Current Drug Metabolism[JOURNAL]
Sun
200 papers
Fluoropyrimidine Toxicity: the Hidden Secrets of DPYD.
Manolopoulos VG, Ragia G
Curr Drug Metab · 2024 · PMID 38504562 · Publisher ↗
BACKGROUND: Fluoropyrimidine-induced toxicity is a main limitation of therapy. Currently, polymorphisms in the DPYD gene, which encodes the 5-FU activation enzyme dihydropyrimidine dehydrogenase (DPD), are used to adjust...
BACKGROUND: Fluoropyrimidine-induced toxicity is a main limitation of therapy. Currently, polymorphisms in the DPYD gene, which encodes the 5-FU activation enzyme dihydropyrimidine dehydrogenase (DPD), are used to adjust the dosage and prevent toxicity. Despite the predictive value of DPYD genotyping, a great proportion of fluoropyrimidine toxicity cannot be solely explained by DPYD variations. OBJECTIVE: We herein summarize additional sources of DPD enzyme activity variability, spanning from epigenetic regulation of DPYD expression, factors potentially inducing protein modifications, as well as drug-enzyme interactions that contribute to fluoropyrimidine toxicity. RESULTS: While seminal studies provided evidence that DPYD promoter methylation downregulates DPD expression, the association of DPYD methylation with fluoropyrimidine toxicity was not replicated in clinical studies. Different non-coding RNA molecules, such as microRNA, piwi-RNAs, circular-RNAs and long non-coding RNAs, are involved in post-transcriptional DPYD regulation. DPD protein modifications and environmental factors affecting enzyme activity may also add a proportion to the pooled variability of DPD enzyme activity. Lastly, DPD-drug interactions are common in therapeutics, with the most well-characterized paradigm the withdrawal of sorivudine due to fluoropyrimidine toxicity deaths in 5-FU treated cancer patients; a mechanism involving DPD severe inhibition. CONCLUSIONS: DPYD polymorphisms are the main source of DPD variability. A study on DPYD epigenetics (both transcriptionally and post-transcriptionally) holds promise to provide insights into molecular pathways of fluoropyrimidine toxicity. Additional post-translational DPD modifications, as well as DPD inhibition by other drugs, may explain a proportion of enzyme activity variability. Therefore, there is still a lot we can learn about the DPYD/DPD fluoropyrimidine-induced toxicity machinery.
Safety Aspects of Herb Interactions: Current Understanding and Future Prospects.
Hazra S, Singh PA
Curr Drug Metab · 2024 · PMID 38482621 · Publisher ↗
BACKGROUND: The use of herbal medicines is on the rise throughout the world due to their perceived safety profile. However, incidences of herb-drug, herb-herb and herb-food interactions considering safety aspects have op...
BACKGROUND: The use of herbal medicines is on the rise throughout the world due to their perceived safety profile. However, incidences of herb-drug, herb-herb and herb-food interactions considering safety aspects have opened new arenas for discussion. OBJECTIVE: The current study aims to provide comprehensive insights into the various types of herb interactions, the mechanisms involved, their assessment, and historical developments, keeping herbal safety at the central point of discussion. METHODS: The authors undertook a focused/targeted literature review and collected data from various databases, including Science Direct, Wiley Online Library, Springer, PubMed, and Google Scholar. Conventional literature on herbal remedies, such as those by the WHO and other international or national organizations. RESULTS: The article considered reviewing the regulations, interaction mechanisms, and detection of herb-herb, herb-drug and herb-food interactions in commonly used yet vital plants, including . The study found that healthcare professionals worry about patients not informing them about their herbal prescriptions (primarily used with conventional treatment), which can cause herb-drug/herb-food/herb-herb interactions. These interactions were caused by altered pharmacodynamic and pharmacokinetic processes, which might be explained using , pharmacogenomics, and pharmacogenetics. Nutrivigilance may be the greatest method to monitor herb-food interactions, but its adoption is limited worldwide. CONCLUSION: This article can serve as a lead for clinicians, guiding them regarding herb-drug, herb-food, and herb-herb interactions induced by commonly consumed plant species. Patients may also be counseled to avoid conventional drugs, botanicals, and foods with a restricted therapeutic window.
Altitude effect on Propofol Pharmacokinetics in Rats.
Li L, Wang X, Wang S … +2 more , Wen L, Zhang H
Curr Drug Metab · 2024 · PMID 38468514 · Full text
BACKGROUND: Propofol is an intravenous agent for clinical anesthesia. As the influence of the hypobaric-hypoxic environment (Qinghai-Tibetan region, altitude: 2800-4300 m, PaO2: 15.1-12.4 kPa) on the metabolism of Propof...
