首页 > 最新文献

Expert Opinion on Drug Metabolism & Toxicology最新文献

英文 中文
Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: Part 1. Physicochemical and pharmacokinetic properties. 提高季铵盐异喹啉类生物碱小檗碱口服生物利用度的探讨策略:第一部分。物理化学和药代动力学性质。
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-03-01 DOI: 10.1080/17425255.2023.2203857
Teruo Murakami, Erik Bodor, Nicholas Bodor

Introduction: Berberine (BBR), a quaternary ammonium isoquinoline alkaloid, is a substrate for P-glycoprotein (P-gp) and cytochrome P450s (CYPs). BBR exhibits a wide variety of pharmacological activities; however, its clinical application is limited due to low oral bioavailability.

Areas covered: Physicochemical and pharmacokinetic properties of BBR and its lipophilic metabolites, berberrubine (BRB) and dihydroberberine (DHBBR), were reviewed including solubility/lipophilicity, salt/ion-pair formation, oral bioavailability, first-pass metabolism, and intestinal microbiota-mediated metabolism, by searching research articles using PubMed.

Expert opinion: Pharmacokinetic analysis of BBR bioavailability data in rats revealed that the oral bioavailability is limited by the extensive CYPs-mediated intestinal first-pass metabolism, insufficient membrane permeability due to the low solubility and P-gp-mediated efflux transport, and the hepatic first-pass metabolism. Various active metabolites are generated by intestinal first-pass metabolism. Intestinal microbiota also contributes to the BBR metabolism and generates lipophilic metabolites; BRB, an active metabolite, and DHBBR, a precursor that can distribute to the brain. The pharmacokinetic analysis of BBR bioavailability data can provide a clue to developing effective dosage routes and/or formulations that can increase the oral bioavailability of BBR.

小檗碱(Berberine, BBR)是一种季铵盐异喹啉生物碱,是p -糖蛋白(P-gp)和细胞色素p450 (CYPs)的底物。BBR具有多种药理活性;然而,由于口服生物利用度低,其临床应用受到限制。研究领域:通过检索PubMed上的研究文章,综述了BBR及其亲脂代谢产物小檗碱(BRB)和二氢小檗碱(DHBBR)的理化和药代动力学性质,包括溶解度/亲脂性、盐/离子对形成、口服生物利用度、首过代谢和肠道微生物介导的代谢。专家意见:大鼠BBR生物利用度数据的药代动力学分析显示,口服生物利用度受到广泛的cyps介导的肠道首过代谢、低溶解度和p- gp介导的外排转运导致的膜通透性不足以及肝脏首过代谢的限制。肠道首过代谢产生多种活性代谢物。肠道菌群也参与BBR代谢,产生亲脂代谢产物;BRB是一种活跃的代谢物,DHBBR是一种可以分布到大脑的前体。BBR生物利用度数据的药代动力学分析可以为开发有效的给药途径和/或配方提供线索,从而提高BBR的口服生物利用度。
{"title":"Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: Part 1. Physicochemical and pharmacokinetic properties.","authors":"Teruo Murakami,&nbsp;Erik Bodor,&nbsp;Nicholas Bodor","doi":"10.1080/17425255.2023.2203857","DOIUrl":"https://doi.org/10.1080/17425255.2023.2203857","url":null,"abstract":"<p><strong>Introduction: </strong>Berberine (BBR), a quaternary ammonium isoquinoline alkaloid, is a substrate for P-glycoprotein (P-gp) and cytochrome P450s (CYPs). BBR exhibits a wide variety of pharmacological activities; however, its clinical application is limited due to low oral bioavailability.</p><p><strong>Areas covered: </strong>Physicochemical and pharmacokinetic properties of BBR and its lipophilic metabolites, berberrubine (BRB) and dihydroberberine (DHBBR), were reviewed including solubility/lipophilicity, salt/ion-pair formation, oral bioavailability, first-pass metabolism, and intestinal microbiota-mediated metabolism, by searching research articles using PubMed.</p><p><strong>Expert opinion: </strong>Pharmacokinetic analysis of BBR bioavailability data in rats revealed that the oral bioavailability is limited by the extensive CYPs-mediated intestinal first-pass metabolism, insufficient membrane permeability due to the low solubility and P-gp-mediated efflux transport, and the hepatic first-pass metabolism. Various active metabolites are generated by intestinal first-pass metabolism. Intestinal microbiota also contributes to the BBR metabolism and generates lipophilic metabolites; BRB, an active metabolite, and DHBBR, a precursor that can distribute to the brain. The pharmacokinetic analysis of BBR bioavailability data can provide a clue to developing effective dosage routes and/or formulations that can increase the oral bioavailability of BBR.</p>","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 3","pages":"129-137"},"PeriodicalIF":4.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9408836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 3
Azole antifungals and inter-individual differences in drug metabolism: the role of pharmacogenomics and precision medicine. 唑类抗真菌药与药物代谢的个体差异:药物基因组学和精准医学的作用。
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-03-01 DOI: 10.1080/17425255.2023.2203860
Mohitosh Biswas, John Shobana, Pimonpan Jinda, Chonlaphat Sukasem

Introduction: Azole antifungal drugs are commonly prescribed to treat invasive fungal infections in various disease conditions. However, these drugs are substrates and inhibitors of cytochrome P450 (CYP) enzymes, UGT1A4, and P-gp. The genetic variants of CYP3A4/5, CYP2C9, CYP2C19, ABCB1, or UGT1A4 can modify the safety or effectiveness of azole antifungals.

Areas covered: This review has collated the recent advances in the pharmacogenomics of azole antifungals pertaining to their metabolism and the safety or effectiveness of their use. A literature search was performed in PubMed from inception to the 5th of December 2022 to retrieve articles focusing on pharmacogenomics of azole antifungals.

