frederico Severino Martins, Luiza Borges, Rene Oliveira do Couto, Stephan Schaller, Osvaldo de Freitas","doi":"10.1002/bdd.2376","DOIUrl":"10.1002/bdd.2376","url":null,"abstract":"<p>Model-informed drug development is an important area recognized by regulatory authorities and is gaining increasing interest from the generic drug industry. Physiologically based biopharmaceutics modeling (PBBM) is a valuable tool to support drug development and bioequivalence assessments. This study aimed to utilize an artificial neural network (ANN) with a multilayer perceptron (MLP) model to develop a sustained-release matrix tablet of metformin HCl 500 mg, and to test the likelihood of the prototype formulation being bioequivalent to Glucophage<sup>®</sup> XR, using PBBM modeling and virtual bioequivalence (vBE). The ANN with MLP model was used to simultaneously optimize 735 formulations to determine the optimal formulation for Glucophage<sup>®</sup> XR release. The optimized formulation was evaluated and compared to Glucophage<sup>®</sup> XR using PBBM modeling and vBE. The optimized formulation consisted of 228 mg of hydroxypropyl methylcellulose (HPMC) and 151 mg of PVP, and exhibited an observed release rate of 42% at 1 h, 47% at 2 h, 55% at 4 h, and 58% at 8 h. The PBBM modeling was effective in assessing the bioequivalence of two formulations of metformin, and the vBE evaluation demonstrated the utility and relevance of translational modeling for bioequivalence assessments. The study demonstrated the effectiveness of using PBBM modeling and model-informed drug development methodologies, such as ANN and MLP, to optimize drug formulations and evaluate bioequivalence. These tools can be utilized by the generic drug industry to support drug development and biopharmaceutics assessments.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 4","pages":"335-343"},"PeriodicalIF":2.1,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10169105","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}
Quantitative in vitro–in vivo extrapolations (IVIVE) have been applied extensively to predict drug metabolism and transporter kinetics (Sodhi & Benet, 2021; Wood et al., 2017; Zamek‐Gliszczynski et al., 2013). However, initially, IVIVE were mainly based on mean in vitro data, giving no estimation of between or within subject variability (BSV/WSV) and, therefore, have a limited ability to address the extremes of risk in real patients or replicate scenarios such as bioequivalence. In other words, ADME properties were estimated considering an average subject, if such a subject exists, under a constant non‐variant condition for all the physiology and biology. Integrating IVIVE with PBPK modeling enables predictions in virtual cohorts including estimation of BSV (Rostami‐Hodjegan & Tucker, 2007), and some recent advances were also made to address the WSV that are essential elements of virtual bioequivalence studies (Bego et al., 2022). Historically, Monte Carlo simulations are used when developing population PBPK models which commonly do not consider the parameter’s inter‐dependencies. However, it is imperative to mechanistically incorporate covariates in these models and to employ correlated Monte Carlo simulations instead (Jamei, 2016; Jamei et al., 2009). In doing so, the predicted PK properties are inherently affected by the relevant covariates (Rostami‐Hodjegan & Tucker, 2007). However, translation of in vitro ADME properties within PBPK models is associated with uncertainties related not only to the knowledge gaps in system parameters, but also to the translatability (scaling) of drug parameters (Rostami‐Hodjegan, 2018). In this context, Mao and co‐workers applied PBPK modeling to predict human PK and assessed model performance retrospectively using clinical data for 18 Genentech compounds (Mao et al., 2023). Currently, the main regulatory application of PBPK modeling is to investigate enzyme‐ or transporter‐mediated drug–drug interactions (Zhang et al., 2020). In this special issue, Vijaywargi and co‐workers compared the performance of static and PBPK models to predict transporter‐mediated DDIs. The authors also discussed the usefulness of endogenous biomarkers, the use of empirical scaling factors, enzyme–transporter interplay, and acceptance criteria for model validation to meet the regulatory expectations (Vijaywargi et al., 2023). The separation between system and drug parameters is an important feature of PBPK modeling with respect to extrapolating results between species and populations. In this special issue Alsmadi and Alzughoul integrate preclinical data and a IVIVE‐PBPK model to extrapolate drug elimination in renally impaired patients (Alsmadi & Alzughoul, 2023). In turn, Liang and co‐workers successfully applied PBPK modeling to optimize azithromycin dosing to pediatrics (Liang et al., 2023) and Zhang and co‐workers developed a PBPK‐based dose decision framework to inform clinical trials with a novel anesthetic agent in special popu