BACKGROUND: Propofol is an intravenous agent for clinical anesthesia. As the influence of the hypobaric-hypoxic environment (Qinghai-Tibetan region, altitude: 2800-4300 m, PaO2: 15.1-12.4 kPa) on the metabolism of Propofol is complex, the research results on the metabolic characteristics of Propofol in high-altitude areas remain unclear. This study aimed to investigate the pharmacokinetic characteristics of Propofol in a high-altitude hypoxic environment using animal experiments. METHODS: Rats were randomly divided into three groups: high-altitude, medium-altitude, and plain groups. The time of disappearance and recovery of the rat righting reflex was recorded as the time of anesthesia induction and awakening, respectively. The plasma concentration of Propofol was determined by gas chromatography-mass spectrometry. A pharmacokinetic analysis software was used to analyze the blood-drug concentrations and obtain the pharmacokinetic parameters. RESULTS: We observed that when Propofol anesthetizes rats, the anesthesia induction time was shortened, and the recovery time was prolonged with increased altitude. Compared with the plain group, the clearance of Propofol decreased, whereas the half-life, area under the concentration-time curve, peak plasma concentration, and average residence time extension increased. CONCLUSION: The pharmacokinetic characteristics of Propofol are significantly altered in high-altitude hypoxic environments.
Safety Issues of Herb-Warfarin Interactions.
Hazra S, Singh PA, Bajwa N
Curr Drug Metab · 2024 · PMID 38465436 · Publisher ↗
Warfarin is a popular anticoagulant with high global demand. However, studies have underlined serious safety issues when warfarin is consumed concomitantly with herbs or its formulations. This review aimed to highlight t...
Warfarin is a popular anticoagulant with high global demand. However, studies have underlined serious safety issues when warfarin is consumed concomitantly with herbs or its formulations. This review aimed to highlight the mechanisms behind herb-warfarin interactions while laying special emphasis on its PKPD interactions and evidence on Herb-Warfarin Interaction (HWI) with regards to three different scenarios, such as when warfarin is consumed with herbs, taken as foods or prescribed as medicine, or when used in special situations. A targeted literature methodology involving different scientific databases was adopted for acquiring information on the subject of HWIs. Results of the present study revealed some of the fatal consequences of HWI, including post-operative bleeding, thrombosis, subarachnoid hemorrhage, and subdural hematomas occurring as a result of interactions between warfarin and herbs or commonly associated food products from , and . In terms of PK-PD parameters, herbs, such as Franch. and Rupr., were found to compete with warfarin for binding with plasma proteins, leading to an increase in free warfarin levels in the bloodstream, resulting in its augmented antithrombic effect. Besides, HWIs were also found to decrease International Normalised Ratio (INR) levels following the consumption of Persea americana or avocado. Therefore, there is an urgent need for an up-to-date interaction database to educate patients and healthcare providers on these interactions, besides promoting the adoption of novel technologies, such as natural language processing, by healthcare professionals to guide them in making informed decisions to avoid HWIs.
A Phase I Clinical Study of the Pharmacokinetics and Safety of Prusogliptin Tablets in Subjects with Mild to Moderate Hepatic Insufficiency and Normal Liver Function.
Zhang H, Bian Y, Zhao W … +6 more , Miao L, Zhang H, Cui J, Zhang X, Zhang X, Cai W
Curr Drug Metab · 2024 · PMID 38454771 · Publisher ↗
BACKGROUND: Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics a...
BACKGROUND: Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics and safety in patients with liver dysfunction is limited. OBJECTIVES: The present study evaluated the pharmacokinetics and safety of Prusogliptin in subjects with mild or moderate hepatic impairment compared with healthy subjects. METHODS: According to the liver function of the subjects, we divided them into a mild liver dysfunction group, a moderate liver dysfunction group and a normal liver function group. All subjects in three groups received a single oral dose of Prusogliptin 100-mg tablets. Pharmacokinetics and safety index collection was carried out before and after taking the drug. Plasma pharmacokinetics of Prusogliptin were evaluated, and geometric least- -squares mean (GLSM) and associated 90% confidence intervals for insufficient groups versus the control group were calculated for plasma exposures. RESULTS: After a single oral administration of 100 mg of Prusogliptin tablets, the exposure level of Prusogliptin in subjects with mild liver dysfunction was slightly higher than that in healthy subjects. The exposure level of Prusogliptin was significantly increased in subjects with moderate liver dysfunction. There were no adverse events in this study. CONCLUSION: The exposure level of Prusogliptin in subjects with liver dysfunction was higher than that in healthy subjects. No participant was observed of adverse events. Prusogliptin tablets were safe and well tolerated in Chinese subjects with mild to moderate liver dysfunction and normal liver function.
Comparative Analysis of Machine Learning Algorithms Evaluating the Single Nucleotide Polymorphisms of Metabolizing Enzymes with Clinical Outcomes Following Intravenous Paracetamol in Preterm Neonates with Patent Ductus Arteriosus.
Sridharan K, Doss C GP, Cathryn R H … +2 more , Kumar D T, Al Jufairi M
Curr Drug Metab · 2024 · PMID 38445694 · Publisher ↗
AIMS: Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamo...
