Current Drug Metabolism[JOURNAL]
Sun
200 papers
The Impact of Certain Pharmacogenetic Differences on the Metabolism of Antiretroviral Drugs Used in A Black South African Population.
Reay R, Viljoen M, Rheeders M
Curr Drug Metab · 2023 · PMID 38008947 · Publisher ↗
BACKGROUND: Genetic polymorphism of drug-metabolising enzymes and transporters may influence the effect and toxicity of antiretroviral drugs. OBJECTIVES: To determine and compare the minimum allele frequency of 20 single...
BACKGROUND: Genetic polymorphism of drug-metabolising enzymes and transporters may influence the effect and toxicity of antiretroviral drugs. OBJECTIVES: To determine and compare the minimum allele frequency of 20 single nucleotide polymorphisms (SNPs) with possible involvement in the metabolism of the antiretroviral drugs with other populations. To investigate the influence of these variants on Reverse transcriptase, Protease and Integrase strand transfer inhibitor drugs. METHOD: DNA samples were collected from 1489 subjects. All SNPs with a gene call score of > 0.6 were selected for genotyping. The R package calculated call rates, MAF and Hardy-Weinberg equilibrium (HWE), test p-values, and Chi-squared analysis were performed on the data. The Fisher's exact test compared the allele frequencies between the populations. RESULTS: The highest similarities in minimum allele frequency (MAF) were between the Prospective Urban and Rural Epidemiological group (PURE), a Black population in South Africa, and the Yoruba and Luhya populations in Africa. The following SNPs were identified with a possible effect on metabolism: CYP2B6 rs28399494 (MAF 11%) is indicated in the toxicity of Efavirenz and Nevirapine. CYP3A5 rs776746 (MAF 17%) and CYP3A4 rs2749674 (MAF 23%) both cause an increase in the metabolism of the protease inhibitors. The very low MAF values for both SCL01B1 rs4149056 (MAF 0.6%) and ABCC rs717620 (MAF 2.8%) are indications that OATP1B1 transport function and glomerular filtration tempo will not be compromised. The high MAF value of 30% for UGTA1 rs10929302 can result in hyperbilirubinemia, which can decrease the clearance of Dolutegravir. CONCLUSION: These results show a possibility of kidney protection and an increase in bilirubin in this population.
Crocin Ameliorates Diabetic Nephropathy through Regulating Metabolism, CYP4A11/PPARγ, and TGF-β/Smad Pathways in Mice.
Chen W, Su J, Liu Y … +7 more , Gao T, Ji X, Li H, Li H, Wang Y, Zhang H, Lv S
Curr Drug Metab · 2023 · PMID 37936469 · Full text
INTRODUCTION: Crocin is one of the main components of Crocus sativus L. and can alleviate oxidative stress and inflammation in diabetic nephropathy (DN). However, the specific mechanism by which crocin treats DN still ne...
INTRODUCTION: Crocin is one of the main components of Crocus sativus L. and can alleviate oxidative stress and inflammation in diabetic nephropathy (DN). However, the specific mechanism by which crocin treats DN still needs to be further elucidated. METHOD: In the present study, a mouse model of DN was first established to investigate the therapeutic effect of crocin on DN mice. Subsequently, non-targeted metabolomics techniques were used to analyze the mechanisms of action of crocin in the treatment of DN. The effects of crocin on CYP4A11/PPARγ and TGF-β/Smad pathway were also investigated. RESULT: Results showed that crocin exhibited significant therapeutic and anti-inflammatory, and anti-oxidative effects on DN mice. In addition, the non-targeted metabolomics results indicated that crocin treatment affected several metabolites in kidney. These metabolites were mainly associated with biotin metabolism, riboflavin metabolism, and arachidonic acid metabolism. Furthermore, crocin treatment upregulated the decreased levels of CYP4A11 and phosphorylated PPARγ, and reduced the increased levels of TGF-β1 and phosphorylated Smad2/3 in the kidneys of DN mice. CONCLUSION: In conclusion, our study validated the considerable therapeutic, anti-inflammatory, and antioxidative impacts of crocin on DN mice. The mechanism of crocin treatment may be related to the regulation of biotin riboflavin and arachidonic acid metabolism, the activation of CYP4A11/PPARγ pathway, and the inhibition of TGF-β/Smad pathway in the kidney.