Expert opinion: Optimizing the safety or effectiveness of most azole antifungals, excluding voriconazole, through pharmacogenomics remains largely theoretical, pending laboratory assessment in future studies. However, the ample evidence of the clinically significant pharmacogenetic impacts of voriconazole, due to the CYP2C19 genetic variability, favors clinical implementation. The inconsistencies of the pharmacogenomics-based dosing guidelines for voriconazole, from different international pharmacogenomics working groups, may hinder clinicians in assimilating and applying such pharmacogenetic information into clinical practice. Consideration of drug-drug interactions along with the pharmacogenetic effects may advance the precision medicine of azole antifungals and allow greater effectiveness in clinical practice.

简介:唑类抗真菌药物通常用于治疗各种疾病条件下的侵袭性真菌感染。然而,这些药物是细胞色素P450 (CYP)酶、UGT1A4和P-gp的底物和抑制剂。CYP3A4/5、CYP2C9、CYP2C19、ABCB1或UGT1A4的基因变异可改变唑类抗真菌药物的安全性或有效性。涵盖领域:本综述整理了唑类抗真菌药物基因组学的最新进展,涉及其代谢及其使用的安全性或有效性。检索PubMed自建站至2022年12月5日的文献,检索有关唑类抗真菌药物基因组学的文章。专家意见:通过药物基因组学优化大多数唑类抗真菌药物(伏立康唑除外)的安全性或有效性在很大程度上仍停留在理论阶段,有待于未来研究的实验室评估。然而,由于CYP2C19的遗传变异性,伏立康唑具有临床显著的药理学影响的充分证据支持临床应用。来自不同国际药物基因组学工作组的基于药物基因组学的伏立康唑给药指南不一致,可能会阻碍临床医生吸收和应用这些药物遗传学信息到临床实践中。考虑药物与药物相互作用以及药物遗传效应,可以推进唑类抗真菌药物的精准用药,并在临床实践中发挥更大的作用。
{"title":"Azole antifungals and inter-individual differences in drug metabolism: the role of pharmacogenomics and precision medicine.","authors":"Mohitosh Biswas,&nbsp;John Shobana,&nbsp;Pimonpan Jinda,&nbsp;Chonlaphat Sukasem","doi":"10.1080/17425255.2023.2203860","DOIUrl":"https://doi.org/10.1080/17425255.2023.2203860","url":null,"abstract":"<p><strong>Introduction: </strong>Azole antifungal drugs are commonly prescribed to treat invasive fungal infections in various disease conditions. However, these drugs are substrates and inhibitors of cytochrome P450 (CYP) enzymes, UGT1A4, and P-gp. The genetic variants of CYP3A4/5, CYP2C9, CYP2C19, ABCB1, or UGT1A4 can modify the safety or effectiveness of azole antifungals.</p><p><strong>Areas covered: </strong>This review has collated the recent advances in the pharmacogenomics of azole antifungals pertaining to their metabolism and the safety or effectiveness of their use. A literature search was performed in PubMed from inception to the 5<sup>th</sup> of December 2022 to retrieve articles focusing on pharmacogenomics of azole antifungals.</p><p><strong>Expert opinion: </strong>Optimizing the safety or effectiveness of most azole antifungals, excluding voriconazole, through pharmacogenomics remains largely theoretical, pending laboratory assessment in future studies. However, the ample evidence of the clinically significant pharmacogenetic impacts of voriconazole, due to the CYP2C19 genetic variability, favors clinical implementation. The inconsistencies of the pharmacogenomics-based dosing guidelines for voriconazole, from different international pharmacogenomics working groups, may hinder clinicians in assimilating and applying such pharmacogenetic information into clinical practice. Consideration of drug-drug interactions along with the pharmacogenetic effects may advance the precision medicine of azole antifungals and allow greater effectiveness in clinical practice.</p>","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 3","pages":"165-174"},"PeriodicalIF":4.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9409302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Genetic variation in organic cation transporters and considerations in drug development. 有机阳离子转运体的遗传变异及其在药物开发中的考虑。
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-03-01 DOI: 10.1080/17425255.2023.2202813
Manthena V S Varma

Introduction: Membrane transporters are now widely recognized for their role in the absorption, distribution, clearance, and elimination of drugs. The organic cation transporters (OCTs, SLC22A) are expressed in the intestine, liver, and kidneys and are of importance in determining systemic pharmacokinetics (PK) and tissue-specific exposure of drugs and metabolites.

Areas covered: An overview of the role of OCTs in drug disposition is presented. Genetic variation in OCTs and the effects on PK and drug response were discussed.

Expert opinion: Clinical studies demonstrated significance of OCT1 and OCT2 in the hepatic uptake and renal secretion of drug, respectively. These mechanisms are important in determining the systemic PK and tissue exposure and thus pharmacodynamics of several drugs (e.g. metformin, morphine, sumatriptan). Emerging pharmacogenomic data also suggests multidrug and toxin extrusion pump (MATE1, SLC47A1) contribution to PK and response of drugs like metformin and cisplatin. Considerations to genotyping of functional and common variants of OCTs should be given, particularly for cationic drugs with hepatic elimination or renal secretion being major clearance pathways, in the clinical development. While the current evidence indicate that pharmacokinetic variability associated with known genotypes of OCTs/MATEs is relatively small, they may be of relevance in the tissue-specific effects and for drugs with low therapeutic index.