AIMS: Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamol for new indications in preterm neonates. BACKGROUND: Paracetamol has recently been preferred as a first-line drug for managing Patent Ductus Arteriosus (PDA) in preterm neonates. Single Nucleotide Polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 have been observed to influence the therapeutic concentrations of paracetamol. OBJECTIVES: The purpose of this study was to evaluate various Machine Learning Algorithms (MLAs) and bioinformatics tools for identifying the key genotype predictor of therapeutic outcomes following paracetamol administration in neonates with PDA. METHODS: Preterm neonates with hemodynamically significant PDA were recruited in this prospective, observational study. The following SNPs were evaluated: CYP2E1*5B, CYP2E1*2, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, CYP3A5*11, CYP1A2*1C, CYP1A2*1K, CYP1A2*3, CYP1A2*4, CYP1A2*6, and CYP2D6*10. Amongst the MLAs, Artificial Neural Network (ANN), C5.0 algorithm, Classification and Regression Tree analysis (CART), discriminant analysis, and logistic regression were evaluated for successful closure of PDA. Generalized linear regression, ANN, CART, and linear regression were used to evaluate maximum serum acetaminophen concentrations. A two-step cluster analysis was carried out for both outcomes. Area Under the Curve (AUC) and Relative Error (RE) were used as the accuracy estimates. Stability analysis was carried out using tools, and Molecular Docking and Dynamics Studies were carried out for the above-mentioned enzymes. RESULTS: Two-step cluster analyses have revealed CYP2D6*10 and CYP1A2*1C to be the key predictors of the successful closure of PDA and the maximum serum paracetamol concentrations in neonates. The ANN was observed with the maximum accuracy (AUC = 0.53) for predicting the successful closure of PDA with CYP2D6*10 as the most important predictor. Similarly, ANN was observed with the least RE (1.08) in predicting maximum serum paracetamol concentrations, with CYP2D6*10 as the most important predictor. Further MDS confirmed the conformational changes for P34A and P34S compared to the wildtype structure of CYP2D6 protein for stability, flexibility, compactness, hydrogen bond analysis, and the binding affinity when interacting with paracetamol, respectively. The alterations in enzyme activity of the mutant CYP2D6 were computed from the molecular simulation results. CONCLUSION: We have identified CYP2D6*10 and CYP1A2*1C polymorphisms to significantly predict the therapeutic outcomes following the administration of paracetamol in preterm neonates with PDA. Prospective studies are required for confirmation of the findings in the vulnerable population.
The Role of CYPs and Transporters in the Biotransformation and Transport of the Anti-hepatitis C Antiviral Agents Asunaprevir, Daclatasvir, and Beclabuvir: Impact of Liver Disease, Race and Drug-drug Interactions on Safety and Efficacy.
Murray M
Curr Drug Metab · 2024 · PMID 38441017 · Publisher ↗
Asunaprevir, daclatasvir, and beclabuvir are direct-acting antiviral agents used in the treatment of patients infected with hepatitis C genotype 1b. This article reviews the biotransformation and disposition of these dru...
Asunaprevir, daclatasvir, and beclabuvir are direct-acting antiviral agents used in the treatment of patients infected with hepatitis C genotype 1b. This article reviews the biotransformation and disposition of these drugs in relation to the safety and efficacy of therapy. CYP3A4 and 3A5 catalyze the oxidative biotransformation of the drugs, while P-glycoprotein mediates their efflux from tissues. Asunaprevir is also a substrate for the influx transporters OATP1B1 and OATP2B1 and the efflux transporter MRP2, while beclabuvir is also a substrate for the efflux transporter BCRP. Liver disease decreases the expression of CYPs and transporters that mediate drug metabolism and disposition. Serum asunaprevir concentrations, but not those of daclatasvir or beclabuvir, are increased in patients with severe liver disease, which may produce toxicity. Pharmacogenomic variation in CYPs and transporters also has the potential to disrupt therapy with asunaprevir, daclatasvir and beclabuvir; some variants are more prevalent in certain racial groups. Pharmacokinetic drug-drug interactions, especially where asunaprevir, daclatasvir, and beclabuvir are victim drugs, are mediated by coadministered rifampicin, ketoconazole and ritonavir, and are attributable to inhibition and/or induction of CYPs and transporters. Conversely, there is also evidence that asunaprevir, daclatasvir and beclabuvir are perpetrators of drug interactions with coadministered rosuvastatin and dextromethorphan. Together, liver disease, pharmacogenomic variation and drug-drug interactions may disrupt therapy with asunaprevir, daclatasvir and beclabuvir due to the impaired function of important CYPs and transporters.
A Combination of Magnoflorine and Spinosin Improves the Antidepressant effects on CUMS Mouse Model.
Bi F, Wang Z, Guo Y … +3 more , Xia M, Zhu X, Qiao W
Curr Drug Metab · 2024 · PMID 38415474 · Publisher ↗
BACKGROUND: Depression is a common neuropsychiatric disease. As a famous traditional Chinese medicine with significant anti-depressive and sleep-promoting effects, Semen (ZSS) has attracted the attention of many researc...
