Current Drug Metabolism - Volume 23, Issue 11, 2022

Background: Global cancer statistics defines the severity of disease even after significant research worldwide. Problem: Failure of the currently available treatment approaches, including surgery, radiation therapy and traditional chemotherapy. Aim: The aim of this review is to discuss the role of phytochemical based nano-formulations for treatment of cancer. Discussion: In the past few decades, phytochemicals have gained popularity for acting as a potential anticancer treatment with low systemic toxicity, especially in terms of cell cycle control and cancer cell killing. Natural resources, with their immense structural variety, serve as a vital source of fresh, therapeutically useful new chemical entities for the treatment of cancer. Vinca alkaloids (VCR), vinblastine, vindesine, vinorelbine, taxanes (PTX), podophyllotoxin and its derivatives (etoposide (ETP), teniposide, camptothecin (CPT) and its derivatives (topotecan, irinotecan), anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin, as natural products or their derivatives account for half of all anticancer drugs approved worldwide, and they have been developed utilising the knowledge learned from the natural small molecules or macromolecules. Trabectedin, an epothilone derivative, ixabepilone, and temsirolimus, three new anticancer medications launched in 2007, were derived from microbial origins. Current therapy regimens require selective drug targeting to enhance efficacy against cancer cells while normal cells remain unharmed. Modified medications and systems for drug delivery based on nanotechnology are in the process of being explored and launched in the industry for enhanced therapy and management of cancer, along with promising outcomes. Many obstacles related to cancer cell drug delivery can be overcome by using nano-particulate drug carriers, including enhancing the stability and solubility of the drug, prolonging half-lives of the drug in the blood, decreasing side effects to undesired organs, and increasing medication concentration at the desired site. The scientific initiatives and studies concerning the use of nanotechnology for some selective compounds derived from plants are discussed in this review article. Conclusion: The present review highlights the phytochemical-based nanoformulations and their strategies in the development of novel systems of drug delivery such as nano-liposomes, functionalized nanoparticles (NPs), and polymer nano-conjugates, SNEDDS (Self nano emulsifying drug delivery system) as this review paper depicts, as well as their rewards over conventional systems of drug delivery, as evidenced by improved biological activity depicted in their in vitro and in vivo anticancer assays.

The lung is exposed to various pollutants and is the primary site for the onset of various diseases, including infections, allergies, and cancers. One possible treatment approach for such pulmonary diseases involves direct administration of therapeutics to the lung so as to maintain the topical concentration of the drug. Particles with nanoscale diameters tend to reach the pulmonary region. Nanoparticles (NPs) have garnered significant interest for applications in biomedical and pharmaceutical industries because of their unique physicochemical properties and biological activities. In this article, we describe the biological and pharmacological activities of NPs as well as summarize their potential in the formulation of drugs employed to treat pulmonary diseases. Recent advances in the use of NPs in inhalation chemotherapy for the treatment of lung diseases have also been highlighted.

Background: Curcumin is a polyphenolic compound derived from rhizomes of Curcuma longa, the golden spice. Curcumin has drawn much attention in recent years of biomedical research owing to its wide variety of biologic and pharmacologic actions. It exerts antiproliferative, antifibrogenic, anti-inflammatory, and antioxidative effects, among various imperative pharmacologic actions. In spite of its well-documented efficacies against numerous disease conditions, the limited systemic bioavailability of curcumin is a continuing concern. Perhaps, the poor bioavailability of curcumin may have curtailed its significant development from kitchen to clinic as a potential therapeutic agent. Subsequently, there have been a considerable number of studies over decades researching the scientific basis of curcumin’s reduced bioavailability and eventually improvement of its bioavailability employing a variety of therapeutic approaches, for instance, in combination with piperine, the bio-active constituent of black pepper. Piperine has remarkable potential to modulate the functional activity of metabolic enzymes and drug transporters, and thus there has been a great interest in the therapeutic application of this widely used spice as alternative medicine and bioavailability enhancer. Growing body of evidence supports the synergistic potential of curcumin against numerous pathologic conditions when administered with piperine. Conclusion: In light of current challenges, the major concern pertaining to poor systemic bioavailability of curcumin, its improvement, especially in combination with piperine, and the necessity of additional research in this setting are together described in this review. Besides, the recent advances in the potential therapeutic rationale and efficacy of curcumin-piperine combination, a promising duo, against various pathologic conditions are delineated.