{"title":"Linking in vitro–in vivo extrapolations with physiologically based modeling to inform drug and formulation development","authors":"Rodrigo Cristofoletti, Amin Rostami-Hodjegan","doi":"10.1002/bdd.2375","DOIUrl":"10.1002/bdd.2375","url":null,"abstract":"Quantitative in vitro–in vivo extrapolations (IVIVE) have been applied extensively to predict drug metabolism and transporter kinetics (Sodhi & Benet, 2021; Wood et al., 2017; Zamek‐Gliszczynski et al., 2013). However, initially, IVIVE were mainly based on mean in vitro data, giving no estimation of between or within subject variability (BSV/WSV) and, therefore, have a limited ability to address the extremes of risk in real patients or replicate scenarios such as bioequivalence. In other words, ADME properties were estimated considering an average subject, if such a subject exists, under a constant non‐variant condition for all the physiology and biology. Integrating IVIVE with PBPK modeling enables predictions in virtual cohorts including estimation of BSV (Rostami‐Hodjegan & Tucker, 2007), and some recent advances were also made to address the WSV that are essential elements of virtual bioequivalence studies (Bego et al., 2022). Historically, Monte Carlo simulations are used when developing population PBPK models which commonly do not consider the parameter’s inter‐dependencies. However, it is imperative to mechanistically incorporate covariates in these models and to employ correlated Monte Carlo simulations instead (Jamei, 2016; Jamei et al., 2009). In doing so, the predicted PK properties are inherently affected by the relevant covariates (Rostami‐Hodjegan & Tucker, 2007). However, translation of in vitro ADME properties within PBPK models is associated with uncertainties related not only to the knowledge gaps in system parameters, but also to the translatability (scaling) of drug parameters (Rostami‐Hodjegan, 2018). In this context, Mao and co‐workers applied PBPK modeling to predict human PK and assessed model performance retrospectively using clinical data for 18 Genentech compounds (Mao et al., 2023). Currently, the main regulatory application of PBPK modeling is to investigate enzyme‐ or transporter‐mediated drug–drug interactions (Zhang et al., 2020). In this special issue, Vijaywargi and co‐workers compared the performance of static and PBPK models to predict transporter‐mediated DDIs. The authors also discussed the usefulness of endogenous biomarkers, the use of empirical scaling factors, enzyme–transporter interplay, and acceptance criteria for model validation to meet the regulatory expectations (Vijaywargi et al., 2023). The separation between system and drug parameters is an important feature of PBPK modeling with respect to extrapolating results between species and populations. In this special issue Alsmadi and Alzughoul integrate preclinical data and a IVIVE‐PBPK model to extrapolate drug elimination in renally impaired patients (Alsmadi & Alzughoul, 2023). In turn, Liang and co‐workers successfully applied PBPK modeling to optimize azithromycin dosing to pediatrics (Liang et al., 2023) and Zhang and co‐workers developed a PBPK‐based dose decision framework to inform clinical trials with a novel anesthetic agent in special popu","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 4","pages":"289-291"},"PeriodicalIF":2.1,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2375","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10200718","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}
Gegenqinlian decoction (GQD) is a classic prescription of traditional Chinese medicine (TCM), which originated from Shanghanlun. The combination of GQD and hypoglycemic drugs (saxagliptin, Sax, metformin) is often used to treat Type 2 diabetes mellitus (T2DM) in TCM clinics. However, the herb–drug interactions (HDIs) between GQD and hypoglycemic drugs are still unclear. In order to determine the safety of the combination, we assessed the influences of GQD on the pharmacokinetics and pharmacodynamics of Sax in T2DM rats. The plasma concentration of Sax (5 mg/kg) pretreated with GQD (freeze-dried powder, 1.35 g/kg) or not was determined by high-performance liquid chromatography (HPLC), and pharmacokinetics parameters were calculated. The influence of GQD on the pharmacodynamics of Sax was investigated by detecting the levels of weight, (see abbreviations list) OGTT, TC, TG, LDL-C, HDL-C, FBG, FINS, HOMA-IR, QUICKI, AST, ALT, and the liver coefficient. The Cmax, AUC0-t,and AUC0-∞ of Sax increased significantly in the combination group whether in normal or T2DM rats. The results of pharmacodynamics showed that the weight of rats in each treatment group increased. FBG, TC, TG, LDL-C, and HOMA-IR decreased, HDL-C, FINS, and QUICKI increased significantly (p < 0.05) compared with the model control group. The result showed that the combination of GQD and Sax could not only improve the hypoglycemic effect but also increase the plasma exposure of Sax. The potential HDIs between GQD and Sax should be taken into consideration in clinics. Moreover, for the complexity of the human compared with experimental animals, as well as genetic differences, the in-depth study should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.