Evaluation of Supervised Machine Learning Algorithms and Computational Structural Validation of Single Nucleotide Polymorphisms Related to Acute Liver Injury with Paracetamol.
Sridharan K, Balasundaram A, Kumar DT … +1 more , Doss CGP
Curr Drug Metab · 2023 · PMID 37927072 · Publisher ↗
AIMS: To identify single nucleotide polymorphisms (SNPs) of paracetamol-metabolizing enzymes that can predict acute liver injury. BACKGROUND: Paracetamol is a commonly administered analgesic/antipyretic in critically ill...
AIMS: To identify single nucleotide polymorphisms (SNPs) of paracetamol-metabolizing enzymes that can predict acute liver injury. BACKGROUND: Paracetamol is a commonly administered analgesic/antipyretic in critically ill and chronic renal failure patients and several SNPs influence the therapeutic and toxic effects. OBJECTIVE: To evaluate the role of machine learning algorithms (MLAs) and bioinformatics tools to delineate the predictor SNPs as well as to understand their molecular dynamics. METHODS: A cross-sectional study was undertaken by recruiting critically ill patients with chronic renal failure and administering intravenous paracetamol as a standard of care. Serum concentrations of paracetamol and the principal metabolites were estimated. Following SNPs were evaluated: . MLAs were used to identify the predictor genetic variable for acute liver failure. Bioinformatics tools such as Predict SNP2 and molecular docking (MD) were undertaken to evaluate the impact of the above SNPs with binding affinity to paracetamol. RESULTS: and genotypes were identified by MLAs to significantly predict hepatotoxicity. The predictSNP2 revealed that was highly deleterious in all the tools. MD revealed binding energy of -5.5 Kcal/mol, -6.9 Kcal/mol, and -6.8 Kcal/mol for , and against paracetamol. MD simulations revealed that and missense variants in affect the binding ability with paracetamol. In-silico techniques found that and are highly harmful. MD simulations revealed (A>G) had decreased binding energy with paracetamol than , and (A>T) and both have greater binding energy with paracetamol. CONCLUSION: Polymorphisms in , and significantly influence paracetamol's clinical outcomes or binding affinity. Robust clinical studies are needed to identify these polymorphisms' clinical impact on the pharmacokinetics or pharmacodynamics of paracetamol.
Differential Pharmacokinetic Interplay of Atorvastatin on Lacosamide and Levetiracetam on Experimental Convulsions in Mice.
Rajangam J, Lakshmanan AP, Palei NN … +4 more , Elumalai K, Kotakonda M, Prakash R, Latha P
Curr Drug Metab · 2023 · PMID 37921161 · Publisher ↗
BACKGROUND: The beneficial effects of statins, other than their hypocholesterolemia role, have been well documented, however, their use as an adjuvant drug with other antiseizure drugs, in the treatment of epilepsy is po...
BACKGROUND: The beneficial effects of statins, other than their hypocholesterolemia role, have been well documented, however, their use as an adjuvant drug with other antiseizure drugs, in the treatment of epilepsy is poorly understood. OBJECTIVE: This study aimed to investigate the symbiotic effect of ATOR along with either lacosamide (LACO) or levetiracetam (LEVE) on experimentally induced epilepsy (Maximal electro-shock-MES or pentylenetetrazol- PTZ) in mice models. METHODS: Conventional elevated-maze (EPM) and rotarod methods were performed to observe the behavioral effects. RESULTS: In both the animal models, we found that co-administration of ATOR along with LACO showed a significant reduction in hind-limb extension (HLE) and clonic convulsion (CC) responses, respectively, but not in the ATOR+LEVE treated group. Intriguingly, comparable Straub tail response and myoclonic convulsion as the diazepam (DIA) group were observed only in the ATOR+LACO treated group. Moreover, a significant muscle-grip strength was observed in both groups. Also, pharmacokinetic analysis has indicated that the mean plasma concentration of ATOR peaked at 2nd hr in the presence of LACO but marginally peaked in the presence of LEVE. An Insilico study has revealed that ATOR has a higher binding affinity toward neuronal sodium channels. CONCLUSION: This study has demonstrated that the plasma concentration of ATOR was potentiated in the presence of LACO, but not in the presence of LEVE and it has provided significant protection against both the electro and chemo-convulsive models in mice. This could be due to the symbiotic pharmacokinetic interplay of ATOR with LACO, and possibly, this interplay may interfere with sodium channel conductance.