膜转运蛋白因其在药物的吸收、分布、清除和消除中的作用而被广泛认识。有机阳离子转运体(OCTs, SLC22A)在肠道、肝脏和肾脏中表达,在确定药物和代谢物的系统药代动力学(PK)和组织特异性暴露中具有重要意义。涵盖领域:概述了oct在药物处置中的作用。讨论了OCTs的遗传变异及其对药代动力学和药物反应的影响。专家意见:临床研究表明,OCT1和OCT2分别在药物的肝脏摄取和肾脏分泌中具有重要意义。这些机制在确定全身PK和组织暴露以及几种药物(如二甲双胍、吗啡、舒马曲坦)的药效学方面很重要。新出现的药物基因组学数据也表明,多药和毒素挤出泵(MATE1, SLC47A1)对二甲双胍和顺铂等药物的PK和反应有贡献。在临床开发中,应考虑功能性和常见oct变异的基因分型,特别是以肝清除或肾分泌为主要清除途径的阳离子药物。虽然目前的证据表明,与已知OCTs/MATEs基因型相关的药代动力学变异性相对较小,但它们可能与组织特异性效应和低治疗指数药物相关。
{"title":"Genetic variation in organic cation transporters and considerations in drug development.","authors":"Manthena V S Varma","doi":"10.1080/17425255.2023.2202813","DOIUrl":"https://doi.org/10.1080/17425255.2023.2202813","url":null,"abstract":"<p><strong>Introduction: </strong>Membrane transporters are now widely recognized for their role in the absorption, distribution, clearance, and elimination of drugs. The organic cation transporters (OCTs, SLC22A) are expressed in the intestine, liver, and kidneys and are of importance in determining systemic pharmacokinetics (PK) and tissue-specific exposure of drugs and metabolites.</p><p><strong>Areas covered: </strong>An overview of the role of OCTs in drug disposition is presented. Genetic variation in OCTs and the effects on PK and drug response were discussed.</p><p><strong>Expert opinion: </strong>Clinical studies demonstrated significance of OCT1 and OCT2 in the hepatic uptake and renal secretion of drug, respectively. These mechanisms are important in determining the systemic PK and tissue exposure and thus pharmacodynamics of several drugs (e.g. metformin, morphine, sumatriptan). Emerging pharmacogenomic data also suggests multidrug and toxin extrusion pump (MATE1, SLC47A1) contribution to PK and response of drugs like metformin and cisplatin. Considerations to genotyping of functional and common variants of OCTs should be given, particularly for cationic drugs with hepatic elimination or renal secretion being major clearance pathways, in the clinical development. While the current evidence indicate that pharmacokinetic variability associated with known genotypes of OCTs/MATEs is relatively small, they may be of relevance in the tissue-specific effects and for drugs with low therapeutic index.</p>","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 3","pages":"149-164"},"PeriodicalIF":4.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9415248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Considerations for laxatives in terms of their interactions with other drugs. 考虑到泻药与其他药物的相互作用。
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-03-01 DOI: 10.1080/17425255.2023.2193326
Gabrio Bassotti, Edda Battaglia
Laxatives represent the main treatment for constipated subjects since ancient times [1], are among the most frequently used drugs worldwide, and impose a substantial economic burden on both patients and health-care systems [2]. Although the use of laxatives is generally perceived as safe in the public opinion, an important issue to take into account is that constipation increases in frequency with age and that aged subjects are those with the major consumption of drugs. This increases the risk of potentially harmful pharmacologic interactions. A significant problem in evaluating this aspect of laxatives is due to the fact that many (probably, most) constipated patients often escape the physicians’ prescription and self treat their symptoms by means of over the counter (OTC) products [3]. Of note, these products are frequently not disclosed to the caring physicians probably because OTCs are not considered as actual drugs, and their use is often strictly linked to person to person (friends, neighbors, etc.) suggestions or pharmacist’s advice. It is also extremely important to remember that many OTC products are represented by herbal formulations (often composed of different and heterogeneous substances, employed for multiple dissimilar pathological conditions) and that these may interact with laxatives [4]. Thus, there is a concrete possibility that, especially in elderly subjects and/or in those treated with multiple drug regimens, the widespread use of laxatives (including the OTC ones) could cause potential interactions with other drugs. Unfortunately, this aspect has been almost neglected by researchers. Therefore, the literature evidence on this topic is relatively scarce, and these interactions are rarely detailed or are based on single-case reports [5].
{"title":"Considerations for laxatives in terms of their interactions with other drugs.","authors":"Gabrio Bassotti,&nbsp;Edda Battaglia","doi":"10.1080/17425255.2023.2193326","DOIUrl":"https://doi.org/10.1080/17425255.2023.2193326","url":null,"abstract":"Laxatives represent the main treatment for constipated subjects since ancient times [1], are among the most frequently used drugs worldwide, and impose a substantial economic burden on both patients and health-care systems [2]. Although the use of laxatives is generally perceived as safe in the public opinion, an important issue to take into account is that constipation increases in frequency with age and that aged subjects are those with the major consumption of drugs. This increases the risk of potentially harmful pharmacologic interactions. A significant problem in evaluating this aspect of laxatives is due to the fact that many (probably, most) constipated patients often escape the physicians’ prescription and self treat their symptoms by means of over the counter (OTC) products [3]. Of note, these products are frequently not disclosed to the caring physicians probably because OTCs are not considered as actual drugs, and their use is often strictly linked to person to person (friends, neighbors, etc.) suggestions or pharmacist’s advice. It is also extremely important to remember that many OTC products are represented by herbal formulations (often composed of different and heterogeneous substances, employed for multiple dissimilar pathological conditions) and that these may interact with laxatives [4]. Thus, there is a concrete possibility that, especially in elderly subjects and/or in those treated with multiple drug regimens, the widespread use of laxatives (including the OTC ones) could cause potential interactions with other drugs. Unfortunately, this aspect has been almost neglected by researchers. Therefore, the literature evidence on this topic is relatively scarce, and these interactions are rarely detailed or are based on single-case reports [5].","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 3","pages":"121-123"},"PeriodicalIF":4.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9446705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Drug-induced liver injury associated with the use of newer antiseizure medications in the elderly: an analysis of data from VigiBase. 药物性肝损伤与老年人使用新型抗癫痫药物相关:VigiBase数据分析
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-03-01 DOI: 10.1080/17425255.2023.2203859
Sanja Petrović, Milena Kovačević, Sandra Vezmar Kovačević, Branislava Miljkovic

