Drug Metabolism and Pharmacokinetics最新文献

英文中文

Micro-physiological system of human lung: The current status and application to drug discovery

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101050

Naoyuki Sone, Shimpei Gotoh

Various attempts have been made to elucidate the mechanisms of human lung development, its physiological functions, and diseases, in the hope of new drug discovery. Recent technological advancements in experimental animals, cell culture, gene editing, and analytical methods have provided new insights and therapeutic strategies. However, the results obtained from animal experiments are often inconsistent with those obtained from human data because of reproducibility issues caused by structural and physiological differences between mice and humans. In addition, it is not possible to accurately reproduce the internal environment of the human lung structure using conventional two-dimensional (2D) or three-dimensional (3D) cell culture methods. As a result, the micro-physiological system (MPS) technology, such as “lung-on-a-chip” that can culture human cells in a state close to human body environment have been developed, and its applications to disease models, toxicological studies, and drug discovery are accelerated worldwide. Here, we focus on the mimetics of the lung, including “lung-on-a-chip” technology, and review their recent progress, achievements and challenges. Finally, we discuss the role of these chips in drug discovery for refractory lung diseases.

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引用次数: 0

In vitro hydrolysis of areca nut xenobiotics in human liver 槟榔异种制剂在人肝脏中的体外水解研究。

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101039

Vincenzo Paolillo , Mahendran Jayakumar , Colton Sheperd , Andrew Tran , Stephanie Hoang , Nhu Dao , Parag Jain , Alan L. Myers

Areca nut (AN) is a substance of abuse consumed by millions worldwide, in spite of established oral and systemic toxicities associated with its use. Previous research demonstrates methyl ester alkaloids in the AN, such as arecoline and guvacoline, exhibit mood-altering and toxicological effects. Nonetheless, their metabolism has not been fully elucidated in humans. In the present study, an HPLC-UV bioanalytical method was developed to evaluate the hydrolytic kinetics and clearance rates of arecoline and guvacoline in human liver microsomes (HLM) and cytosol (HLC). The bioassay was capable of quantifying arecoline and guvacoline (and carboxylate metabolites arecaidine and guvacine, respectively) with good sensitivity, accuracy, and precision. Kinetics of arecoline and guvacoline hydrolysis best followed the Michaelis-Menten model. Apparent intrinsic clearance (Cl_{int.in vivo}) of arecoline was 57.8 ml/min/kg in HLM and 11.6 mL/min/kg in HLC, a 5-fold difference. Unexpectedly, guvacoline was dramatically less hydrolyzed than arecoline in both HLM and HLC, with Cl_{int.in vivo} estimates of 0.654 ml/min/kg and 0.466 ml/min/kg, respectively. These results demonstrate, for the first time, arecoline undergoes significant hydrolysis with high clearance rates in the liver. Furthermore, differential tissue metabolic rates and utilization of specific esterase inhibitors unequivocally demonstrated arecoline is a substrate for CES1 and not CES2.

尽管口腔和全身中毒已得到证实，但全世界仍有数百万人滥用阿雷卡坚果（Areca nut，AN）。以前的研究表明，Areca 坚果中的甲酯生物碱（如 arecoline 和 guvacoline）具有改变情绪和毒性的作用。然而，它们在人体中的新陈代谢尚未完全阐明。本研究开发了一种高效液相色谱-紫外生物分析方法，用于评估人肝脏微粒体（HLM）和细胞质（HLC）中阿司考林和古瓦考林的水解动力学和清除率。该生物测定法能够以良好的灵敏度、准确度和精密度定量检测山豆根碱和愈创木酚碱（以及分别为山豆根碱和愈创木酚碱的羧酸代谢物）。山豆根碱和愈创木酚碱的水解动力学最符合 Michaelis-Menten 模型。在 HLM 和 HLC 中，arecoline 的表观体内清除率（Clint.体内）分别为 57.8 毫升/分钟/千克和 11.6 毫升/分钟/千克，相差 5 倍。出乎意料的是，在 HLM 和 HLC 中，guvacoline 的水解率大大低于 arecoline，Clint.体内估计值分别为 0.654 ml/min/kg 和 0.466 ml/min/kg。这些结果首次证明，在肝脏中，异甲唑啉会以较高的清除率被大量水解。此外，不同的组织代谢率和对特异性酯酶抑制剂的利用也明确表明，异甲唑啉是 CES1 而非 CES2 的底物。