{"title":"Influence of Gegenqinlian decoction on pharmacokinetics and pharmacodynamics of saxagliptin in type 2 diabetes mellitus rats","authors":"Chao Yu, Mingyu Cui, Yifeng Yin, Fengmei Zhu, Yue Sui, Xueying Yan, Yingli Gai","doi":"10.1002/bdd.2374","DOIUrl":"10.1002/bdd.2374","url":null,"abstract":"<p>Gegenqinlian decoction (GQD) is a classic prescription of traditional Chinese medicine (TCM), which originated from Shanghanlun. The combination of GQD and hypoglycemic drugs (saxagliptin, Sax, metformin) is often used to treat Type 2 diabetes mellitus (T2DM) in TCM clinics. However, the herb–drug interactions (HDIs) between GQD and hypoglycemic drugs are still unclear. In order to determine the safety of the combination, we assessed the influences of GQD on the pharmacokinetics and pharmacodynamics of Sax in T2DM rats. The plasma concentration of Sax (5 mg/kg) pretreated with GQD (freeze-dried powder, 1.35 g/kg) or not was determined by high-performance liquid chromatography (HPLC), and pharmacokinetics parameters were calculated. The influence of GQD on the pharmacodynamics of Sax was investigated by detecting the levels of weight, (see abbreviations list) OGTT, TC, TG, LDL-C, HDL-C, FBG, FINS, HOMA-IR, QUICKI, AST, ALT, and the liver coefficient. The <i>C</i><sub>max</sub>, <i>AUC</i><sub>0-t</sub>,and <i>AUC</i><sub>0-∞</sub> of Sax increased significantly in the combination group whether in normal or T2DM rats. The results of pharmacodynamics showed that the weight of rats in each treatment group increased. FBG, TC, TG, LDL-C, and HOMA-IR decreased, HDL-C, FINS, and QUICKI increased significantly (<i>p</i> < 0.05) compared with the model control group. The result showed that the combination of GQD and Sax could not only improve the hypoglycemic effect but also increase the plasma exposure of Sax. The potential HDIs between GQD and Sax should be taken into consideration in clinics. Moreover, for the complexity of the human compared with experimental animals, as well as genetic differences, the in-depth study should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 6","pages":"396-405"},"PeriodicalIF":2.1,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9159000","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}
Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody–drug conjugate, comprising an anti-HER2 antibody at a drug-to-antibody ratio of 7–8 with the topoisomerase I inhibitor DXd. In this study, the concentrations of antibody-conjugated DXd and total antibody were determined and observed to decrease over time following intravenous administration of T-DXd to monkeys. The drug-to-antibody ratio of T-DXd also decreased in a time-dependent manner, which reached approximately 2.5 in 21 days after administration. It was suggested that antibody-conjugated DXd of T-DXd was relatively stable in vivo compared with that of other reported antibody–drug conjugates.