Background: Data on drug-induced liver injury (DILI) caused by newer antiseizure medications (ASMs) in the elderly are scarce and mainly come from literature case reports. We analyzed Individual Case Safety Reports (ICSRs) of DILI in elderly patients treated with newer ASMs reported to VigiBase.

Research design and methods: Empirica™ Signal software was used to retrieve ICSRs reported to VigiBase up to 31 December 2021 and to calculate Empirical Bayesian Geometric Mean and corresponding 90% confidence intervals (EB05, EB95) for each drug-event pair. EB05 > 2, N > 0 was considered a signal. Analysis by age subgroups and gender was performed to assess the influence of these factors on ICSR characteristics and identified signals.

Results: There were 1399 ICSRs reporting 1947 events of hepatotoxicity. 56.97% of the reports were reported in females, 67.05% were serious, and 3.36% resulted in death. For one or more events of hepatotoxicity, signals were detected for lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide. Age- and gender-biased reporting frequency was identified for topiramate-induced hyperammonemia, with disproportionally higher reporting frequency in ≥75-year-old male patients.

Conclusions: The results of our study indicate differences among newer ASMs in their potential to cause DILI in the elderly. Further studies are needed to confirm the associations identified in this study.

背景:关于老年人新型抗癫痫药物(asm)引起的药物性肝损伤(DILI)的数据很少,主要来自文献病例报道。我们分析了VigiBase报告的接受较新asm治疗的老年患者DILI的个案安全报告(ICSRs)。研究设计和方法:使用Empirica™Signal软件检索截至2021年12月31日报告给VigiBase的icsr,并计算每个药物事件对的Empirical Bayesian Geometric Mean和相应的90%置信区间(EB05, EB95)。认为EB05 > 2, N > 0为信号。按年龄亚组和性别进行分析,以评估这些因素对ICSR特征和已识别信号的影响。结果:1399份icrs报告了1947例肝毒性事件。其中女性占56.97%,重症占67.05%,死亡占3.36%。对于一个或多个肝毒性事件,检测了拉莫三嗪、左乙拉西坦、奥卡西平、托吡酯和唑尼沙胺的信号。托吡酯引起的高氨血症的报告频率存在年龄和性别偏见,≥75岁男性患者的报告频率不成比例地更高。结论:我们的研究结果表明,新发asm在引起老年人DILI的可能性方面存在差异。需要进一步的研究来证实本研究中发现的关联。
{"title":"Drug-induced liver injury associated with the use of newer antiseizure medications in the elderly: an analysis of data from VigiBase.","authors":"Sanja Petrović,&nbsp;Milena Kovačević,&nbsp;Sandra Vezmar Kovačević,&nbsp;Branislava Miljkovic","doi":"10.1080/17425255.2023.2203859","DOIUrl":"https://doi.org/10.1080/17425255.2023.2203859","url":null,"abstract":"<p><strong>Background: </strong>Data on drug-induced liver injury (DILI) caused by newer antiseizure medications (ASMs) in the elderly are scarce and mainly come from literature case reports. We analyzed Individual Case Safety Reports (ICSRs) of DILI in elderly patients treated with newer ASMs reported to VigiBase.</p><p><strong>Research design and methods: </strong>Empirica™ Signal software was used to retrieve ICSRs reported to VigiBase up to 31 December 2021 and to calculate Empirical Bayesian Geometric Mean and corresponding 90% confidence intervals (EB05, EB95) for each drug-event pair. EB05 > 2, <i>N</i> > 0 was considered a signal. Analysis by age subgroups and gender was performed to assess the influence of these factors on ICSR characteristics and identified signals.</p><p><strong>Results: </strong>There were 1399 ICSRs reporting 1947 events of hepatotoxicity. 56.97% of the reports were reported in females, 67.05% were serious, and 3.36% resulted in death. For one or more events of hepatotoxicity, signals were detected for lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide. Age- and gender-biased reporting frequency was identified for topiramate-induced hyperammonemia, with disproportionally higher reporting frequency in ≥75-year-old male patients.</p><p><strong>Conclusions: </strong>The results of our study indicate differences among newer ASMs in their potential to cause DILI in the elderly. Further studies are needed to confirm the associations identified in this study.</p>","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 3","pages":"175-183"},"PeriodicalIF":4.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9409294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: part 2. development of oral dosage formulations. 提高季铵盐异喹啉生物碱小檗碱口服生物利用度的探讨策略:第二部分。开发口服剂型。
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-03-01 DOI: 10.1080/17425255.2023.2203858
Teruo Murakami, Erik Bodor, Nicholas Bodor

Introduction: Berberine (BBR) possesses a wide variety of pharmacological activities. However, the oral bioavailability of BBR is low due to extensive intestinal first-pass metabolism by cytochrome P450s (CYPs), insufficient absorption due to low solubility and P-glycoprotein (P-gp)-mediated efflux transport, and hepatic first-pass metabolism in rats.