BACKGROUND: Depression is a common neuropsychiatric disease. As a famous traditional Chinese medicine with significant anti-depressive and sleep-promoting effects, Semen (ZSS) has attracted the attention of many researchers. Although it is well known that Magnoflorine (MAG) and Spinosin (SPI) were the main active components isolated from ZSS, there is a lack of research on the combined treatment of depression with these two ingredients. METHODS: The shaking bottle method was used to simulate the human environment for detecting the changes in oil-water partition coefficient before and after the drug combination. Cell viability was evaluated by the MTT assay. To establish a mouse model of depression and insomnia by CUMS method, and then to explore the effect of combined administration of MAG and SPI on depression in CUMS model by observing behavior and analyzing pharmacokinetics. RESULTS: The change in LogP values affected the lipid solubility of MAG and increased the water solubility of SPI, allowing them to penetrate more easily through the blood-brain barrier into the brain. Compared with the model group, MAG-SPI with a concentration of 60 μM significantly increased cell survival rate. In both the TST and FST experiments, the mice showed a decrease in immobilization time. Pharmacokinetic results showed that the pharmacokinetic parameters, C and AUC of MAG and SPI, were increased in the case of combination, which resulted in enhancement of their relative bioavailability and improvement of effects. CONCLUSIONS: The present study demonstrated that a combination of MAG and SPI had a synergistic antidepressant effect in CUMS mouse model.
Effect of High Altitude Environment on Pharmacokinetic and Pharmacodynamic of Warfarin in Rats.
Zhang X, Mu H, Zhong Y … +2 more , Wang R, Li W
Curr Drug Metab · 2024 · PMID 38409697 · Publisher ↗
BACKGROUND: High altitude environment affects the pharmacokinetic (PK) parameters of drugs and the PK parameters are an important theoretical basis for guiding the rational clinical use of drugs. Warfarin is an oral anti...
BACKGROUND: High altitude environment affects the pharmacokinetic (PK) parameters of drugs and the PK parameters are an important theoretical basis for guiding the rational clinical use of drugs. Warfarin is an oral anticoagulant of the coumarin class commonly used in clinical practice, but it has a narrow therapeutic window and wide individual variation. However, the effect of high altitude environment on PK and pharmacodynamic (PD) of warfarin is unclear. OBJECTIVE: The objective of this study is to investigate the effect of a high altitude environment on PK and PD of warfarin in rats. METHOD: Rats were randomly divided into plain group and high altitude group and blood samples were collected through the orbital venous plexus after administration of 2 mg/kg warfarin. Warfarin concentrations in plasma samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and PK parameters were calculated by the non-compartment model using WinNonlin 8.1 software. Meanwhile, the expression of PXR, P-gp and CYP2C9 in liver tissues was also determined by western blotting. The effect of high altitude environment on PD of warfarin was explored by measuring activated partial thromboplastin time (APTT) and prothrombin time (PT) values and then calculated international normalized ratio (INR) values based on PT. RESULTS: Significant changes in PK behaviors and PD of warfarin in high altitude-rats were observed. Compared with the plain-rats, the peak concentration (C) and the area under the plasma concentration-time curve (AUC) increased significantly by 50.9% and 107.46%, respectively. At the same time, high altitude environment significantly inhibited the expression of PXR, P-gp and CYP2C9 in liver tissues. The results of the PD study showed that high altitude environments significantly prolonged PT, APTT and INR values. CONCLUSION: High altitude environment inhibited the metabolism and increased the absorption of warfarin in rats and increased the effect of anticoagulant effect, suggesting that the optimal dose of warfarin for patients at high altitude should be reassessed.
Recent Advances in Hepatic Metabolic Regulation by the Nuclear Factor Rev-erbɑ.
Zhang Q, Chen Y, Li J … +3 more , Xia H, Tong Y, Liu Y
Curr Drug Metab · 2024 · PMID 38409696 · Publisher ↗
Rev-erbɑ (NR1D1) is a nuclear receptor superfamily member that plays a vital role in mammalian molecular clocks and metabolism. Rev-erbɑ can regulate the metabolism of drugs and the body's glucose metabolism, lipid metab...
Rev-erbɑ (NR1D1) is a nuclear receptor superfamily member that plays a vital role in mammalian molecular clocks and metabolism. Rev-erbɑ can regulate the metabolism of drugs and the body's glucose metabolism, lipid metabolism, and adipogenesis. It is even one of the important regulatory factors regulating the occurrence of metabolic diseases (e.g., diabetes, fatty liver). Metabolic enzymes mediate most drug metabolic reactions in the body. Rev-erbɑ has been recognized to regulate drug metabolic enzymes (such as Cyp2b10 and Ugt1a9). Therefore, this paper mainly reviewed that Rev-erbɑ regulates I and II metabolic enzymes in the liver to affect drug pharmacokinetics. The expression of these drug metabolic enzymes (up-regulated or down-regulated) is related to drug exposure and effects/ toxicity. In addition, our discussion extends to Rev-erbɑ regulating some transporters (such as P-gp, Mrp2, and Bcrp), as they also play an essential role in drug metabolism. Finally, we briefly describe the role and mechanism of nuclear receptor Rev-erbɑ in lipid and glucose homeostasis, obesity, and metabolic disorders syndrome. In conclusion, this paper aims to understand better the role and mechanism of Rev-erbɑ in regulating drug metabolism, lipid, glucose homeostasis, obesity, and metabolic disorders syndrome, which explores how to target Rev-erbɑ to guide the design and development of new drugs and provide scientific reference for the molecular mechanism of new drug development, rational drug use, and drug interaction.