Nrf2 Regulates the Expression of by Inhibiting the Activity of Krüppel-Like Factor 9 (KLF9).
Siswanto FM, Handayani MDN, Firmasyah RD … +2 more , Oguro A, Imaoka S
Curr Drug Metab · 2023 · PMID 37916628 · Publisher ↗
AIMS: The aim of the present study is to gain insight into the biology of Parkinson's disease (PD) and cancer to drive translational advances enabling more effective prevention and/or potential treatments. BACKGROUND: Th...
AIMS: The aim of the present study is to gain insight into the biology of Parkinson's disease (PD) and cancer to drive translational advances enabling more effective prevention and/or potential treatments. BACKGROUND: The expression of Cytochrome P450 2D6 (CYP2D6) is correlated with various diseases such as PD and cancer; therefore, exploring its regulatory mechanism at transcriptional levels is of interest. NF-E2-related factor 2 (Nrf2) has been known to be responsible for regulating phase II and phase III drug-metabolizing genes. OBJECTIVES: The objectives of this study are to investigate the transcriptional regulation of by Nrf2 and to analyze its role in PD and cancer. METHODS: Nrf2 was transiently expressed in human hepatoma Hep3B cells, and the expression of was examined by RT-qPCR. The promoter activity of and the DNA binding of Nrf2 were examined by luciferase and ChIP assay, respectively. We then investigated the expression and correlation of Nrf2 and in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. RESULTS: In the present study, we demonstrated that Nrf2 down-regulated mRNA expression in hepatoma Hep3B cells. Mechanistically, Nrf2 binds to the antioxidant responsive element (ARE) in the proximity of krüppel- like factor 9 (KLF9)-binding site within the -550/+51 of promoter. The inhibition and activation of Nrf2 enhanced and suppressed KLF9 effects on expression, respectively. The expression levels of Nrf2 and were upregulated and downregulated in the PD patient GEO datasets compared to the healthy control tissues, and Nrf2 was negatively correlated with . In liver cancer patients, decreased levels were apparent and associated with a lower probability of survival. CONCLUSION: Our work revealed the inhibitory role of Nrf2 in regulating expression. Moreover, Nrf2- dependent regulation of can be used as a prognostic factor and therapeutic strategy in PD and liver cancer.
Pharmacokinetics and Tissue Distribution of Isovitexin-2''-O-β-D-glucopyranoside (IVG) in Sprague-Dawley Rats.
Zhao X, Fang L, Yang T … +2 more , Zhang Y, Xie J
Curr Drug Metab · 2023 · PMID 37881073 · Publisher ↗
BACKGROUND: Isovitexin-2"-O-D-glucopyranoside (IVG) has been known to exhibit sedative and hypnotic effects. However, there is little understanding of the in vivo pharmacokinetics and tissue distribution of IVG. OBJECTIV...
BACKGROUND: Isovitexin-2"-O-D-glucopyranoside (IVG) has been known to exhibit sedative and hypnotic effects. However, there is little understanding of the in vivo pharmacokinetics and tissue distribution of IVG. OBJECTIVE: This study aimed to investigate the pharmacokinetics and tissue distribution of IVG. METHODS: The study employed an HPLC-ESI-MS/MS method to analyze the pharmacokinetics and tissue distribution of IVG. RESULTS: Under mass spectrometry, IVG and internal standard (IS) showed strong negative ionization signals. MRM analysis chose ion transitions m/z 593.3 → 293.0 (IVG) and m/z 579.8 → 271.4 (IS). Method validation indicated high precision, accuracy, and reliability with a quantitation limit under 20 ng/mL. After intravenously administering 5.0 mg/kg of IVG, rapid clearance from rat plasma was observed, with a half-life (t) of 3.49 ± 0.99 h and a clearance rate of 54.53 ± 11.90 mL/kg/h. The area under the curve (AUC) of 37.79 ± 7.65 μg·h/mL indicated a brisk metabolic rate. Evaluating the tissue distribution, the highest accumulation was seen in the liver (30.32 ± 3.06 μg/g), followed by the kidney (20.58 ± 2.12 μg/g) and intestine (6.69 ± 0.93 μg/g), suggesting a propensity for IVG to concentrate in these tissues. Importantly, the presence of IVG in the brain underlines its potential to traverse the blood-brain barrier. These findings revealed that following intravenous administration, IVG was swiftly and broadly distributed throughout various rat tissues. CONCLUSION: This study provides valuable information on the pharmacokinetics and tissue distribution of IVG, implicating its potential as a novel and effective drug candidate for sedative and anxiolytic treatment.