Areas covered: Various dosage formulations were developed to increase the oral bioavailability of BBR by overcoming the reducing factors. This article provides the developing strategy of oral dosage formulations of BBR based on the physicochemical (low solubility, formation of salts/ion-pair complex) and pharmacokinetic properties (substrate of P-gp/CYPs, extensive intestinal first-pass metabolism). Literature was searched using PubMed.

Expert opinion: Here, formulations increasing the dissolution rates/solubility; formulations containing a P-gp inhibitor; formulations containing solubilizer exhibiting P-gp and/or CYPs inhibitors; formulations containing absorption enhancers; gastro/duodenal retentive formulations; lipid-based formulations; formulations targeting lymphatic transport; and physicochemical modifications increasing lipophilicity were reviewed. Among these formulations, formulations that can reduce intestinal first-pass metabolisms such as formulations containing CYPs inhibitor(s) and formulations containing absorption enhancer(s) significantly increased the oral bioavailability of BBR. Further studies on other dosing routes that can avoid first-pass metabolism such as the rectal route would also be important to increase the bioavailability of BBR.

小檗碱(Berberine, BBR)具有多种药理活性。然而,由于细胞色素p450 (CYPs)广泛的肠道首过代谢、低溶解度和p -糖蛋白(P-gp)介导的外排转运以及大鼠肝脏首过代谢,BBR的口服生物利用度较低。涉及领域:开发了各种剂量配方,通过克服减少因素来提高BBR的口服生物利用度。本文根据BBR的理化特性(低溶解度,形成盐/离子对复合物)和药代动力学特性(P-gp/CYPs底物,广泛的肠道首过代谢),提出了口服剂型的开发策略。文献检索使用PubMed。专家意见:这里,配方增加了溶解速率/溶解度;含有P-gp抑制剂的配方;含有P-gp和/或CYPs抑制剂的增溶剂的配方;含有吸收增强剂的配方;胃/十二指肠保留配方;lipid-based配方;针对淋巴运输的制剂;并对提高亲脂性的理化修饰进行了综述。在这些制剂中,能够降低肠道首过代谢的制剂,如含有CYPs抑制剂的制剂和含有吸收促进剂的制剂,显著提高了BBR的口服生物利用度。进一步研究其他可以避免首过代谢的给药途径,如直肠给药途径,对提高BBR的生物利用度也很重要。
{"title":"Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: part 2. development of oral dosage formulations.","authors":"Teruo Murakami,&nbsp;Erik Bodor,&nbsp;Nicholas Bodor","doi":"10.1080/17425255.2023.2203858","DOIUrl":"https://doi.org/10.1080/17425255.2023.2203858","url":null,"abstract":"<p><strong>Introduction: </strong>Berberine (BBR) possesses a wide variety of pharmacological activities. However, the oral bioavailability of BBR is low due to extensive intestinal first-pass metabolism by cytochrome P450s (CYPs), insufficient absorption due to low solubility and P-glycoprotein (P-gp)-mediated efflux transport, and hepatic first-pass metabolism in rats.</p><p><strong>Areas covered: </strong>Various dosage formulations were developed to increase the oral bioavailability of BBR by overcoming the reducing factors. This article provides the developing strategy of oral dosage formulations of BBR based on the physicochemical (low solubility, formation of salts/ion-pair complex) and pharmacokinetic properties (substrate of P-gp/CYPs, extensive intestinal first-pass metabolism). Literature was searched using PubMed.</p><p><strong>Expert opinion: </strong>Here, formulations increasing the dissolution rates/solubility; formulations containing a P-gp inhibitor; formulations containing solubilizer exhibiting P-gp and/or CYPs inhibitors; formulations containing absorption enhancers; gastro/duodenal retentive formulations; lipid-based formulations; formulations targeting lymphatic transport; and physicochemical modifications increasing lipophilicity were reviewed. Among these formulations, formulations that can reduce intestinal first-pass metabolisms such as formulations containing CYPs inhibitor(s) and formulations containing absorption enhancer(s) significantly increased the oral bioavailability of BBR. Further studies on other dosing routes that can avoid first-pass metabolism such as the rectal route would also be important to increase the bioavailability of BBR.</p>","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 3","pages":"139-148"},"PeriodicalIF":4.3,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9778676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
A critical review of methotrexate clinical interactions: role of transporters. 甲氨蝶呤临床相互作用的重要回顾:转运蛋白的作用。
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-02-01 DOI: 10.1080/17425255.2023.2193325
Fatemeh Jafari, Omid Arasteh, Hesamoddin Hosseinjani, Abolghasem Allahyari, Sajad Ataei Azimi, Vahid Reza Askari

Introduction: Methotrexate (MTX) is an antifolate and immunosuppressive drug prescribed for various malignancies and immune diseases. However, delayed elimination of MTX associated with concomitant use of some medications can lead to severe and lifethreatening adverse effects.

Areas covered: This paper investigated drugMTX interactions that lead to elevated MTX levels and related adverse effects due to the role of transporters. Methotrexate toxicity occurs at both low and high doses administrations. According to the studies we reviewed in this paper, most interaction records with methotrexate occurred with coadministration of indomethacin, ketoprofen, omeprazole, piperacillin/tazobactam, ciprofloxacin, cotrimoxazole, probenecid, and imatinib, mainly due to the role of transporters. However, most studies were performed as case reports or series, and confirming the exact drugmethotrexate interaction still needs further clinical investigations.

Expert opinion: Our findings showed no firm evidence of interactions of proton pump inhibitors (PPIs), levetiracetam, and NSAIDS with MTX. Moreover, patients' risk factors, hypoalbuminemia, renal failure, third space fluid retention, the elderly, polypharmacy, and transport inhibition are the most critical factors for MTX toxicity. If substitution or temporary discontinuation is not possible, healthcare providers should be aware of interactions, especially in patients with risk factors for MTX toxicity.