Inhibitory Effects of Tricyclic Antidepressants on Human Liver Microsomal Morphine Glucuronidation: Application of IVIVE to Predict Potential Drug-Drug Interactions in Humans.
Uchaipichat V
Curr Drug Metab · 2023 · PMID 38270153 · Publisher ↗
BACKGROUND: Tricyclic antidepressants (TCAs) are commonly co-administered with morphine as an adjuvant analgesic. Nevertheless, there remains a lack of information concerning metabolic drug-drug interactions (DDIs) resul...
BACKGROUND: Tricyclic antidepressants (TCAs) are commonly co-administered with morphine as an adjuvant analgesic. Nevertheless, there remains a lack of information concerning metabolic drug-drug interactions (DDIs) resulting from TCA inhibition on morphine glucuronidation. OBJECTIVE: This study aimed to (i) examine the inhibitory effects of TCAs (., amitriptyline, clomipramine, imipramine, and nortriptyline) on human liver microsomal morphine 3- and 6-glucuronidation and (ii) evaluate the potential of DDI in humans by employing extrapolation (IVIVE) approaches. METHOD: The inhibition parameters for TCA inhibition on morphine glucuronidation were derived from the system containing 2% BSA. The K values were employed to predict the DDI magnitude by using static and dynamic mechanistic PBPK approaches Results: TCAs moderately inhibited human liver microsomal morphine glucuronidation, with clomipramine exhibiting the most potent inhibition potency. Amitriptyline, clomipramine, imipramine, and nortriptyline competitively inhibited morphine 3- and 6-glucuronide formation with the respective K values of 91 ± 7.5 and 82 ± 11 μM, 23 ± 1.3 and 14 ± 0.7 μM, 103 ± 5 and 90 ± 7 μM, and 115 ± 5 and 110 ± 3 μM. Employing the static mechanistic IVIVE, a prediction showed an estimated 20% elevation in the morphine AUC when co-administered with either clomipramine or imipramine, whereas the predicted increase was <5% for amitriptyline or nortriptyline. PBPK modelling predicted an increase of less than 10% in the morphine AUC due to the inhibition of clomipramine and imipramine in both virtual healthy and cirrhotic populations. CONCLUSION: The results suggest that the likelihood of potential clinical DDIs arising from tricyclic antidepressant inhibition on morphine glucuronidation is low.
Drug-Protein Interactions Prediction Models Using Feature Selection and Classification Techniques.
Idhaya T, Suruliandi A, Raja SP
Curr Drug Metab · 2023 · PMID 38270152 · Publisher ↗
BACKGROUND: Drug-Protein Interaction (DPI) identification is crucial in drug discovery. The high dimensionality of drug and protein features poses challenges for accurate interaction prediction, necessitating the use of...
BACKGROUND: Drug-Protein Interaction (DPI) identification is crucial in drug discovery. The high dimensionality of drug and protein features poses challenges for accurate interaction prediction, necessitating the use of computational techniques. Docking-based methods rely on 3D structures, while ligand-based methods have limitations such as reliance on known ligands and neglecting protein structure. Therefore, the preferred approach is the chemogenomics-based approach using machine learning, which considers both drug and protein characteristics for DPI prediction. METHODS: In machine learning, feature selection plays a vital role in improving model performance, reducing overfitting, enhancing interpretability, and making the learning process more efficient. It helps extract meaningful patterns from drug and protein data while eliminating irrelevant or redundant information, resulting in more effective machine-learning models. On the other hand, classification is of great importance as it enables pattern recognition, decision-making, predictive modeling, anomaly detection, data exploration, and automation. It empowers machines to make accurate predictions and facilitates efficient decision-making in DPI prediction. For this research work, protein data was sourced from the KEGG database, while drug data was obtained from the DrugBank data machine-learning base. RESULTS: To address the issue of imbalanced Drug Protein Pairs (DPP), different balancing techniques like Random Over Sampling (ROS), Synthetic Minority Over-sampling Technique (SMOTE), and Adaptive SMOTE were employed. Given the large number of features associated with drugs and proteins, feature selection becomes necessary. Various feature selection methods were evaluated: Correlation, Information Gain (IG), Chi-Square (CS), and Relief. Multiple classification methods, including Support Vector Machines (SVM), Random Forest (RF), Adaboost, and Logistic Regression (LR), were used to predict DPI. Finally, this research identifies the best balancing, feature selection, and classification methods for accurate DPI prediction. CONCLUSION: This comprehensive approach aims to overcome the limitations of existing methods and provide more reliable and efficient predictions in drug-protein interaction studies.
