Current drug metabolism最新文献

Background: Piperaquine (PQ) and its pharmacologically active metabolite PQ N-oxide (PM1) can be metabolically interconverted via hepatic cytochrome P450 and FMO enzymes.

Objectives: The reductive metabolism of PM1 and its further N-oxidation metabolite (PM2) by intestinal microflora was evaluated, and its role in PQ elimination was also investigated.

Methods: The hepatic and microbial reduction metabolism of PM1 and PM2 was studied in vitro. The reaction phenotyping experiments were performed using correlation analysis, selective chemical inhibition, and human recombinant CYP/FMO enzymes. The role of microbial reduction metabolism in PQ elimination was evaluated in mice pretreated with antibiotics. The effect of the reduction metabolism on PQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model.

Results: Both hepatic P450/FMOs enzymes and microbial nitroreductases (NTRs) contributed to the reduction metabolism of two PQ N-oxide metabolites. In vitro physiologic and enzyme kinetic studies of both N-oxides showed a comparable intrinsic clearance by the liver and intestinal microflora. Pretreatment with antibiotics did not lead to a significant (P > 0.05) change in PQ pharmacokinetics in mice after an oral dose. The predicted pharmacokinetic profiles of PQ in humans did not show an effect of metabolic recycling.

Conclusion: Microbial NTRs and hepatic P450/FMO enzymes contributed to the reduction metabolism of PQ Noxide metabolites. The reduction metabolism by intestinal microflora did not affect PQ clearance, and the medical warning in patients with NTRs-related disease (e.g., hyperlipidemia) will not be clinically meaningful.

Background: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,β- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites.

Objective: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST.

Methods: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer.

Results: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor.

Conclusion: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).

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 ex vivo everted gut sac model was implemented to predict the potential of proton pump inhibitors i.e., 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 ex vivo 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 ex vivo 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.

Monkeypox is a zoonotic viral disease and remains endemic in tropical regions of Central and West Africa. Since May of 2022, cases of monkeypox have soared and spread worldwide. Confirmed cases have shown no travel history to the endemic regions as seen in the past. The World Health Organization declared monkeypox a global public health emergency in July 2022, and the United States government followed suit one month later. The current outbreak, in contrast to traditional epidemics, has high coinfection rates, particularly with HIV (human immunodeficiency virus), and to a lesser extent with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the pathogen of COVID-19. No drugs have been approved specifically for monkeypox. However, there are therapeutic agents authorized to treat monkeypox under the Investigational New Drug protocol, including brincidofovir, cidofovir, and tecovirimat. In contrast to limited options for monkeypox treatment, there are available drugs specifically for HIV or SARS-CoV-2 infection. Interestingly, these HIV and COVID-19 medicines share metabolism pathways with those authorized to treat monkeypox, particularly of hydrolysis, phosphorylation, and active membrane transport. This review discusses how these pathways shared by these medicines should be considered to gain therapeutic synergy and maximize safety for treating monkeypox coinfections.

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.

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.

Aim: The study aimed to identify the key pharmacogenetic variable influencing the therapeutic outcomes of warfarin using machine learning algorithms and bioinformatics tools.

Background: Warfarin, a commonly used anticoagulant drug, is influenced by cytochrome P450 (CYP) enzymes, particularly CYP2C9. MLAs have been identified to have great potential in personalized therapy.

Objective: The purpose of the study was to evaluate MLAs in predicting the critical outcomes of warfarin therapy and validate the key predictor genotyping variable using bioinformatics tools.

Methods: An observational study was conducted on adults receiving warfarin. Allele discrimination method was used for estimating the single nucleotide polymorphisms (SNPs) in CYP2C9, VKORC1, and CYP4F2. MLAs were used for identifying the significant genetic and clinical variables in predicting the poor anticoagulation status (ACS) and stable warfarin dose. Advanced computational methods (SNPs' deleteriousness and impact on protein destabilization, molecular dockings, and 200 ns molecular dynamics simulations) were employed for examining the influence of CYP2C9 SNPs on structure and function.

Results: Machine learning algorithms revealed CYP2C9 to be the most important predictor for both outcomes compared to the classical methods. Computational validation confirmed the altered structural activity, stability, and impaired functions of protein products of CYP2C9 SNPs. Molecular docking and dynamics simulations revealed significant conformational changes with mutations R144C and I359L in CYP2C9.

Conclusion: We evaluated various MLAs in predicting the critical outcome measures associated with warfarin and observed CYP2C9 as the most critical predictor variable. The results of our study provide insight into the molecular basis of warfarin and the CYP2C9 gene. A prospective study validating the MLAs is urgently needed.

Meropenem, as a carbapenem antibiotic, is commonly used in critically ill pediatric patients with severe infection because of its broad antimicrobial spectrum, high penetration into tissues, and favorable safety profile. Due to pathophysiological changes in critically ill children, the available evidence has demonstrated that the standard dosage regimens of meropenem could not meet an appropriate pharmacodynamic (PD) target attainment in severely infected children. Therefore, we reviewed the pharmacokinetic (PK) profile of meropenem in critically ill children, therapeutic drug monitoring (TDM), and dose optimization based on PK/PD. Meropenem kills bacteria in a timedependent manner and its efficacy is positively correlated with the percentage of the time of dosing interval during which the free serum concentration of meropenem remains above the minimum inhibitory concentration (MIC) of the pathogen (%fT>MIC), which is related to PK/PD targets. For critically ill children, TDM-based dosage optimization and setting even higher PK/PD targets seem necessary to be considered. The currently available studies have revealed that increasing the dose and the application of the extended or continuous infusion of meropenem were able to achieve better PK/PD targets. According to limited clinical data on efficacy and safety, these treatment measures cannot yet be adopted as routine regimens only when serious infections caused by drug-resistant bacteria or strains with high values of MIC are suspected. Further high-quality randomized controlled trials (RCTs) or observational studies with sufficient sample sizes are required to confirm the efficacy and safety of these modes of administration.

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.

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.