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引用次数: 0

Population pharmacokinetic and exposure-response analysis to support a dosing regimen of CPX-351 (NS-87) in Japanese adult and pediatric patients with untreated high-risk acute myeloid leukemia 人群药代动力学和暴露反应分析支持CPX-351 （NS-87）在日本成人和儿童未经治疗的高危急性髓性白血病患者中的给药方案。

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101038

Shunji Imai , Ayane Kitada , Aya Ogura , Michiyo Akagi , Mayumi Hasegawa , Grygoriy Vasilinin , J.F. Marier , Qi Wang , Tomohiko Ichikawa , Kazutomi Kusano

CPX-351 (NS-87; Vyxeos®) has a characteristic liposomal formulation and contains cytarabine and daunorubicin at a 5:1 molar ratio, which demonstrates synergistic activity in both in vitro and in vivo animal models. It has been approved in several countries for the treatment of newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Since there are very few Asian patients, especially Japanese adult and pediatric patients, only a small clinical study has been conducted in Japanese adult patients and no study in Japanese pediatric patients. Therefore, we need to continue collecting data to ensure efficacy, especially in Japan. The objectives of this study were to evaluate the exposure and efficacy of CPX-351 in adult and pediatric Japanese patients. For these purposes, population pharmacokinetic and exposure-response analysis was conducted based on the established model/analysis using non-Japanese data by incorporating the newly obtained results of a Japanese clinical trial. No significant differences in pharmacokinetic exposure and efficacy were observed between non-Japanese adult patients and Japanese adult or pediatric patients. This information supports CPX-351 as a treatment option for untreated Japanese t-AML/AML-MRC patients on the basis of efficacy and safety when referred to the evidence from non-Japanese subjects.

cpx - 351 (ns - 87;Vyxeos®)具有独特的脂质体配方，含有阿糖胞苷和柔红霉素，摩尔比为5:1，在体外和体内动物模型中均显示出协同作用。它已在多个国家被批准用于治疗新诊断的治疗相关急性髓性白血病（t-AML）或AML伴骨髓增生异常相关改变（AML- mrc）。由于亚洲患者极少，尤其是日本的成人和儿科患者，目前只对日本成人患者进行了少量的临床研究，没有针对日本儿科患者的研究。因此，我们需要继续收集数据以确保疗效，特别是在日本。本研究的目的是评估CPX-351在日本成人和儿童患者中的暴露和疗效。为此，在使用非日本数据的既定模型/分析的基础上，结合日本临床试验新获得的结果，进行了人群药代动力学和暴露反应分析。非日本成年患者与日本成人或儿童患者的药代动力学暴露和疗效无显著差异。参考来自非日本受试者的证据，该信息支持CPX-351作为未治疗的日本t-AML/AML-MRC患者的治疗选择，基于有效性和安全性。

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引用次数: 0

Development of intestinal organoids and microphysiological systems and their application to drug discovery

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101045

Takahiro Iwao, Tamihide Matsunaga

The intestines are an important organ with a variety of functions. For drug discovery research, experimental animals and Caco-2 cells derived from a human colon carcinoma may be used to evaluate the absorption and safety of orally administered drugs. These systems have issues, such as species differences with humans in experimental animals, variations in gene expression patterns, very low drug-metabolizing activities in Caco-2 cells, and the recent trend toward reduced animal testing. Thus, there is a need for new evaluation systems. Intestinal organoid technology and microphysiological systems (MPS) have attracted attention as novel evaluation systems for predicting drug disposition, safety, and efficacy in humans in vitro. Intestinal organoids are three-dimensional structures that contain a variety of intestinal cells. They also contain crypt-villus structures similar to those of living bodies. Using MPS, it is possible to improve the functionality of cells and evaluate the linkage and crosstalk between the intestine and the liver. These systems are expected to be powerful tools for drug discovery research to predict efficacy and toxicity in humans. This review outlines the current status of intestinal organoids and MPS studies.

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引用次数: 0

Organoids and microphysiological systems for pharmaceutical research of viral respiratory infections

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101041

Sayaka Deguchi , Fuki Yokoi , Kazuo Takayama

In the pharmaceutical research of viral respiratory infections, cell culture models have traditionally been used to evaluate the therapeutic effects of candidate compounds. Although cell lines are easy to handle and cost-effective, they do not fully replicate the characteristics of human respiratory organs. Recently, organoids and microphysiological systems (MPS) have been employed to overcome this limitation for in vitro testing of drugs against viral respiratory infections. Advanced disease modeling using organoids, self-organized three-dimensional (3D) cell culture models derived from stem cells, or MPS, models for culturing multiple cell types in a microfluidic device and capable of recapitulating a physiological 3D dynamic environment, can accurately replicate the complex functions of respiratory organs, thus making them valuable tools for elucidating the organ damages caused by viral respiratory infections and evaluating the efficacy of candidate drugs against them. Recently, a wide range of organoids and MPS have been developed to model the complex pathophysiology caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and assess therapeutic drugs. In this review, we evaluate the latest pharmaceutical research on coronavirus disease 2019 (COVID-19) that utilizes organoids and MPS and discuss future perspectives of their applications.