Effect of Dexketoprofen on the Disposition Kinetics of Moxifloxacin in Plasma and Lung in Male and Female Rats.
Erdogan T, Oguz H, Corum O
Curr Drug Metab · 2024 · PMID 38258775 · Publisher ↗
BACKGROUND: The simultaneous use of NSAIDs and antibiotics is recommended for bacterial diseases in human and veterinary medicine. Moxifloxacin (MFX) and dexketoprofen (DEX) can be used simultaneously in bacterial infect...
BACKGROUND: The simultaneous use of NSAIDs and antibiotics is recommended for bacterial diseases in human and veterinary medicine. Moxifloxacin (MFX) and dexketoprofen (DEX) can be used simultaneously in bacterial infections. However, there are no studies on how the simultaneous use of DEX affects the pharmacokinetics of MFX in rats. OBJECTIVES: The aim of this study was to determine the effect of DEX on plasma and lung pharmacokinetics of MFX in male and female rats. METHODS: A total of 132 rats were randomly divided into 2 groups: MFX (n=66, 33 males/33 females) and MFX+DEX (n=66, 33 females/33 males). MFX at a dose of 20 mg/kg and DEX at a dose of 25 mg/kg were administered intraperitoneally. Plasma and lung concentrations of MFX were determined using the highperformance liquid chromatography-UV and pharmacokinetic parameters were evaluated by noncompartmental analysis. RESULTS: Simultaneous administration of DEX increased the plasma and lung area under the curve from 0 to 8 h (AUC) and peak concentration (C) of MFX in rats, while it significantly decreased the total body clearance (CL/F). When female and male rats were compared, significant differences were detected in AUC, C, CL/F and volume of distribution. The AUC/AUC ratios of MFX were calculated as 1.68 and 1.65 in female rats and 5.15 and 4.90 in male rats after single and combined use, respectively. CONCLUSION: MFX was highly transferred to the lung tissue and this passage was remarkably higher in male rats. However, DEX administration increased the plasma concentration of MFX in both male and female rats but did not change its passage to the lung. However, there is a need for a more detailed investigation of the difference in the pharmacokinetics of MFX in male and female rats.
Nutritional Therapy Strategies Targeting Tumor Energy Metabolism.
Chen T, Yu H
Curr Drug Metab · 2023 · PMID 38155471 · Publisher ↗
Cancer is the second leading cause of mortality worldwide. The heightened nutrient uptake, particularly glucose, and elevated glycolysis observed in rapidly proliferating tumor cells highlight the potential targeting of...
Cancer is the second leading cause of mortality worldwide. The heightened nutrient uptake, particularly glucose, and elevated glycolysis observed in rapidly proliferating tumor cells highlight the potential targeting of energy metabolism pathways for the treatment of cancer. Numerous studies and clinical trials have demonstrated the efficacy of nutritional therapy in mitigating the adverse effects of chemotherapy and radiotherapy, enhancing treatment outcomes, prolonging survival, and improving the overall quality of life of patients. This review article comprehensively examines nutritional therapy strategies that specifically address tumor energy metabolism. Moreover, it explores the intricate interplay between energy metabolism and the gut microbiota in the context of nutritional therapy. The findings aim to provide valuable insights for future clinical research endeavors in this field.
The Impacts and Changes Related to the Cancer Drug Resistance Mechanism.
Varshney P, Sharma V, Yadav D … +9 more , Kumar Y, Singh A, Kagithala NR, Sharma PK, Porwal O, Fuloria NK, Sharma PK, Gupta AK, Gsn KR
Curr Drug Metab · 2023 · PMID 38141188 · Publisher ↗
BACKGROUND: Cancer drug resistance remains a difficult barrier to effective treatment, necessitating a thorough understanding of its multi-layered mechanism. OBJECTIVE: This study aims to comprehensively explore the dive...
BACKGROUND: Cancer drug resistance remains a difficult barrier to effective treatment, necessitating a thorough understanding of its multi-layered mechanism. OBJECTIVE: This study aims to comprehensively explore the diverse mechanisms of cancer drug resistance, assess the evolution of resistance detection methods, and identify strategies for overcoming this challenge. The evolution of resistance detection methods and identification strategies for overcoming the challenge. METHODS: A comprehensive literature review was conducted to analyze intrinsic and acquired drug resistance mechanisms, including altered drug efflux, reduced uptake, inactivation, target mutations, signaling pathway changes, apoptotic defects, and cellular plasticity. The evolution of mutation detection techniques, encompassing clinical predictions, experimental approaches, and computational methods, was investigated. Strategies to enhance drug efficacy, modify pharmacokinetics, optimizoptimizee binding modes, and explore alternate protein folding states were examined. RESULTS: The study comprehensively overviews the intricate mechanisms contributing to cancer drug resistance. It outlines the progression of mutation detection methods and underscores the importance of interdisciplinary approaches. Strategies to overcome drug resistance challenges, such as modulating ATP-binding cassette transporters and developing multidrug resistance inhibitors, are discussed. The study underscores the critical need for continued research to enhance cancer treatment efficacy. CONCLUSION: This study provides valuable insights into the complexity of cancer drug resistance mechanisms, highlights evolving detection methods, and offers potential strategies to enhance treatment outcomes.