{"title":"Transition of average drug-to-antibody ratio of trastuzumab deruxtecan in systemic circulation in monkeys using a hybrid affinity capture liquid chromatography-tandem mass spectrometry","authors":"Hiromi Habara, Hiromi Okamoto, Yoko Nagai, Masataka Oitate, Hideo Takakusa, Nobuaki Watanabe","doi":"10.1002/bdd.2371","DOIUrl":"10.1002/bdd.2371","url":null,"abstract":"<p>Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody–drug conjugate, comprising an anti-HER2 antibody at a drug-to-antibody ratio of 7–8 with the topoisomerase I inhibitor DXd. In this study, the concentrations of antibody-conjugated DXd and total antibody were determined and observed to decrease over time following intravenous administration of T-DXd to monkeys. The drug-to-antibody ratio of T-DXd also decreased in a time-dependent manner, which reached approximately 2.5 in 21 days after administration. It was suggested that antibody-conjugated DXd of T-DXd was relatively stable <i>in vivo</i> compared with that of other reported antibody–drug conjugates.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 5","pages":"380-384"},"PeriodicalIF":2.1,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9927776","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}
The present study was undertaken to develop a self-micellizing solid dispersion (SMSD) of tacrolimus (TAC) to improve the biopharmaceutical properties of TAC. An SMSD formulation of TAC (SMSD/TAC) and amorphous solid dispersion formulation of TAC (ASD/TAC) were prepared with Soluplus®, an amphiphilic copolymer, and hydroxypropyl cellulose, respectively. Physicochemical properties were characterized in terms of morphology, crystallinity, storage stability, interaction of TAC with Soluplus®, and micelle-forming potency; pharmacokinetic behavior was also evaluated in rats. Tacrolimus in both formulations was in an amorphous state. After storage at 40°C/75% relativity humidity for 4 weeks, there were no significant changes in the crystallinity of TAC between nonaged and aged SMSD/TAC, whereas slight recrystallization was observed in aged ASD/TAC. The results of circular dichroism (CD) and infrared spectroscopic analyses were indicative of the potent drug–polymer interaction in SMSD/TAC, possibly leading to the prevention of recrystallization. Compared with other TAC samples, SMSD/TAC exhibited significant improvement in the dissolution behavior of TAC through the immediate formation of fine micelles. After the oral administration of TAC samples (10 mg TAC/kg) to rats, there was marked enhancement in systemic exposure to TAC with both formulations; in particular, SMSD/TAC achieved an increase in bioavailability ca. 20-fold higher than crystalline TAC. The SMSD approach might provide an effective dosage form for TAC with enhanced physicochemical stability and oral absorption.
{"title":"Self-micellizing solid dispersion of tacrolimus: Physicochemical and pharmacokinetic characterization","authors":"Keisuke Makino, Ryota Tsukada, Atsushi Kambayashi, Kohei Yamada, Hideyuki Sato, Satomi Onoue","doi":"10.1002/bdd.2373","DOIUrl":"10.1002/bdd.2373","url":null,"abstract":"<p>The present study was undertaken to develop a self-micellizing solid dispersion (SMSD) of tacrolimus (TAC) to improve the biopharmaceutical properties of TAC. An SMSD formulation of TAC (SMSD/TAC) and amorphous solid dispersion formulation of TAC (ASD/TAC) were prepared with Soluplus<sup>®</sup>, an amphiphilic copolymer, and hydroxypropyl cellulose, respectively. Physicochemical properties were characterized in terms of morphology, crystallinity, storage stability, interaction of TAC with Soluplus<sup>®</sup>, and micelle-forming potency; pharmacokinetic behavior was also evaluated in rats. Tacrolimus in both formulations was in an amorphous state. After storage at 40°C/75% relativity humidity for 4 weeks, there were no significant changes in the crystallinity of TAC between nonaged and aged SMSD/TAC, whereas slight recrystallization was observed in aged ASD/TAC. The results of circular dichroism (CD) and infrared spectroscopic analyses were indicative of the potent drug–polymer interaction in SMSD/TAC, possibly leading to the prevention of recrystallization. Compared with other TAC samples, SMSD/TAC exhibited significant improvement in the dissolution behavior of TAC through the immediate formation of fine micelles. After the oral administration of TAC samples (10 mg TAC/kg) to rats, there was marked enhancement in systemic exposure to TAC with both formulations; in particular, SMSD/TAC achieved an increase in bioavailability ca. 20-fold higher than crystalline TAC. The SMSD approach might provide an effective dosage form for TAC with enhanced physicochemical stability and oral absorption.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 6","pages":"387-395"},"PeriodicalIF":2.1,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9912095","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}
Irinotecan causes severe gastrointestinal damage, which may affect the expression of intestinal transporters. However, neither the expression of peptide transporter 1 (Pept1) nor the pharmacokinetics of Pept1 substrate drugs has been investigated under irinotecan-induced gastrointestinal damage. Therefore, the present study quantitatively investigated the effects of irinotecan-induced gastrointestinal damage on the intestinal expression of Pept1 and absorption of cephalexin (CEX), a typical Pept1 substrate, in rats. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. The expression of Pept1 mRNA and the Pept1 protein in the upper, middle, and lower segments of the small intestine of irinotecan-treated rats was assessed by quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. The pharmacokinetic profile of CEX was examined after its oral or intravenous administration (10 mg/kg). In irinotecan-treated rats, ∼2-fold increases in Pept1 protein levels were observed in all three segments, whereas mRNA levels remained unchanged. The oral bioavailability of CEX significantly decreased to 76% of that in control rats. The decrease in passive diffusion caused by intestinal damage may have overcome the increase in Pept1-mediated uptake. In conclusion, irinotecan may decrease the intestinal absorption of Pept1 substrate drugs; however, it increased the expression of intestinal Pept1.
