Current drug metabolism最新文献

Background: Cycloastragenol (CAG) is a sapogenin derived from the main bioactive constituents of Astragali Radix (AR). However, the current research on CAG metabolism in vivo and in vitro is still inadequate, and the metabolite cluster is incomplete due to incomplete analysis strategy.

Objective: The objective of this study was to screen and identify the metabolic behavior of CAG in vivo and in vitro.

Methods: A simple and rapid analysis strategy based on UHPLC-Q-Exactive Orbitrap mass spectrometry combined with data-mining processing technology was developed and used to screen and identify CAG metabolites in rat body fluids and tissues after oral administration.

Results: As a result, a total of 82 metabolites were fully or partially characterized based on their accurate mass, characteristic fragment ions, retention times, corresponding Clog P values, and so on. Among the metabolites, 61 were not been reported in previous reports. These metabolites (6 metabolites in vitro and 91 in vivo) were generated through reactions of hydroxylation, glucuronidation, sulfation, hydrogenation, hydroxylation, demethylation, deisopropylation, dehydroxylation, ring cleavage, and carboxyl substitution and their composite reactions, and the hydroxylation might be the main metabolic reaction of CAG. In addition, the characteristic fragmentation pathways of CAG were summarized for the subsequent metabolite identification.

Conclusion: The current study not only clarifies the metabolite cluster-based and metabolic regularity of CAG in vivo and in vitro, but also provides ideas for metabolism of other saponin compounds.

Traditional Chinese medicine Heshouwu, named Polygoni Multiflori Radix in Pharmacopoeia of the People's Republic of China (PPRC, 2020), is derived from the root tuber of Polygonum multiflorum Thunb., Heshouwu or processed Heshouwu is well known for its function in reducing lipids and nourishing the liver. However, increasing cases of Heshouwu-induced hepatotoxicity were reported in recent years. Researchers have begun to study the paradoxical effects of Heshouwu on the liver. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an abundant functional component of Heshouwu, shows various biological activities, among which its effect on the liver is worthy of attention. This paper reviews the current studies of TSG on hepatoprotection and hepatotoxicity, and summarizes the doses, experimental models, effects, and mechanisms of action involved in TSG's hepatoprotection and hepatotoxicity, aiming to provide insight for future study of TSG and understanding the effects of Heshouwu on the liver. Emerging evidence suggests that TSG ameliorates both pathological liver injury and chemical-induced liver injury by modulating lipid metabolism, inhibiting the inflammatory response and oxidative stress in the liver. However, with the reports of clinical cases of Heshouwu induced liver injury, it has been found that long-term exposure to a high dose of TSG cause hepatocyte or hepatic tissue damage. Moreover, TSG may cause hepatotoxicity by affecting the transport and metabolism of other possible hepatoxic compounds in Heshouwu. Studies indicate that trans-TSG can be isomerized into cis-TSG under illumination, and cis-TSG had a less detrimental dose to liver function than trans- TSG in LPS-treated rats. In brief, TSG has protective effects on the liver, but liver injury usually occurs under highdose TSG or is idiosyncratic TSG-induced liver injury.

Nucleic acid strands can be synthesized into various nucleic acid-based nanomaterials (NANs) through strict base pairing. The self-assembled NANs are programmable, intelligent, biocompatible, non-immunogenic, and non-cytotoxic. With the rapid development of nanotechnology, the application of NANs in the biomedical fields, such as drug delivery and biological sensing, has attracted wide attention. However, the stability of NANs is often affected by the cation concentrations, enzymatic degradation, and organic solvents. This susceptibility to degradation is one of the most important factors that have restricted the application of NANs. NANs can be denatured or degraded under conditions of low cation concentrations, enzymatic presence, and organic solvents. To deal with this issue, a lot of methods have been attempted to improve the stability of NANs, including artificial nucleic acids, modification with specific groups, encapsulation with protective structures, etc. In this review, we summarized the relevant methods to have a deeper understanding of the stability of NANs.

Background: Erzhi formula (EZF) is a traditional Chinese medicine prescription, which has been widely used in the treatment of osteoporosis and premature ovarian failure.

Objective: To enhance curative effects, the other two herbal medicines, including Spatholobi Caulis (SC) and Achyranthes bidentata Blume (ABB), were added into the original EZF formula to obtain two new Jiawei-EZF (JW-EZF) preparations. To clarify the effect of the compatibility of herbs for original formulas, the chemical constituents and bioactive compounds in vivo were detected.

Methods: An efficient and sensitive targeted and untargeted UHPLC/ESI-Q-Orbitrap MS method, together with mass defect filter and precursor ion list, was established firstly for the profiling of different EZF formulas. Furthermore, eleven absorbed compounds (apigenin, luteoloside, luteolin, oleuropein, wedelolactone, acteoside, specnuezhenide, 11-methyloleoside, ecliptasaponin A, formononetin, and β-ecdysone) were simultaneously quantified in rat plasma.

Results: A total of 124, 162, and 177 compounds were identified or tentatively identified in EZF, JW-3-EZF (EZF+SC) and JW-4-EZF (EZF+SC+ABB), respectively. 110 compounds were found to be common constituents in the three formulas. Moreover, 66 prototypes were unambiguously identified in the rats' plasma after oral administration of the three formulas using the same strategy. 11 out of the 66 absorbed components were simultaneously quantitated in the pharmacokinetic (PK) study. Compared to the original EZF, the plasma AUC_(0-24h) and AUC_(0-∞) of apigenin, 11-methyloleoside, luteolin, luteoloside, wedelolactone, and acteoside were found to be significantly increased after oral administration of JW-3-EZF, and plasma AUC_(0-24h) and AUC_(0-∞) of apigenin, wedelolactone, and acteoside, were also found to be significantly increased after JW-4-EZF administration.

Conclusion: The combined qualitative and quantitative methods were used to provide a potential approach to the characterization and quality control of the Traditional Chinese Medicine (TCM) and its preparations.

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.

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.