简介:甲氨蝶呤(MTX)是一种抗叶酸和免疫抑制药物,用于各种恶性肿瘤和免疫疾病。然而,与同时使用某些药物相关的MTX的延迟消除可能导致严重和危及生命的不良反应。涉及领域:本文研究了药物与MTX相互作用导致MTX水平升高,以及由于转运体的作用而产生的相关不良反应。甲氨蝶呤的毒性在低剂量和高剂量均有发生。根据我们回顾的研究,大多数与甲氨喋呤的相互作用记录发生在吲哚美辛、酮洛芬、奥美拉唑、哌拉西林/他唑巴坦、环丙沙星、复方新诺明、probenecid和伊马替尼共同给药时,主要是由于转运体的作用。然而,大多数研究都是病例报告或系列研究,确切的药物与甲氨蝶呤相互作用还需要进一步的临床研究。专家意见:我们的研究结果显示,没有确凿的证据表明质子泵抑制剂(PPIs)、左乙拉西坦和非甾体抗炎药与甲氨蝶呤相互作用。低白蛋白血症、肾功能衰竭、第三空间液体潴留、老年人、多药、转运抑制是MTX毒性的最关键因素。如果替代或暂时停药是不可能的,医疗保健提供者应该意识到相互作用,特别是对有MTX毒性危险因素的患者。
{"title":"A critical review of methotrexate clinical interactions: role of transporters.","authors":"Fatemeh Jafari,&nbsp;Omid Arasteh,&nbsp;Hesamoddin Hosseinjani,&nbsp;Abolghasem Allahyari,&nbsp;Sajad Ataei Azimi,&nbsp;Vahid Reza Askari","doi":"10.1080/17425255.2023.2193325","DOIUrl":"https://doi.org/10.1080/17425255.2023.2193325","url":null,"abstract":"<p><strong>Introduction: </strong>Methotrexate (MTX) is an antifolate and immunosuppressive drug prescribed for various malignancies and immune diseases. However, delayed elimination of MTX associated with concomitant use of some medications can lead to severe and lifethreatening adverse effects.</p><p><strong>Areas covered: </strong>This paper investigated drugMTX interactions that lead to elevated MTX levels and related adverse effects due to the role of transporters. Methotrexate toxicity occurs at both low and high doses administrations. According to the studies we reviewed in this paper, most interaction records with methotrexate occurred with coadministration of indomethacin, ketoprofen, omeprazole, piperacillin/tazobactam, ciprofloxacin, cotrimoxazole, probenecid, and imatinib, mainly due to the role of transporters. However, most studies were performed as case reports or series, and confirming the exact drugmethotrexate interaction still needs further clinical investigations.</p><p><strong>Expert opinion: </strong>Our findings showed no firm evidence of interactions of proton pump inhibitors (PPIs), levetiracetam, and NSAIDS with MTX. Moreover, patients' risk factors, hypoalbuminemia, renal failure, third space fluid retention, the elderly, polypharmacy, and transport inhibition are the most critical factors for MTX toxicity. If substitution or temporary discontinuation is not possible, healthcare providers should be aware of interactions, especially in patients with risk factors for MTX toxicity.</p>","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 2","pages":"91-107"},"PeriodicalIF":4.3,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9269418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
A fresh look at proton pump inhibitor (PPI)-associated adverse events through a CYP2C19 pharmacogenetic lens. 通过CYP2C19药理学透镜对质子泵抑制剂(PPI)相关不良事件进行新的观察。
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-02-01 DOI: 10.1080/17425255.2023.2190883
Rachel Chevalier, Thomas Attard, Sara L Van Driest, Valentina Shakhnovich
Since their introduction in 1980s, proton pump inhibitors (PPI) heralded a sweeping change in the management of acidrelated disorders. Their efficacy and ease to obtain have led to common use of PPIs. Perhaps a direct consequence of decreasing stomach acidity, appreciation of the wide-ranging physiologic functions of low stomach pH increased; functions such asfacilitation of vitamin and mineral absorption and suppression of enteric infections. Incidental and recurrent Clostridioides difficile infections cause significant morbidity, but pneumonia and exacerbation of hepatic encephalopathy have also been reported with both shortand long-term PPI use. With chronic use, unopposed hypergastrinemia, gastric atrophy, and bacterial overgrowth have been associated with an increased incidence of gastric cancer [1]. Additionally, idiosyncratic reactions unrelated to their pharmacotherapeutic profile have also been reported, notably interstitial nephritis (IN). Media attention and litigation followed hard to replicate and often conflicting PPI side effect evidence [2] in nested case–control studies, retrospective observational studies (including studies based on secondary use of administrative health databases), and their meta-analysis. These studies show a spectrum of risks associated with PPI use and are beset by limitations inherent to the study population. Long-term PPI use, for example, is more common among older individuals with multiple confounding comorbidities and polypharmacy (directly relevant to C. difficile and IN risk, respectively). Limitations also exist in the study methodology, including cohort definition [3] with respect to dose and duration of PPI use, compounded by difficulties in finding precisely matching controls not treated with PPIs. With the results of these pharmacoepidemiology studies conflicting, prescribers and patients are left with the same question: Are the results of big data analysis a true risk signal or noise? We do not advocate that PPIs be used without consideration of consequences, rather that further prospective studies are needed to measure risk and provide mechanistic insights for adverse effects (AE). Until then, a rational approach to begin is to stratify the available AE data by the patients’ phenotype for cytochrome P450 (CYP) 2C19, the hepatic enzyme responsible for PPI drug metabolism.
{"title":"A fresh look at proton pump inhibitor (PPI)-associated adverse events through a CYP2C19 pharmacogenetic lens.","authors":"Rachel Chevalier,&nbsp;Thomas Attard,&nbsp;Sara L Van Driest,&nbsp;Valentina Shakhnovich","doi":"10.1080/17425255.2023.2190883","DOIUrl":"https://doi.org/10.1080/17425255.2023.2190883","url":null,"abstract":"Since their introduction in 1980s, proton pump inhibitors (PPI) heralded a sweeping change in the management of acidrelated disorders. Their efficacy and ease to obtain have led to common use of PPIs. Perhaps a direct consequence of decreasing stomach acidity, appreciation of the wide-ranging physiologic functions of low stomach pH increased; functions such asfacilitation of vitamin and mineral absorption and suppression of enteric infections. Incidental and recurrent Clostridioides difficile infections cause significant morbidity, but pneumonia and exacerbation of hepatic encephalopathy have also been reported with both shortand long-term PPI use. With chronic use, unopposed hypergastrinemia, gastric atrophy, and bacterial overgrowth have been associated with an increased incidence of gastric cancer [1]. Additionally, idiosyncratic reactions unrelated to their pharmacotherapeutic profile have also been reported, notably interstitial nephritis (IN). Media attention and litigation followed hard to replicate and often conflicting PPI side effect evidence [2] in nested case–control studies, retrospective observational studies (including studies based on secondary use of administrative health databases), and their meta-analysis. These studies show a spectrum of risks associated with PPI use and are beset by limitations inherent to the study population. Long-term PPI use, for example, is more common among older individuals with multiple confounding comorbidities and polypharmacy (directly relevant to C. difficile and IN risk, respectively). Limitations also exist in the study methodology, including cohort definition [3] with respect to dose and duration of PPI use, compounded by difficulties in finding precisely matching controls not treated with PPIs. With the results of these pharmacoepidemiology studies conflicting, prescribers and patients are left with the same question: Are the results of big data analysis a true risk signal or noise? We do not advocate that PPIs be used without consideration of consequences, rather that further prospective studies are needed to measure risk and provide mechanistic insights for adverse effects (AE). Until then, a rational approach to begin is to stratify the available AE data by the patients’ phenotype for cytochrome P450 (CYP) 2C19, the hepatic enzyme responsible for PPI drug metabolism.","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 2","pages":"53-56"},"PeriodicalIF":4.3,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9440455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Clinical management of drug-induced cardiotoxicity in patients with HER-2+ breast cancer: current recommendations and future outlook. HER-2+乳腺癌患者药物性心脏毒性的临床管理:当前建议和未来展望
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-02-01 DOI: 10.1080/17425255.2023.2197589
Michela Chianca, Serena L'Abbate, Iacopo Fabiani, Alberto Aimo, Michele Emdin, Claudio Passino, Antonella Fedele, Carlo Maria Cipolla, Daniela Maria Cardinale

