Current Drug Metabolism - Online First

Cancer poses a tough global health challenge, prompting the exploration of innovative prevention and treatment strategies. Polyphenols, bioactive compounds abundant in various plant-based foods, have gained significant attention for their potential anticancer properties. Legumes, characterized by their excellent nutritional profile, offer a promising source of polyphenols such as ferulic acid, caffeic acid, genistein, and kaempferol, which exhibit notable antioxidative and anti-inflammatory effects.

This review systematically analyzed peer-reviewed literature on the polyphenolic content of various legumes. No original research or experimental work was carried out as part of this study. Databases such as PubMed, Google Scholar, Scopus, SpringerLink, and ScienceDirect were searched for studies focusing on the identification and pharmacokinetic profiles of legume-derived polyphenols. Emphasis was placed on examining the mechanisms of action, including modulation of cell signalling pathways, induction of apoptosis, inhibition of angiogenesis, and influence on detoxification enzymes. The review also assessed the ADME (absorption, distribution, metabolism, and excretion) properties of key polyphenols to evaluate their bioavailability and therapeutic efficacy.

The analysis revealed that legumes are significant sources of polyphenols with demonstrated anticancer activity. Compounds like genistein and kaempferol modulate key signalling pathways such as PI3K/Akt, MAPK, and NF-kB, which are involved in cell proliferation, survival, and inflammation. Additionally, these polyphenols can promote apoptosis and inhibit angiogenesis, thereby impeding tumor growth and metastasis.

The findings underscore the potential of legume-derived polyphenols in cancer prevention and management. By addressing the ADME of Polyphenols, this study aims to deepen our understanding of their pharmacological potential, providing a foundation for developing dietary strategies and functional foods to effectively prevent and manage cancer. Addressing the limitations in bioavailability through novel delivery systems and dietary formulations could enhance their effectiveness.

Combining polyphenol-rich legume diets with conventional cancer therapies may offer a synergistic therapeutic effect and promote better health outcomes. However, it is essential to first establish through rigorous scientific research that polyphenols do not produce any unwanted adverse effects when used alongside standard medications. Further research focusing on improving bioavailability and validating in vivo efficacy will be crucial for translating these findings into practical cancer prevention treatment approaches.

Numerous chronic illnesses, including diabetes, cancer, cardiovascular disease, and neurological disorders, are mostly caused by oxidative stress, which is defined as an imbalance between the body's antioxidant defenses and the generation of reactive oxygen species (ROS). The success of traditional treatments for oxidative stress has been limited because antioxidant medications are not well-absorbed, are quickly broken down, and do not target specific areas of the body.

Drug delivery methods based on nanotechnology offer a viable solution to these issues by providing therapeutic molecules with improved release characteristics, enhanced bioavailability, and targeted capabilities. Recent developments in nanotechnology have enabled the creation of multipurpose carriers that can simultaneously transmit genes for endogenous antioxidant enzymes and antioxidants.

This integration promotes a long-term healing response and addresses the immediate oxidative stress. Likewise, functionalizing nanocarriers with particular ligands improves localization to oxidative stress locations, including inflammatory tissues or tumor microenvironments, boosting therapeutic efficacy. The potential of nanotherapeutics in reducing oxidative stress-driven diseases is examined in this article.

Nanotechnology-based drug delivery approaches offer a novel avenue for the treatment of several oxidative stress-induced diseases. These delivery systems are highly target-specific and have a longer duration of action. Still, more research is needed to address issues, such as safety margins, large-scale production, and approval of medicine use.

We address several nanocarrier platforms, such as liposomes, polymeric nanoparticles, dendrimers, and metallic nanoparticles that have proven more effective in delivering therapeutic drugs and antioxidants to specific sites of oxidative damage. Furthermore, nanotherapeutics may enhance their therapeutic potential by protecting these bioactive substances from premature degradation and clearance.

Remimazolam is a short-acting sedative/anesthetic. For safe breastfeeding, information on the extent and possible risks of remimazolam being passed over to the infant through mother´s milk is needed. The objective of this work was to study the transfer of remimazolam from maternal to infant circulation by mother´s milk in an animal model.

Three lactating British milk sheep received intravenous remimazolam (0.4 mg/kg bolus plus 4-hr-infusion at 1 or 2 mg/kg/hour). Drug profiles were recorded in plasma and milk. Six suckling lambs were administered remimazolam by intravenous and oral gavage administration for a comparison of plasma concentration profiles of remimazolam and its primary metabolite, CNS7054.

Treatment of lactating sheep induced dose-dependent sedation and loss of consciousness. At the end of infusion, the concentration of remimazolam was higher in milk than in plasma. The subsequent elimination of remimazolam from milk was rapid, although somewhat slower than from plasma.

In lambs, intravenous, but not oral, remimazolam (2 mg) caused different grades of sedation/anesthesia (fully reversible within 8 to 15 min). Mean plasma Cmax was 278.3 ng/mL after intravenous and 1.3 ng/mL after oral administration. Oral gavage resulted in a sizable plasma concentration of CNS7054 (Cmax around 100 ng/mL), indicating efficient intestinal absorption of the parent drug, followed by extensive first-pass metabolic elimination, leading to negligible bioavailability of oral remimazolam.

In mother´s milk, remimazolam reaches higher concentrations than in plasma and is cleared by redistribution to the central compartment for final hepatic elimination. In lambs, oral remimazolam results in minimal plasma concentrations, suggesting that safety concerns regarding breast-fed infants would be minor and could be completely alleviated by a short nursing interruption.

Tetrandrine (TET) demonstrates therapeutic potential for hypoxic pulmonary hypertension (HPH); however, its precise pharmacological mechanisms remain unclear. In this study, we aimed to investigate the effects of TET on pulmonary vascular remodeling (PVR) in HPH and elucidate the molecular pathways through which TET ameliorates HPH.

