Pub Date : 2023-03-01DOI: 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.
{"title":"Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: Part 1. Physicochemical and pharmacokinetic properties.","authors":"Teruo Murakami, Erik Bodor, 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}
Pub Date : 2023-03-01DOI: 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.
{"title":"Azole antifungals and inter-individual differences in drug metabolism: the role of pharmacogenomics and precision medicine.","authors":"Mohitosh Biswas, John Shobana, Pimonpan Jinda, 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}
Pub Date : 2023-03-01DOI: 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.
{"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}
Pub Date : 2023-03-01DOI: 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, 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}
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, Milena Kovačević, Sandra Vezmar Kovačević, 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}
Pub Date : 2023-03-01DOI: 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.
{"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, Erik Bodor, 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}
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.
{"title":"A critical review of methotrexate clinical interactions: role of transporters.","authors":"Fatemeh Jafari, Omid Arasteh, Hesamoddin Hosseinjani, Abolghasem Allahyari, Sajad Ataei Azimi, 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}
Pub Date : 2023-02-01DOI: 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, Thomas Attard, Sara L Van Driest, 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}
Pub Date : 2023-02-01DOI: 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.
{"title":"Clinical management of drug-induced cardiotoxicity in patients with HER-2+ breast cancer: current recommendations and future outlook.","authors":"Michela Chianca, Serena L'Abbate, Iacopo Fabiani, Alberto Aimo, Michele Emdin, Claudio Passino, Antonella Fedele, Carlo Maria Cipolla, 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}
Pub Date : 2023-02-01DOI: 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.
{"title":"Individualizing busulfan dose in specific populations and evaluating the risk of pharmacokinetic drug-drug interactions.","authors":"David Combarel, Julie Tran, Julia Delahousse, Gilles Vassal, 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}