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引用次数: 0

Substrate inhibition potential of arachidonic acid on 14,15-epoxidation, a biological drug developmental target, mediated by recombinant human cytochrome P450 2J2 and 2C8 enzymes

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-01-17 DOI: 10.1016/j.dmpk.2025.101052

Ayaka Kojima , Masayuki Nadai , Hiroshi Yamazaki , Miki Katoh

Arachidonic acid is metabolized to biologically active (±)14(15)-epoxy-5Z,8Z,11Z-eicosatrienoic acid (14,15-EET), and suppression of this step is believed to be a drug developmental target in cancer treatment. Although the key 14,15-epoxidation mediated by human cytochrome P450 (P450 or CYP) 2J2 has been demonstrated, inconsistencies in reported in vitro reaction kinetics have been observed worldwide. The purpose of this study was to clarify the detailed kinetics of arachidonic acid 14,15-expoxidation by recombinant human CYP2J2 and CYP2C8 using precise liquid chromatography–tandem mass spectrometry. In the absence of an NADPH-generating system, substrate-dependent 14,15-EET was detected in multiple batches of commercially available arachidonic acid at minor but constant levels, regardless of incubation period or P450 concentration. Recombinant CYP2J2 and CYP2C8 mediated minor and extensive arachidonic acid 14,15-epoxidation in a substrate inhibition manner after subtracting 14,15-EET impurities from total 14,15-EET formation. CYP2J2 exhibited similar Michaelis (K_m) and substrate inhibition (K_s) constants; however, CYP2C8 had a lower K_s value, indicating more potent substrate inhibition in CYP2C8 than that in CYP2J2. To determine the effects of a given drug on arachidonic acid 14,15-epoxidation during drug development, experiments should be recommended with arachidonic acid of <20 μM for CYP2J2 and <5.0 μM for CYP2C8.

{"title":"Substrate inhibition potential of arachidonic acid on 14,15-epoxidation, a biological drug developmental target, mediated by recombinant human cytochrome P450 2J2 and 2C8 enzymes","authors":"Ayaka Kojima , Masayuki Nadai , Hiroshi Yamazaki , Miki Katoh","doi":"10.1016/j.dmpk.2025.101052","DOIUrl":"10.1016/j.dmpk.2025.101052","url":null,"abstract":"<div><div>Arachidonic acid is metabolized to biologically active (±)14(15)-epoxy-5Z,8Z,11Z-eicosatrienoic acid (14,15-EET), and suppression of this step is believed to be a drug developmental target in cancer treatment. Although the key 14,15-epoxidation mediated by human cytochrome P450 (P450 or CYP) 2J2 has been demonstrated, inconsistencies in reported <em>in vitro</em> reaction kinetics have been observed worldwide. The purpose of this study was to clarify the detailed kinetics of arachidonic acid 14,15-expoxidation by recombinant human CYP2J2 and CYP2C8 using precise liquid chromatography–tandem mass spectrometry. In the absence of an NADPH-generating system, substrate-dependent 14,15-EET was detected in multiple batches of commercially available arachidonic acid at minor but constant levels, regardless of incubation period or P450 concentration. Recombinant CYP2J2 and CYP2C8 mediated minor and extensive arachidonic acid 14,15-epoxidation in a substrate inhibition manner after subtracting 14,15-EET impurities from total 14,15-EET formation. CYP2J2 exhibited similar Michaelis (<em>K</em><sub>m</sub>) and substrate inhibition (<em>K</em><sub><em>s</em></sub>) constants; however, CYP2C8 had a lower <em>K</em><sub><em>s</em></sub> value, indicating more potent substrate inhibition in CYP2C8 than that in CYP2J2. To determine the effects of a given drug on arachidonic acid 14,15-epoxidation during drug development, experiments should be recommended with arachidonic acid of <20 μM for CYP2J2 and <5.0 μM for CYP2C8.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"61 ","pages":"Article 101052"},"PeriodicalIF":2.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Establishment of endogenous canine MUC1 knock-out MDCKII cells using CRISPR-Cas9 and evaluation of drug permeation