Introduction: Human epidermal growth factor receptor two (HER2) target therapies have drastically revolutionized the treatment of HER2-positive breast cancer. Starting with trastuzumab, early phase III trials have already highlighted its significant cardiotoxicity, which is also present, albeit to a lesser extent, in the new generation drugs. Also given the growing population of patients with cardiovascular diseases, it is vital to set up proper long-term follow-up to prevent morbidity related to the development of cardiotoxicity.

Areas covered: This review discusses the mechanisms of action underlying the cardiotoxicity of HER2 targeted therapies and the main clinical evidence on the toxicity of these drugs. In addition, the patterns of patient assessment prior to the initiation of therapy with HER2 targeted therapies are discussed, as well as the main evidence concerning the follow-up and management of cardiotoxicity.

Expert opinion: The mechanisms of cardiotoxicity of new HER2 drugs need further study and, likewise, methods to prevent, monitor and identify HER-2-induced cardiotoxicity need to be implemented. Although some studies highlight the validity of cardiac biomarkers as predictive factors for cardiotoxicity, their actual usefulness and timing is still debated. Further studies are needed to assess the effectiveness of possible pharmacological primary prevention.

人表皮生长因子受体2 (HER2)靶向治疗已经彻底改变了HER2阳性乳腺癌的治疗。从曲妥珠单抗开始,早期的III期试验已经强调了其显著的心脏毒性,这在新一代药物中也存在,尽管程度较轻。此外,鉴于心血管疾病患者人数不断增加,建立适当的长期随访以预防与心脏毒性发展相关的发病率至关重要。涵盖领域:本综述讨论了HER2靶向治疗心脏毒性的作用机制以及这些药物毒性的主要临床证据。此外,本文还讨论了HER2靶向治疗开始前的患者评估模式,以及有关心脏毒性随访和管理的主要证据。专家意见:新的HER2药物的心脏毒性机制需要进一步研究,同样,需要实施预防、监测和识别her -2诱导的心脏毒性的方法。尽管一些研究强调了心脏生物标志物作为心脏毒性预测因素的有效性,但它们的实际用途和时间仍然存在争议。需要进一步的研究来评估可能的药理学一级预防的有效性。
{"title":"Clinical management of drug-induced cardiotoxicity in patients with HER-2+ breast cancer: current recommendations and future outlook.","authors":"Michela Chianca,&nbsp;Serena L'Abbate,&nbsp;Iacopo Fabiani,&nbsp;Alberto Aimo,&nbsp;Michele Emdin,&nbsp;Claudio Passino,&nbsp;Antonella Fedele,&nbsp;Carlo Maria Cipolla,&nbsp;Daniela Maria Cardinale","doi":"10.1080/17425255.2023.2197589","DOIUrl":"https://doi.org/10.1080/17425255.2023.2197589","url":null,"abstract":"<p><strong>Introduction: </strong>Human epidermal growth factor receptor two (HER2) target therapies have drastically revolutionized the treatment of HER2-positive breast cancer. Starting with trastuzumab, early phase III trials have already highlighted its significant cardiotoxicity, which is also present, albeit to a lesser extent, in the new generation drugs. Also given the growing population of patients with cardiovascular diseases, it is vital to set up proper long-term follow-up to prevent morbidity related to the development of cardiotoxicity.</p><p><strong>Areas covered: </strong>This review discusses the mechanisms of action underlying the cardiotoxicity of HER2 targeted therapies and the main clinical evidence on the toxicity of these drugs. In addition, the patterns of patient assessment prior to the initiation of therapy with HER2 targeted therapies are discussed, as well as the main evidence concerning the follow-up and management of cardiotoxicity.</p><p><strong>Expert opinion: </strong>The mechanisms of cardiotoxicity of new HER2 drugs need further study and, likewise, methods to prevent, monitor and identify HER-2-induced cardiotoxicity need to be implemented. Although some studies highlight the validity of cardiac biomarkers as predictive factors for cardiotoxicity, their actual usefulness and timing is still debated. Further studies are needed to assess the effectiveness of possible pharmacological primary prevention.</p>","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 2","pages":"109-119"},"PeriodicalIF":4.3,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9257040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Individualizing busulfan dose in specific populations and evaluating the risk of pharmacokinetic drug-drug interactions. 在特定人群中个体化布硫丹剂量和评估药代动力学药物相互作用的风险。
IF 4.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-02-01 DOI: 10.1080/17425255.2023.2192924
David Combarel, Julie Tran, Julia Delahousse, Gilles Vassal, Angelo Paci