{"title":"Irinotecan-induced gastrointestinal damage alters the expression of peptide transporter 1 and absorption of cephalexin in rats","authors":"Ayuko Imaoka, Tomoki Hattori, Takeshi Akiyoshi, Hisakazu Ohtani","doi":"10.1002/bdd.2372","DOIUrl":"10.1002/bdd.2372","url":null,"abstract":"<p>Irinotecan causes severe gastrointestinal damage, which may affect the expression of intestinal transporters. However, neither the expression of peptide transporter 1 (Pept1) nor the pharmacokinetics of Pept1 substrate drugs has been investigated under irinotecan-induced gastrointestinal damage. Therefore, the present study quantitatively investigated the effects of irinotecan-induced gastrointestinal damage on the intestinal expression of Pept1 and absorption of cephalexin (CEX), a typical Pept1 substrate, in rats. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. The expression of <i>Pept1</i> mRNA and the Pept1 protein in the upper, middle, and lower segments of the small intestine of irinotecan-treated rats was assessed by quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. The pharmacokinetic profile of CEX was examined after its oral or intravenous administration (10 mg/kg). In irinotecan-treated rats, ∼2-fold increases in Pept1 protein levels were observed in all three segments, whereas mRNA levels remained unchanged. The oral bioavailability of CEX significantly decreased to 76% of that in control rats. The decrease in passive diffusion caused by intestinal damage may have overcome the increase in Pept1-mediated uptake. In conclusion, irinotecan may decrease the intestinal absorption of Pept1 substrate drugs; however, it increased the expression of intestinal Pept1.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 5","pages":"372-379"},"PeriodicalIF":2.1,"publicationDate":"2023-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9890940","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}
Suberosin is a natural phytoconstituent isolated from Citropsis articulata, especially employed for its anticoagulant properties. Although metabolic studies assessing suberosin have been conducted, it is possible interactions with drugs and food have not yet been investigated. In the present study, we analyzed the selective inhibitory effects of suberosin on cytochrome P450 (CYP) enzymes using a cocktail probe assay. Various concentrations of suberosin (0–50 μM) were incubated with isoform-specific CYP probes in human liver microsomes (HLMs). We found that suberosin significantly inhibited CYP1A2-catalyzed phenacetin O-deethylation, exhibiting IC50 values of 9.39 ± 2.05 and 3.07 ± 0.45 μM with and without preincubation in the presence of β-NADPH, respectively. Moreover, suberosin showed concentration-dependent, but not time-dependent, CYP1A2 inhibition in HLMs, indicating that suberosin acts as a substrate and reversible CYP1A2 inhibitor. Using a Lineweaver-Burk plot, we found that suberosin competitively inhibited CYP1A2-catalyzed phenacetin O-deethylation. Furthermore, suberosin showed similar inhibitory effects on recombinant human CYP1A1 and 1A2. In conclusion, suberosin may elicit herb–drug interactions by selectively inhibiting CYP1A2 during the concurrent administration of drugs that act as CYP1A2 substrates.