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-01-15 DOI: 10.1016/j.dmpk.2025.101051

Hisanao Kishimoto , Kaori Miyazaki , Moeko Omori , Kei Higuchi , Yoshiyuki Shirasaka , Katsuhisa Inoue

Most orally administered drugs are absorbed by simple diffusion across the intestinal epithelium. Monolayers of MDCKII cells and parallel artificial membrane permeability assay are widely used to evaluate simple diffusion as an in vitro model; however, these models do not account for the contribution of mucus glycoprotein, which may play a significant role in drug permeation. We focused on the role of MUC1, a membrane-bound mucin that is found on the luminal surface of the gastrointestinal epithelium, in the simple diffusion of lipophilic drugs. We generated endogenous canine Mdr1 (cMdr1) and Muc1 (cMuc1) knock-out MDCKII cells by genomic editing and evaluated the effect of cMuc1 on the simple diffusion of various drugs. The absence of cMuc1 significantly increased the membrane permeation of lipophilic drugs, such as griseofulvin as well as paclitaxel and rhodamine 123, substrates of the MDR1 efflux transporter, which suggests that cMuc1 is one of the key factors that modulate the membrane permeation of these drugs. Taken together, we successfully established MDCKII cell lines with a complete knock-out of endogenous cMuc1 and cMdr1 expressions. This provides a novel in vitro model system for studying the mechanisms underlying drug absorption and transport, with potential applications for drug development.

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引用次数: 0

Corrigendum to “Establishment of human intestinal organoids derived from commercially available cryopreserved intestinal epithelium and evaluation for pharmacokinetic study” [Drug Metabol Pharmacokinet 53 (2024) 100532] 对 "从市售低温保存的肠上皮细胞中提取的人体肠器官组织的建立和药代动力学研究评估"[Drug Metabol Pharmacokinet 53 (2024) 100532]的更正。

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2024-12-01 DOI: 10.1016/j.dmpk.2024.101042

Kentaro Okada , Jumpei Yokota , Tomoki Yamashita , Tatsuya Inui , Wataru kishimoto , Hiroshi Nakase , Hiroyuki Mizuguchi

引用次数: 0

In vitro characterization of taurine transport using the human brain microvascular endothelial cell line as a human blood-brain barrier model

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2024-11-15 DOI: 10.1016/j.dmpk.2024.101040

Yuma Tega , Yusuke Kawauchi , Shin-ichi Akanuma , Mai Inagaki , Masanori Tachikawa , Ken-ichi Hosoya

Taurine, a sulfur-containing β-amino acid, has various roles in the brain including cellular osmoregulation and neuroprotection. For adequate supply to the brain, taurine has to pass through the blood-brain barrier (BBB); however, the associated mechanism behind crossing the human BBB is not fully understood. Therefore, we characterized taurine transport in vitro using the human brain microvascular endothelial (hCMEC/D3) cell line, a model of human BBB function. [³H]Taurine uptake by hCMEC/D3 cells exhibited time-, as well as extracellular Na⁺- and Cl⁻-dependence. The uptake was saturable with a K_m of 19 μM and was inhibited by GABA at an IC₅₀ of 328 μM, which were similar to K_m values of taurine transporter (TauT)-mediated transport of taurine and GABA, respectively, suggesting that TauT is a major contributor to taurine uptake. For distribution to the brain, taurine must undergo cellular efflux after uptake. Taurine efflux from hCMEC/D3 cells increased for at least 60 min, and monocarboxylate transporter 7 (MCT7)-targeted siRNA significantly reduced MCT7 mRNA levels and [³H]taurine efflux by 93 % and 12 %, respectively, suggesting that MCT7 partly contributes to taurine efflux from hCMEC/D3 cells. Taken together, these results suggest that TauT and MCT7 function cooperatively in the human BBB.