Comparative Pharmacokinetics of Intravenous Enrofloxacin in One- Six- And Twelve-Month-Old Sheep.
Coskun D, Corum O, Corum DD … +1 more , Uney K
Curr Drug Metab · 2023 · PMID 38141187 · Publisher ↗
BACKGROUND: Enrofloxacin (ENR) is a fluoroquinolone antibiotic approved for use in sheep of all ages. The body composition and metabolic capability change with age. These changes may alter the pharmacokinetics of drugs a...
BACKGROUND: Enrofloxacin (ENR) is a fluoroquinolone antibiotic approved for use in sheep of all ages. The body composition and metabolic capability change with age. These changes may alter the pharmacokinetics of drugs and thus their effect. Therefore, the pharmacokinetics of drugs need to be established in target- age animals. OBJECTIVE: To determine the pharmacokinetics of ENR and its active metabolite, ciprofloxacin (CIP), following a single intravenous administration of ENR at a dose of 10 mg/kg in different ages of sheep. METHODS: The study was carried out in the one-, six- and twelve-month age period of the sheep. A single dose of 10 mg/kg ENR was administered intravenously through the jugular vein to sheep in all age periods. ENR and CIP plasma concentrations were determined using HPLC-UV and analyzed using a non-compartmental method. RESULTS: ENR was detected in the plasma until 36 h in one-month-old and up to 24 h in other ages. CIP was detected in the plasma up to 24 h in all age groups. The t and V were significantly higher in one-month-old sheep than in six and twelve-months old sheep. There was no difference in Cl and AUC values in different age groups. AUCCIP/AUC ratios were higher in one-month-old than in six- and twelve-months sheep. CONCLUSION: The most important pharmacokinetic changes associated with aging in sheep are decreased V and t of ENR and the low ratio metabolizing of ENR to CIP. Pharmacokinetic/pharmacodynamic data showed that ENR after IV administration of 10 mg/kg dose provided the optimal AUC/MIC ratios for and spp. (>125) with MIC of 0.37 µg/mL and for S. aureus (>30) with MIC of 0.5 µg/mL in all ages of sheep.
Reassessment of Radiation Exposure From Bone Scintigraphy.
Tanyildizi-Kökkülünk H, Şenişik AM, Yüksel M
Curr Drug Metab · 2023 · PMID 38141186 · Publisher ↗
AIM: This study was aimed to re-determine the radiation dose rate emitted from the patients who underwent bone scintigraphy. MATERIAL AND METHODS: A mean of 20.87±2.54 mCi Tc-MDP was injected into patients. A GM counter...
AIM: This study was aimed to re-determine the radiation dose rate emitted from the patients who underwent bone scintigraphy. MATERIAL AND METHODS: A mean of 20.87±2.54 mCi Tc-MDP was injected into patients. A GM counter was used to measure dose rates in 3 different periods, at intervals of 25, 50, 100, 150, and 200 cm from the patient's anterior for head, thorax, abdomen, and pelvis levels. Measurements were used to determine patient-induced environmental doses and radiation doses to personnel/patient relatives. RESULTS AND DISCUSSION: There were strong correlations between mean dose rate (mRhmCi) and time at all regions and distances. The received dose for staff was calculated between a range of 0.01-0.02 mSv/mCi per patient. The total dose to be received by the companion was estimated to be between 0.019-0.039 and 0.011-0.022 mSv for public and personal vehicle transportation, respectively. The radiation dose exposed by nurses (4th, 6th, and 8th hours after injection) was found to be 0.012-0.064, 0.006-0.038, and 0.002-0.018 mSv/- patient, respectively. CONCLUSION: The fact that the doses of personnel and patient relatives in the study were below the legal limits shows that the study was carried out within a safe range. However, in terms of radiation protection, it is necessary to limit the time spent with the patient as much as possible and increase the distance. Since the dangers of low radiation dosages are unknown, there is a need to inform the patient's relatives and staff about the potential risks.
Theoretical Evaluation of Oleocanthal Reactive Centers.
Asgarshamsi MH, Dehkordi MM, Nazifi SMR … +1 more , Zborowski KK
Curr Drug Metab · 2023 · PMID 38099536 · Publisher ↗
BACKGROUND: Decarboxymethyl ligstroside aglycone (Oleocanthal) is an essential component of olive oil. It is therefore interesting to study its metabolism in the human body. In order to find the best possible starting po...