Factors Influencing ADME Properties Of Drugs: Advances and Applications (Part II).
Zhang SQ, Chen F
Curr Drug Metab · 2023 · PMID 37872775 · Publisher ↗
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Comprehensive Investigation of the Influence of High-Altitude Hypoxia on Clopidogrel Metabolism and Gut Microbiota.
Zhang J, Sun Y, He J … +3 more , Wu G, Wang R, Zhang J
Curr Drug Metab · 2023 · PMID 37842900 · Publisher ↗
BACKGROUND: The amount of metabolites converted into active metabolites is correspondingly reduced since only more than 50% of clopidogrel is absorbed. OBJECTIVE: Exploring the effect of gut microbiota altered by altitud...
BACKGROUND: The amount of metabolites converted into active metabolites is correspondingly reduced since only more than 50% of clopidogrel is absorbed. OBJECTIVE: Exploring the effect of gut microbiota altered by altitude hypoxia on the pre-absorption metabolism of clopidogrel. METHODS: In vitro and in vivo experiments were conducted to analyze the metabolism of clopidogrel through LCMS/ MS, while 16S rRNA analysis was used to investigate the changes in the gut microbiota of high-altitude animals. RESULTS: We demonstrated that the intestinal flora is involved in the metabolism of clopidogrel through in vivo and in vitro experiments. In addition, the plateau environment caused changes in the number and composition of intestinal microbes. Intriguingly, alterations in the microbial population could lead to an increase in the pre-absorption metabolism of clopidogrel after rapid entry into the plateau, the amount of absorbed blood is thus reduced, which may affect the bioavailability and therapeutic effect of clopidogrel. CONCLUSION: Our results not only as a first clinical reference for dose adjustment of clopidogrel in high-altitude environments but also would be helpful to provide a statement on the broader significance within the field of pharmacokinetics or personalized medicine.
Corrigendum: Intracellular Delivery: Exploiting Viral Membrane Topic Peptide.
Galdiero S, Vitiello M, Falanga A … +3 more , Cantisani M, Incoronato N, Galdiero M
Curr Drug Metab · 2023 · PMID 37823473 · Publisher ↗
The authors declare that after the publication of the article, it was noticed that two citations were inadvertently omitted. The references have now been included as [74b] and [74c]: [74] (b) Vitiello, M.; Galdiero, M.;...
The authors declare that after the publication of the article, it was noticed that two citations were inadvertently omitted. The references have now been included as [74b] and [74c]: [74] (b) Vitiello, M.; Galdiero, M.; Galdiero, M. Inhibition of Viral-Induced Membrane Fusion by Peptides. Protein Pep. Lett., 2009, 16(7), 786-793. (c) Galdiero, S.; Falanga, A.; Vitiello, M.; D'Isanto, M.; Cantisani, M.; Kampanaraki, A.; Benedetti, E.; Browne, H.; Galdiero, M. Peptides containing membrane-interacting motifs inhibit herpes simplex virus type 1 infectivity. Peptides, 2008, 29(9), 1461- 1471. The authors would like to include this reference in the online version of the article to ensure completeness.
Artificial Intelligence in Drug Formulation and Development: Applications and Future Prospects.
Noorain, Srivastava V, Parveen B … +1 more , Parveen R
Curr Drug Metab · 2023 · PMID 37779408 · Publisher ↗
Artificial Intelligence (AI) has emerged as a powerful tool in various domains, and the field of drug formulation and development is no exception. This review article aims to provide an overview of the applications of AI...
Artificial Intelligence (AI) has emerged as a powerful tool in various domains, and the field of drug formulation and development is no exception. This review article aims to provide an overview of the applications of AI in drug formulation and development and explore its future prospects. The article begins by introducing the fundamental concepts of AI, including machine learning, deep learning, and artificial neural networks and their relevance in the pharmaceutical industry. Furthermore, the article discusses the network and tools of AI and its applications in the pharmaceutical development process, including various areas, such as drug discovery, manufacturing, quality control, clinical trial management, and drug delivery. The utilization of AI in various conventional as well as modified dosage forms has been compiled. It also highlights the challenges and limitations associated with the implementation of AI in this field, including data availability, model interpretability, and regulatory considerations. Finally, the article presents the future prospects of AI in drug formulation and development, emphasizing the potential for personalized medicine, precision drug targeting, and rapid formulation optimization. It also discusses the ethical implications of AI in this context, including issues of privacy, bias, and accountability.