Introduction: Busulfan is an alkylating agent widely used in the conditioning of hematopoietic stem cell transplantation possessing a complex metabolism and a large interindividual and intra-individual variability, especially in children. Combined with the strong rationale of busulfan PK/PD relationships, factors altering its clearance (e.g. weight, age, and GST-A genetic polymorphism mainly) can also affect clinical outcomes.

Areas covered: This review aims to provide an overview of the current knowledge on busulfan pharmacokinetics, its pharmacokinetics variabilities in pediatric populations, drug-drug interactions (DDI), and their consequences regarding dose individualization. This review was based on medical literature up until October 2021.

Expert opinion: To ensure effective busulfan exposure in pediatrics, different weight-based nomograms have been established to determine busulfan dosage and provided improved results (65-80% of patients correctly exposed). In addition to nomograms, therapeutic drug monitoring (TDM) of busulfan measuring plasmatic concentrations to estimate busulfan pharmacokinetic parameters can be used. TDM is now widely carried out in routine practices and aims to ensure the targeting of the reported therapeutic windows by individualizing busulfan dosing based on the clearance estimations from a previous dose.

Busulfan是一种烷基化剂,广泛应用于造血干细胞移植调节,代谢复杂,个体间和个体内差异大,尤其是儿童。结合busulfan PK/PD关系的强大理论基础,改变其清除率的因素(如体重,年龄,主要是GST-A遗传多态性)也可以影响临床结果。涵盖领域:本综述旨在概述目前关于丁硫丹药代动力学的知识,其在儿科人群中的药代动力学变异性,药物-药物相互作用(DDI),以及它们对剂量个体化的影响。本综述基于截至2021年10月的医学文献。专家意见:为了确保儿科学中有效的丁硫丹暴露,已经建立了不同的基于体重的诺图来确定丁硫丹的剂量,并提供了更好的结果(65-80%的患者正确暴露)。除了形态图,治疗药物监测(TDM),测量血浆浓度,以估计药代动力学参数,可用于丁磺芬。TDM现在在常规实践中广泛开展,其目的是根据以前剂量的清除率估计,通过个体化布硫丹剂量来确保靶向报道的治疗窗口。
{"title":"Individualizing busulfan dose in specific populations and evaluating the risk of pharmacokinetic drug-drug interactions.","authors":"David Combarel,&nbsp;Julie Tran,&nbsp;Julia Delahousse,&nbsp;Gilles Vassal,&nbsp;Angelo Paci","doi":"10.1080/17425255.2023.2192924","DOIUrl":"https://doi.org/10.1080/17425255.2023.2192924","url":null,"abstract":"<p><strong>Introduction: </strong>Busulfan is an alkylating agent widely used in the conditioning of hematopoietic stem cell transplantation possessing a complex metabolism and a large interindividual and intra-individual variability, especially in children. Combined with the strong rationale of busulfan PK/PD relationships, factors altering its clearance (e.g. weight, age, and GST-A genetic polymorphism mainly) can also affect clinical outcomes.</p><p><strong>Areas covered: </strong>This review aims to provide an overview of the current knowledge on busulfan pharmacokinetics, its pharmacokinetics variabilities in pediatric populations, drug-drug interactions (DDI), and their consequences regarding dose individualization. This review was based on medical literature up until October 2021.</p><p><strong>Expert opinion: </strong>To ensure effective busulfan exposure in pediatrics, different weight-based nomograms have been established to determine busulfan dosage and provided improved results (65-80% of patients correctly exposed). In addition to nomograms, therapeutic drug monitoring (TDM) of busulfan measuring plasmatic concentrations to estimate busulfan pharmacokinetic parameters can be used. TDM is now widely carried out in routine practices and aims to ensure the targeting of the reported therapeutic windows by individualizing busulfan dosing based on the clearance estimations from a previous dose.</p>","PeriodicalId":12250,"journal":{"name":"Expert Opinion on Drug Metabolism & Toxicology","volume":"19 2","pages":"75-90"},"PeriodicalIF":4.3,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9256584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
期刊
Expert Opinion on Drug Metabolism & Toxicology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1