{"title":"In vitro characterization of taurine transport using the human brain microvascular endothelial cell line as a human blood-brain barrier model","authors":"Yuma Tega , Yusuke Kawauchi , Shin-ichi Akanuma , Mai Inagaki , Masanori Tachikawa , Ken-ichi Hosoya","doi":"10.1016/j.dmpk.2024.101040","DOIUrl":"10.1016/j.dmpk.2024.101040","url":null,"abstract":"<div><div>Taurine, a sulfur-containing β-amino acid, has various roles in the brain including cellular osmoregulation and neuroprotection. For adequate supply to the brain, taurine has to pass through the blood-brain barrier (BBB); however, the associated mechanism behind crossing the human BBB is not fully understood. Therefore, we characterized taurine transport <em>in vitro</em> using the human brain microvascular endothelial (hCMEC/D3) cell line, a model of human BBB function. [<sup>3</sup>H]Taurine uptake by hCMEC/D3 cells exhibited time-, as well as extracellular Na<sup>+</sup>- and Cl<sup>−</sup>-dependence. The uptake was saturable with a <em>K</em><sub>m</sub> of 19 μM and was inhibited by GABA at an <em>IC</em><sub>50</sub> of 328 μM, which were similar to <em>K</em><sub>m</sub> values of taurine transporter (TauT)-mediated transport of taurine and GABA, respectively, suggesting that TauT is a major contributor to taurine uptake. For distribution to the brain, taurine must undergo cellular efflux after uptake. Taurine efflux from hCMEC/D3 cells increased for at least 60 min, and monocarboxylate transporter 7 (MCT7)-targeted siRNA significantly reduced MCT7 mRNA levels and [<sup>3</sup>H]taurine efflux by 93 % and 12 %, respectively, suggesting that MCT7 partly contributes to taurine efflux from hCMEC/D3 cells. Taken together, these results suggest that TauT and MCT7 function cooperatively in the human BBB.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"61 ","pages":"Article 101040"},"PeriodicalIF":2.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of plasma vonoprazan and CYP3A activity using its endogenous marker and genetic variants in patients with digestive system disorders 利用消化系统疾病患者的内源性标记物和遗传变异分析血浆中伏诺派赞和 CYP3A 活性的特征

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2024-10-01 DOI: 10.1016/j.dmpk.2024.101027

Kenta Sakaguchi , Takafumi Naito , Kohei Hoshikawa , Yukari Miyadera , Hironari Tanaka , Emi Nakatsugawa , Takahisa Furuta , Ken Sugimoto , Junichi Kawakami

Factors that determine clinical responses to vonoprazan remain unknown. This study aimed to characterize plasma vonoprazan and CYP3A activity using its endogenous marker and genetic variants in patients with digestive system disorders. Fifty-three patients who were receiving vonoprazan for at least 3 days were enrolled. Blood samples for determination of plasma vonoprazan and its metabolite (ODA-VP) were obtained. Plasma 4β-hydroxycholesterol (4β-OHC), CYP3A5 and ABCB1 genotypes, and plasma gastrin were determined. CYP3A recognition for vonoprazan was evaluated using recombinant CYP3A proteins. Plasma vonoprazan levels exhibited a large interindividual variation. The absolute plasma concentration of vonoprazan was correlated with its dose-normalized value, and had a positive correlation with the inverse value of its metabolic ratio. A negative correlation was observed between plasma vonoprazan and 4β-OHC levels. The metabolic ratio of vonoprazan was positively correlated with the plasma 4β-OHC level. Genetic variants of CYP3A5 and ABCB1 were not associated with the plasma concentration of vonoprazan and its metabolic ratio. Possible saturated metabolism of vonoprazan to its major metabolite was observed at a therapeutic dose. Although the CYP3A5 genotype did not alter plasma vonoprazan, CYP3A activity based on plasma 4β-OHC partially explained the variation in plasma vonoprazan in patients with digestive system disorders.

决定对伏诺普拉赞临床反应的因素尚不清楚。本研究旨在利用消化系统疾病患者的内源性标记物和基因变异来描述血浆中伏诺派赞和 CYP3A 活性的特征。53 名患者接受了至少 3 天的 Vonoprazan 治疗。采集血样测定血浆中伏诺派赞及其代谢物（ODA-VP）。还测定了血浆 4β- 羟基胆固醇（4β-OHC）、CYP3A5 和 ABCB1 基因型以及血浆胃泌素。使用重组 CYP3A 蛋白评估了 CYP3A 对 vonoprazan 的识别能力。血浆中的沃诺普拉赞水平存在较大的个体差异。血浆中 vonoprazan 的绝对浓度与其剂量归一化值相关，与其代谢比值的倒数呈正相关。血浆中的沃诺普拉赞与 4β-OHC 水平呈负相关。沃诺普拉赞的代谢比值与血浆中 4β-OHC 的水平呈正相关。CYP3A5和ABCB1的基因变异与血浆中vonoprazan的浓度及其代谢比率无关。在治疗剂量下，vonoprazan可能饱和代谢为其主要代谢物。虽然 CYP3A5 基因型不会改变血浆中的沃诺普拉赞，但基于血浆 4β-OHC 的 CYP3A 活性可部分解释消化系统疾病患者血浆中沃诺普拉赞的变化。

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引用次数: 0

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