Nucleic Acid Nanomaterials: Biostability and Applications.
Gao S, Lin Y
Curr Drug Metab · 2023 · PMID 37728080 · Publisher ↗
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The Influence of Atorvastatin, Amlodipine and Ethoxidol on Ubiquinol and Ubiquinone Endogenous Plasma Concentrations in Patients with Chronic Heart Failure.
Zozina VI, Kondratenko SN, Shikh EV … +3 more , Krasnykh LM, Melnikov ES, Kukes VG
Curr Drug Metab · 2023 · PMID 37711113 · Publisher ↗
BACKGROUND: Coenzyme Q10 is a key component of the mitochondrial respiratory chain and a fat-soluble endogenous antioxidant performing many vital functions in the human body. Many researchers studied the plasma concentra...
BACKGROUND: Coenzyme Q10 is a key component of the mitochondrial respiratory chain and a fat-soluble endogenous antioxidant performing many vital functions in the human body. Many researchers studied the plasma concentrations of ubiquinol, ubiquinone, total CoQ10 and the redox state (ubiquinol/ubiquinone ratio) of CoQ10 in healthy volunteers. However, these parameters in the plasma of patients with chronic heart failure (CHF) remain almost uninvestigated. OBJECTIVE: The aim of this case-control study was to investigate the effect of atorvastatin, amlodipine and ethoxidol on endogenous plasma concentrations of ubiquinol, ubiquinone, total CoQ10 and its redox state in patients with CHF. METHODS: The study included 62 patients with CHF divided into four groups depending on the prescribed therapy. For the quantitative determination of ubiquinol, ubiquinone, and total CoQ10 in the plasma of patients, HPLCMS/ MS was used. RESULTS: It was established that the endogenous plasma concentration of total CoQ10 in patients with CHF is significantly lower than in healthy volunteers, and the ratio of reduced and oxidized forms of CoQ10 is shifted towards ubiquinone. It was a statistically significant effect of drugs with different physicochemical structures and pharmacological action on the plasma concentrations of ubiquinol, ubiquinone and total CoQ10: atorvastatin administration led to a decrease in the concentration of ubiquinol (-33.3Δ%), and total CoQ10 (-15Δ%), administration of amlodipine contributed to an increase in the levels of ubiquinol (+27.7Δ%) and total CoQ10 (+18.2Δ%), and the administration of ethoxidol caused an increase in the concentration of ubiquinol (+25Δ%), ubiquinone (+17.7Δ%) and total CoQ10 (+20.2Δ%). CONCLUSION: Amlodipine is able to neutralize the negative effect of atorvastin on the redox balance of CoQ10 in patients with CHF. An additional prescription of the antioxidant ethoxidol to standard therapy for patients with CHF was substantiated. Determination of the redox state of CoQ10 in plasma can be used to diagnose and assess the degree of oxidative stress in patients with cardiovascular diseases, as well as to assess the efficacy and safety of ongoing pharmacotherapy.
Which can Predict the Outcome of Antidepressants: Metabolic Genes or Pharmacodynamic Genes?
Zheng N, Niu M, Zang Y … +4 more , Zhuang H, Jia F, Bao S, Liu S
Curr Drug Metab · 2023 · PMID 37691197 · Publisher ↗
Drug therapy is the primary modality for depression; however, its outcome is often unpredictable, ranging from beneficial effects to serious adverse effects. Genetic variations in drug metabolizing enzymes and pharmacody...
Drug therapy is the primary modality for depression; however, its outcome is often unpredictable, ranging from beneficial effects to serious adverse effects. Genetic variations in drug metabolizing enzymes and pharmacodynamic molecules are responsible for a considerable proportion of interindividual differences in the effectiveness and toxicity of antidepressants. For the improvement in the use of antidepressants, the focus is mainly on personalized treatment emphasizing interindividual differences in genes. This study provides a comprehensive review of the literature on the clinical applications of pharmacogenomics for antidepressant therapy. The polymorphisms of metabolizing enzymes (, and others) governing the pharmacokinetic behavior of drugs are potential predictors of side effects or treatment failure with medications and there are good pharmacogenetic clinical recommendations for a wide selection of psychopharmacological agents based on functional diplotypes of and . The relationship between pharmacodynamic genes, including , and , and clinical outcomes varies in different races. Receptors that are currently used as drug targets for antidepressant drugs are evolutionarily conserved to a higher extent than genes encoding drug metabolism, and the actionability of pharmacodynamic-related genotyping is currently still questionable. The limited availability of largescale, long-term clinical studies on different races and medications currently impedes the implementation of pharmacogenomics in antidepressant treatment. The use of pharmacokinetic and pharmacodynamic modeling, and therapeutic drug monitoring combined with genetic, somatic, dietary, and environmental factors represents a promising avenue for improving the precision and effectiveness of antidepressant therapy.