{"title":"Selective inhibitory effects of suberosin on CYP1A2 in human liver microsomes","authors":"Sanjita Paudel, Hyoje Jo, Taeho Lee, Sangkyu Lee","doi":"10.1002/bdd.2370","DOIUrl":"10.1002/bdd.2370","url":null,"abstract":"<p>Suberosin is a natural phytoconstituent isolated from <i>Citropsis articulata,</i> especially employed for its anticoagulant properties. Although metabolic studies assessing suberosin have been conducted, it is possible interactions with drugs and food have not yet been investigated. In the present study, we analyzed the selective inhibitory effects of suberosin on cytochrome P450 (CYP) enzymes using a cocktail probe assay. Various concentrations of suberosin (0–50 μM) were incubated with isoform-specific CYP probes in human liver microsomes (HLMs). We found that suberosin significantly inhibited CYP1A2-catalyzed phenacetin <i>O</i>-deethylation, exhibiting IC<sub>50</sub> values of 9.39 ± 2.05 and 3.07 ± 0.45 μM with and without preincubation in the presence of β-NADPH, respectively. Moreover, suberosin showed concentration-dependent, but not time-dependent, CYP1A2 inhibition in HLMs, indicating that suberosin acts as a substrate and reversible CYP1A2 inhibitor. Using a Lineweaver-Burk plot, we found that suberosin competitively inhibited CYP1A2-catalyzed phenacetin <i>O</i>-deethylation. Furthermore, suberosin showed similar inhibitory effects on recombinant human CYP1A1 and 1A2. In conclusion, suberosin may elicit herb–drug interactions by selectively inhibiting CYP1A2 during the concurrent administration of drugs that act as CYP1A2 substrates.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 5","pages":"365-371"},"PeriodicalIF":2.1,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9779521","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}
Today real word data (RWD) are playing a greater role in informing health care decisions. A physiologically based pharmacokinetic model (PBPK) and observed exposure–risk relationship predicted an increased bleeding risk induced by rivaroxaban (RXB) in patients with mild to moderate chronic kidney disease (CKD) taking concomitant medications that are combined Pgp-CYP3A inhibitors. In this commentary, we explore the potential use of RWD to assess the clinical consequence of this complex drug–drug interaction predicted from PBPK. This is a retrospective, case control, pilot study using a RWD dataset of 896,728 patients with mild to moderate chronic kidney disease and rivaroxaban use that was refined based upon combined Pgp-CYP3A inhibitor exposure and report of drug-induced bleeding (DIB). The odds ratio of patients with mild to moderate chronic kidney disease taking rivaroxaban with or without concurrent Pgp-CYP3A inhibitor use having a DIB was calculated. The odds ratio for DIB was 2.04 (CI95 1.82, 2.3; p < 0.001) suggesting an approximate doubling of bleeding risk which is consistent with the rivaroxaban exposure changes predicted by the published PBPK model and observed exposure–risk relationship. This exploratory analysis demonstrated the potential utility of RWD to assess model-based predictions as part of a drugs life cycle management.
{"title":"Coming full circle: The potential utility of real-world evidence to discern predictions from a physiologically based pharmacokinetic model","authors":"Joseph A. Grillo, Douglas McNair, Ping Zhao","doi":"10.1002/bdd.2369","DOIUrl":"10.1002/bdd.2369","url":null,"abstract":"<p>Today real word data (RWD) are playing a greater role in informing health care decisions. A physiologically based pharmacokinetic model (PBPK) and observed exposure–risk relationship predicted an increased bleeding risk induced by rivaroxaban (RXB) in patients with mild to moderate chronic kidney disease (CKD) taking concomitant medications that are combined Pgp-CYP3A inhibitors. In this commentary, we explore the potential use of RWD to assess the clinical consequence of this complex drug–drug interaction predicted from PBPK. This is a retrospective, case control, pilot study using a RWD dataset of 896,728 patients with mild to moderate chronic kidney disease and rivaroxaban use that was refined based upon combined Pgp-CYP3A inhibitor exposure and report of drug-induced bleeding (DIB). The odds ratio of patients with mild to moderate chronic kidney disease taking rivaroxaban with or without concurrent Pgp-CYP3A inhibitor use having a DIB was calculated. The odds ratio for DIB was 2.04 (CI<sub>95</sub> 1.82, 2.3; <i>p</i> < 0.001) suggesting an approximate doubling of bleeding risk which is consistent with the rivaroxaban exposure changes predicted by the published PBPK model and observed exposure–risk relationship. This exploratory analysis demonstrated the potential utility of RWD to assess model-based predictions as part of a drugs life cycle management.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 4","pages":"344-347"},"PeriodicalIF":2.1,"publicationDate":"2023-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10537760","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}
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