BACKGROUND: Decarboxymethyl ligstroside aglycone (Oleocanthal) is an essential component of olive oil. It is therefore interesting to study its metabolism in the human body. In order to find the best possible starting point for this metabolism, a theoretical study was carried out using DFT calculations and docking studies. METHODS: The DFT, B3LYP/6-311++G** and the PCM solvation model calculations were used to study the initial process of Oleocanthal metabolism by the CYP1A2 enzyme. Structures of radicals formed by homolytic dissociation of hydrogen atoms from the Oleocanthal structure were obtained and their properties were studied. Several parameters such as HOMO and LUMO energy gaps, Bond Dissociation Energy (BDE), hardness, and spin density of possible Oleocanthal radicals were taken into account. Docking of Oleocanthal into an enzyme binding pocket was also performed to locate the most probably metabolic site. Detailed analysis of the theoretical results allows the determination of the most likely reaction sites in Oleocanthal. The mode of binding of Oleocanthal to the CYP1A2 enzyme was also predicted. RESULTS: The results of the molecular docking studies are in agreement with the calculated quantum parameters. The theoretical predictions were compared with experimental data available in the scientific literature. A high correlation between theoretical calculations and experimental data was observed. The most likely site of Oleocanthal metabolism was identified. CONCLUSION: The results of our research support the usefulness of theoretical calculations in predicting metabolic pathways.
Pharmacokinetics, Mass Balance, Tissue Distribution and Metabolism of [C]101BHG-D01, a Novel Muscarinic Receptor Antagonist, in Rats.
Gao H, Yang C, Hu W … +5 more , Ding J, Diao X, Zheng Y, Shu C, Ding L
Curr Drug Metab · 2023 · PMID 38073103 · Publisher ↗
BACKGROUND: 101BHG-D01, a novel long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD), is undergoing Phase Ib clinical trial in patients and has shown...
BACKGROUND: 101BHG-D01, a novel long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD), is undergoing Phase Ib clinical trial in patients and has shown its potential efficacy. Its preparation method and medical use thereof have been patented in the United States (Patent No.US9751875B2). OBJECTIVE: In this study, the pharmacokinetics, mass balance, tissue distribution and metabolism of radioactive 101BHG-D01 were investigated in rats after an intravenous dose of 1 mg/kg [C]101BHG-D01 (100 μCi/kg). METHODS: Radioactivity in rat plasma, urine, feces, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling and identification were conducted by UHPLC-β-RAM and UHPLC-Q-Exactive Plus MS. RESULTS: The total radioactivity of the study drug in rat plasma rapidly declined with an average terminal elimination half-life of 0.35 h. The radioactivity in most tissues reached the maximum concentration at 0.25 h post-- dosing. The radioactivity mainly concentrated in the kidney and pancreas. The drug-related substances tended to be distributed into the blood cells in the circulation. At 168 h post dosing, the mean recovery of the total radioactivity in urine and feces was 78.82%. Fecal excretion was the major excretion route, accounting for approximately 61% of the radioactive dose. The study drug was metabolized extensively, and a total of 17 metabolites were identified in rat plasma, urine, and feces. The major metabolic pathways involved oxidation, oxidation and dehydrogenation, and O-dephenylation. CONCLUSION: In conclusion, the study results are useful for better understanding the pharmacokinetic profiles of 101BHG-D01 and provide a robust foundation for subsequent clinical studies.
In Silico Tools to Thaw the Complexity of the Data: Revolutionizing Drug Research in Drug Metabolism, Pharmacokinetics and Toxicity Prediction.
Kommalapati HS, Pilli P, Golla VM … +2 more , Bhatt N, Samanthula G
Curr Drug Metab · 2023 · PMID 38058088 · Publisher ↗
In silico tool is the flourishing pathway for Researchers and budding chemists to strain the analytical data in a snapshot. Traditionally, drug research has heavily relied on labor-intensive experiments, often limited by...
In silico tool is the flourishing pathway for Researchers and budding chemists to strain the analytical data in a snapshot. Traditionally, drug research has heavily relied on labor-intensive experiments, often limited by time, cost, and ethical constraints. In silico tools have paved the way for more efficient and cost-effective drug development processes. By employing advanced computational algorithms, these tools can screen large libraries of compounds, identifying potential toxicities and prioritizing safer drug candidates for further investigation. Integrating in silico tools into the drug research pipeline has significantly accelerated the drug discovery process, facilitating early-stage decision-making and reducing the reliance on resource-intensive experimentation. Moreover, these tools can potentially minimize the need for animal testing, promoting the principles of the 3Rs (reduction, refinement, and replacement) in animal research. This paper highlights the immense potential of in silico tools in revolutionizing drug research. By leveraging computational models to predict drug metabolism, pharmacokinetics, and toxicity. Researchers can make informed decisions and prioritize the most promising drug candidates for further investigation. The synchronicity of In silico tools in this article on trending topics is insightful and will play an increasingly integral role in expediting drug development.
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