Novel Techniques and Models for Studying Drug Metabolism and Transport.
Zeng S, Bi H, Yong Chan EC
Curr Drug Metab · 2023 · PMID 37638615 · Publisher ↗
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Preclinical Pharmacokinetics and CYP Modulation Activity of Chebulinic Acid: A Potent Molecule Against Metabolic Disease.
Biswas A, Verma SK, Kumar S … +9 more , Mishra T, Kumar M, Choudhury AD, Agrawal S, Sanap SN, Bisen AC, Mishra A, Narender T, Bhatta RS
Curr Drug Metab · 2023 · PMID 37592800 · Publisher ↗
BACKGROUND: Chebulinic acid (CA) is an active constituent of fruits with therapeutic potential against multiple metabolic diseases, including dementia, benign prostate hyperplasia, and osteoporosis. OBJECTIVE: The prese...
BACKGROUND: Chebulinic acid (CA) is an active constituent of fruits with therapeutic potential against multiple metabolic diseases, including dementia, benign prostate hyperplasia, and osteoporosis. OBJECTIVE: The present work intends to explore the preclinical pharmacokinetics, including the absolute bioavailability of CA and its influence on the gene expression of cytochrome P450 enzymes in the liver. METHODS: Quantifying CA and probe drugs samples and preclinical serum samples of male rats were performed using LC-MS/MS. The influence of CA on the hepatic CYPs and their gene expression was analyzed in rat liver by quantitative real-time polymerase chain reaction. RESULTS: The plasma protein binding was found to be 84.81 ± 7.70 and 96.34 ± 3.12, blood-to-plasma ratio of 0.62 ± 0.16 and 0.80 ± 0.23 at 1 μM and 10 μM concentrations, respectively. Again, the absolute oral bioavailability of CA at 100 mg/kg was found to be 37.56 ± 7.3%. The pharmacokinetic profile of probe drugs revealed CA to have significant inducing effects on CYP1A2, 2C11, 2D2, and 2E1 after 14 days, which correlates to both rat microsomal data and gene expression results. CONCLUSION: Altogether, pharmacokinetic parameters reveal CA to have an affinity to distribute across different extravascular tissues and induce rat liver CYP enzymes.
Herbal Medicines as Adjuvants for the Treatment of Chemotherapy-Induced Diarrhea.
Zheng Z, Srinual S, Chen J … +5 more , Li L, Du T, Hu M, Sun R, Gao S
Curr Drug Metab · 2023 · PMID 37592799 · Publisher ↗
BACKGROUND: Chemotherapeutic drugs used in cancer treatment often result in gastrointestinal toxicity, notably diarrhea, impacting patients' quality of life. Complementary and Alternative Medicine (CAM) has garnered incr...
BACKGROUND: Chemotherapeutic drugs used in cancer treatment often result in gastrointestinal toxicity, notably diarrhea, impacting patients' quality of life. Complementary and Alternative Medicine (CAM) has garnered increasing interest as an alternative to conventional approaches as a potential solution for managing chemotherapyinduced diarrhea (CID). OBJECTIVE: To summarize current research focusing on herbal medicines as adjuvant therapy to prevent or treat chemotherapy-induced diarrhea, including clinical assessments, mechanism of actions, active components, and potential pharmacokinetic interactions between herbal medicines and chemotherapeutic drugs. METHODS: We performed the literature review from PubMed, CNKI, Google Scholar, Web of Science, and Scopus using "Chemotherapy", "Diarrhea," and "Complementary and Alternative Medicine" as the search keywords. RESULTS: Using herbal medicines as adjuvants provides an effective approach to treating or preventing CID with improved or unaffected antitumor activity of chemotherapeutic drugs. Among these herbal formulations, scutellaria, ginger, and ginseng are the most frequently used herbs in the prescriptions for CID. The main antidiarrheal components in herbs include wogonin, baicalin, chrysin, quercetin, gingerol, and ginsenosides. These herbs, formulations, and bioactive components relieved CID through different mechanisms, including directly decreasing local drug exposure, anti-inflammation, inhibiting epithelial apoptosis, or promoting epithelium stem cell regeneration. The application of herbal medicines as adjunctive therapies showed efficacy in preventing or treating CID in multiple clinical trials. However, more well-designed clinical studies are expected to validate the results further. Despite some clinical studies demonstrating that certain herbal medicines could potentially attenuate CID and improve efficacy, it remains necessary to evaluate herbal safety. The interactions between herbs and drugs are also potential concerns, but few clinical trials have focused on investigating this aspect. CONCLUSION: In clinical practise, herbal medications show potential as adjuvant treatments for gastrointestinal toxicities induced by chemotherapy, particularly diarrhoea. Further well-designed clinical studies are needed to validate their efficacy, ensure safety, and explore potential drug-herb interactions.