We established a rat model of HPH and evaluated the therapeutic effects of TET by measuring hemodynamic parameters, assessing right ventricular hypertrophy, and analyzing pathological changes in lung tissue. To explore the molecular mechanisms, we carried out comprehensive analyses using transcriptome and untargeted metabolomics technologies to examine the impact of TET on gene expression and metabolite profiles in the lung tissue of HPH rats. Using data from these multi-omics analyses, we performed biochemical assays, immunofluorescence staining, and Western blotting to validate the effects of TET on vasoconstriction and angiogenesis-related factors. These experiments provide further evidence of the anti-HPH and anti-PVR properties of TET.

TET intervention significantly reduced hemodynamic parameters, including mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP), as well as right ventricular hypertrophy indices, such as the right ventricular hypertrophy index (RVHI) and right ventricle-to-body weight ratio (RV/BW), in HPH rats. TET inhibited smooth muscle cell proliferation and alleviated pathological changes in lung tissue. Transcriptome and metabolome analyses revealed that genes affected by TET intervention were enriched in pathways related to PVR, including those involved in endothelial and smooth muscle cell proliferation, angiogenesis, and blood vessel morphogenesis. Metabolites were predominantly associated with the arachidonic acid (AA) metabolism pathway. Differentially expressed genes included Cyp4a1, Cyp4a3, Cyp2u1, and Alox15. Validation experiments demonstrated that TET upregulated ALOX15 protein expression and downregulated CYP4A and CYP2U1 proteins, modulating levels of arachidonate metabolites 20-HETE and 15(S)-HPETE. We further observed that TET reduced the levels of PVR markers, including endothelin-1 (ET-1) secretion, while increasing nitric oxide (NO) release. TEt also decreased the expression of cell proliferation markers PCNA and Ki-67 and elevated the endothelial marker CD31. Moreover, TET intervention suppressed angiogenic and vasoconstrictive factors, such as MMP-9, TGF-β1, IGF2, and PDGF-B, while enhancing levels of FGF9 and NOS3.

Our findings highlight the protective effects of TET on lung tissue in HPH mediated through the regulation of 15(S)-HPETE and 20-HETE within the arachidonic acid metabolism pathway. This regulation inhibits pulmonary angiogenesis and vasoconstriction, ultimately improving PVR in HPH.

This review aims to explore the therapeutic potential and safety of herbal bioactive compounds in the treatment of various liver disorders. As the liver plays a critical role in digestion, detoxification, energy storage, and protein synthesis, any impairment in its function can lead to significant health complications. The study aims to identify effective herbal agents that may support liver health.

A comprehensive literature search was conducted using scientific databases and platforms including Web of Science, Scopus, PubMed, HINARI, ScienceDirect, and Google Scholar. The review includes studies that investigate the hepatoprotective potential of herbal bioactives, while research related to hepatic cancers was excluded to maintain a focus on non-malignant liver disorders.

The review identifies several medicinal plants and their active constituents that exhibit hepatoprotective properties. These bioactives function through various pharmacological mechanisms at the molecular level. Common liver conditions addressed include fatty liver, hepatitis, fibrosis, steatosis, and cirrhosis. The reviewed compounds demonstrate antioxidant, anti-inflammatory, and antifibrotic activities, supporting their role in liver disease management.

The findings support growing evidence that herbal bioactives can modulate key molecular pathways involved in liver disorders. These results align with existing studies highlighting the benefits of plant-based treatments. However, the limitations include a lack of clinical trial data, poor bioavailability of some compounds, and the need for standardized formulations. Further research is necessary to validate these results in human populations.

Herbal bioactives such as flavonoids, polyphenols, alkaloids, glycosides, saponins, vitamins, and essential oils show promising hepatoprotective effects. This review emphasizes the importance of understanding their precise molecular mechanisms and ADME (absorption, distribution, metabolism, and excretion) profiles. These insights are crucial for developing safe, effective, and standardized herbal therapies for liver disease management.

Carboplatin (CP) is a widely used chemotherapeutic agent with poor oral bioavailability and potential systemic toxicity when administered intravenously. There is a growing interest in developing sustained-release oral formulations to improve therapeutic efficacy and patient compliance.

The present study aimed to develop and evaluate an oral, enteric-coated, PEGylated multi-walled carbon nanotube (MWCNT) formulation (F2) of carboplatin and assess its pharmacokinetic and histopathological profile in comparison with the marketed intravenous product, Kemocarb^®.

A sensitive and robust HPLC method was developed for the quantification of CP in rabbit plasma. Stability studies were performed at 4 °C for 4 hours and -80°C for 4 weeks. Histopathological evaluation was conducted on major organs of mice to assess toxicity. CP and caffeine were extracted with minimal matrix interference. Pharmacokinetic studies were performed following oral administration of the F2 formulation and compared with Kemocarb^®.

The developed HPLC method demonstrated good sensitivity, accuracy, and robustness. CP was stable under both short-term and long-term storage conditions. Histological analysis revealed no significant pathological damage in mice organs. The F2 formulation exhibited sustained drug release for up to 24 hours. The Tmax, Cmax, and MRT of CP for F2 were different compared to Kemocarb^®, with a relative bioavailability of 1.182 ± 0.24. The Cmax and MRT of F2 were 12.327 ± 0.03* and 3.5805 ± 0.26 h, respectively.

The developed F2 formulation of carboplatin demonstrates sustained release and improved relative bioavailability following oral administration. It may offer a promising alternative to commercial intravenous CP injections (Kemocarb^®), potentially supporting metronomic chemotherapy strategies with improved patient compliance and reduced systemic toxicity.