Metabolism of Nifurtimox and the Drug-Drug Interaction Potential Including its Major Metabolites.
Schulz SI, Lang D, Schmuck G … +4 more , Gerisch M, Bairlein M, Fricke R, Stass H
Curr Drug Metab · 2023 · PMID 37592798 · Full text
BACKGROUND: Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited. OBJECTIVE: This study aimed to better understand the fate of oral nifurt...
BACKGROUND: Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited. OBJECTIVE: This study aimed to better understand the fate of oral nifurtimox . METHODS: We investigated the exposure and excretion pathways of [C]-labeled nifurtimox and its metabolites in rats. We then quantified the prominent metabolites and nifurtimox in the urine and plasma of patients receiving nifurtimox using LC-HRMS with reference standards and quantified these compounds in rat plasma after a single, high dose of nifurtimox. We also investigated potential drug-drug interactions (DDIs) of these compounds . RESULTS: In rats, orally administered nifurtimox was rapidly absorbed (t 0.5 h) and eliminated (t 1.4 h). Metabolism of nifurtimox yielded six predominant metabolites (M-1 to M-6) in urine and plasma, and the dose was excreted equally via the renal and fecal routes with only traces of unchanged nifurtimox detectable due to its instability in excreta. In patients with Chagas disease, only M-6 and M-4 achieved relevant exposure levels, and the total amount of excreted metabolites in urine was higher in fed fasted patients, consistent with the higher systemic exposure. For nifurtimox, M-6, and M-4, no potential perpetrator pharmacokinetic DDIs with the main cytochrome P- 450 enzymes and drug transporters were identified . CONCLUSION: This contemporary analysis of the complex metabolite profile and associated exposures emerging after oral dosing of nifurtimox in rats and humans, together with the expected low risk for clinically relevant DDIs, expands the understanding of this important anti-trypanosomal drug.
Molecular Insights into the Mechanism of Modulatory Effects of Proton Pump Inhibitors on P-glycoprotein Mediated Drug Transport of Palbociclib and Ribociclib.
Desai MP, Harish Patil P, Vullendula SKA … +6 more , Birangal S, Shenoy GG, Rao M, Dengale SJ, Bhat K, Channabasavaiah JP
Curr Drug Metab · 2023 · PMID 37581514 · Publisher ↗
BACKGROUND: Palbociclib and ribociclib are substrates of efflux transporter P-glycoprotein which plays a key role in absorption and transport of these drugs. Proton pump inhibitors, when co-administered with them are kno...
BACKGROUND: Palbociclib and ribociclib are substrates of efflux transporter P-glycoprotein which plays a key role in absorption and transport of these drugs. Proton pump inhibitors, when co-administered with them are known to show inhibitory effect on P-glycoprotein. OBJECTIVE: Therefore, this study aims to investigate the role of proton pump inhibitors in inhibition of P-glycoprotein mediated efflux of palbociclib and ribociclib. METHOD: A combined approach of molecular docking and everted gut sac model was implemented to predict the potential of proton pump inhibitors , omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole to inhibit the P-glycoprotein mediated intestinal transport of palbociclib and ribociclib and study the molecular basis of interaction taking place. RESULTS: Molecular docking studies revealed that omeprazole, rabeprazole and pantoprazole bound to the ATP site of nucleotide binding domain with binding energies of -27.53, -29.56 and -38.44 Kcal/mol respectively. In studies, rabeprazole and omeprazole, affected the absorptive permeability of palbociclib by 3.04 and 1.26 and ribociclib by 1.76 and 2.54 folds, respectively. Results of molecular docking studies and studies highlighted that proton pump inhibitors bound to the ATP binding site to block its hydrolysis thereby inhibiting the P-glycoprotein mediated efflux of palbociclib and ribociclib. CONCLUSION: The experimental evidence presented highlights the fact that proton pump inhibitors have potential to inhibit P-glycoprotein, giving rise to drug interactions with palbociclib and ribociclib. Hence, monitoring is required while proton pump inhibitors and cyclin-dependent kinase inhibitors are being co-administered to avoid adverse events.
Comparative Analysis of Pharmacokinetics and Metabolites of Three Main Terpenoids before and after Compatibility of Frankincense and Myrrh in Rats by UHPLC-MS.
Fan RY, Gao RM, Li JS … +4 more , Su SL, Shang EX, Qian DW, Duan JA
Curr Drug Metab · 2023 · PMID 37559536 · Publisher ↗
BACKGROUND: 3-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) are the main active components of frankincense as pentacyclic triterpenoids, which are designated by the European Pharmacopoeia 8.0...
BACKGROUND: 3-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) are the main active components of frankincense as pentacyclic triterpenoids, which are designated by the European Pharmacopoeia 8.0 as the quality standard for the evaluation of Indian frankincense, 2-methoxy-8,12-epoxygermacra- 1(10),7,11-trien-6-one (MCS134) is a non-volatile sesquiterpene compound in myrrh. OBJECTIVE: In this paper, the absorption pharmacokinetics and metabolites of AKBA, KBA and MCS134 after frankincense, myrrh and their compatibility were analyzed, elaborated their absorption and metabolism mechanism and provided the ideas for the research on the bioactive components of frankincense and myrrh compatibility . METHODS: The area under the blood concentration time curve (AUC), half-life (<i>t<sub>1/2<sub></i>) and drug clearance (<i>CL</i>) of AKBA, KBA and MCS134 in rats were analyzed by LC-TQ / MS. The metabolites of AKBA, KBA and MCS134 in rats were analyzed by ultra-high pressure liquid chromatography with a linear ion trap-high resolution Orbitrap mass spectrometry system (UHPLC-LTQ-Orbitrap-MS). RESULTS: The results showed that AKBA, KBA and MCS134 reached the maximum plasma concentration at about 2 h, 2 h and 15 min, respectively. <i>AUC<sub>0-t</sub></i> and <i>t<sub>1/2<sub></i> of the three components increased in varying degrees after compatibility, and the clearance/ bioavailability (<i>CL/F</i>) decreased. AKBA, KBA and MCS134 were metabolized in phase I and phase II in rats, and there represented differences before and after compatibility. CONCLUSION: After the compatibility of frankincense and myrrh, the absorption of effective components was improved to some extent, and there were some differences in the metabolites in rats. The results provide ideas for elucidating the effect mechanism of frankincense and myrrh.
A Mini-review on Recent Strategies and Applications of Nanomedicines to Combat Antimicrobial Resistance.
Chahar K, Sharma Y, Patel P … +2 more , Asati V, Das Kurmi B
Curr Drug Metab · 2023 · PMID 37519199 · Publisher ↗
One of the key factors contributing to mortality and morbidity globally is infectious ailments. According to recent statistics from WHO, amplified antimicrobial resistance occurrence among bacteria signifies the utmost t...
One of the key factors contributing to mortality and morbidity globally is infectious ailments. According to recent statistics from WHO, amplified antimicrobial resistance occurrence among bacteria signifies the utmost threat to global public health. Bacteria have developed various strategies to resist antimicrobials, including enzymatic inactivation of antibiotics, drug efflux, modifications of the antibiotic molecule or chemical alteration of the antibiotic, limited drug uptake, etc. Furthermore, the inefficiency of antimicrobial drugs against resistant bacteria due to low solubility, instability, and associated side effects augments challenges to combat these resistant pathogens. This has attracted the attention of researchers to create nano-delivery and targeting techniques. This review presents an overview of antimicrobial resistance (AMR), its various subtypes, as well as mechanisms involved in AMR. This review also describes current strategies and applications of various nanocarriers, including nanoparticles, liposomes, lipid-based nanoparticles, micelles, and polymeric nanoparticles.
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