Background: Andrographolide is a promising natural substance with numerous pharmacotherapy uses. 14-deoxy-12(R)-sulfo andrographolide (SAP) is the main metabolite of andrographolide in the intestine. Objective: To investigate the pharmacokinetic properties of SAP, a precise and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of SAP concentration in rat plasma was developed and validated in this study. Methods: Chromatographic separation was achieved on an Acpuity UPLC BEH C18 column with gradient elution that consisted of methanol and water at a flow rate of 0.3 mL/min. MS/MS detection was carried out by the multiple reaction monitoring (MRM) mode with negative electrospray ionization (ESI-) source, with the transitions of m/z 413.2→m/z 287.2 for SAP and m/z 269→m/z 133 for genistein [which was used as an internal standard (IS)]. Results: The calibration curve of SAP was linear over the concentration range of 5-120 ng/mL. The selectivity, precision, accuracy, extraction recovery, matrix effect, and stability of the method were within acceptable ranges. This SAP quantification method was then successfully applied to a pharmacokinetic study of SAP. The area under the curve (AUC) of SAP in rats treated with SAP at 60 mg/kg by intravenous administration was 7498.53 ± 2405.02 mg/L·min. The AUC of SAP in rats treated with SAP at 60 mg/kg by oral administration was 97.74 ± 39.56 mg/L·min. Thus, the absolute oral bioavailability of SAP was determined to be 1.40%.

Background: Cabozantinib is a multiple receptor tyrosine kinases inhibitor (TKI) approved to treat progressive, metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma. Drugdrug interactions (DDIs) for cabozantinib have been identified involving the role of cytochromes P450. Although the previous study reported that cabozantinib showed a slight inhibition of UDP-glucuronosyltransferase (UGT) 1A1 at the highest concentration tested, there are no reports on the potential for UGTs-mediated-DDIs. Hence, the current study aims to address this knowledge gap. Objective: This study aimed to investigate the inhibitory effect of cabozantinib on human UGTs and to quantitatively evaluate the DDI potential via UGT inhibition. Methods: The inhibitory effects of cabozantinib on UGTs were determined by measuring the formation rates for 4- methylumbelliferone (4-MU) glucuronide and trifluoperazine N-glucuronide using recombinant human UGT isoforms in the absence or presence of cabozantinib. Inhibition kinetic studies were conducted to determine the type of inhibition of cabozantinib on UGTs and the corresponding inhibition constant (Ki) value. In vitro-in vivo extrapolation (IVIVE) was further employed to predict the potential risk of DDI in vivo. Results: Cabozantinib displayed potent inhibition of UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15. Cabozantinib exhibited noncompetitive inhibition towards UGT1A1 and 1A3 and inhibition towards UGT1A7 and 1A9. The Ki,u values (mean ± standard deviation) were calculated to be 2.15±0.11 μM, 0.83±0.05 μM, 0.75±0.04 μM and 0.18 ± 0.10 μM for UGT1A1, 1A3, 1A7 and 1A9, respectively. Co-administration of cabozantinib at the clinically approved dose of 60 mg/day or 140 mg/day may result in approximately a 26% to 60% increase in the systemic exposure of drugs predominantly cleared by UGT1A9, implying a high risk of DDIs. Conclusion: Cabozantinib has the potential to cause DDIs via the inhibition of UGT1A9; therefore, additional attention should be paid to the safety of the combined use of cabozantinib and drugs metabolized by UGT1A9.

Background and Objective: Securing the airway in the surgery of maxillofacial disorders and traumas is fundamental during the operation. The present study aims to investigate the beneficial sedative effects of dexmedetomidine (DEX) in patients who underwent maxillofacial surgery with regional anesthesia compared to general anesthesia. Methods: Fifty patients, aged 20-45 years old were randomly divided into two groups of regional anesthesia (RA) and general anesthesia (GA) (each n=25). The group RA received regional block with sedation (DEX: 1 μg/kg infused over 10 min followed by the maintenance dose of 0.5 μg/kg/h) and the group GA underwent general anesthesia (DEX: 0.1 μg/kg/min over 10 min followed by 0.4–0.7 μg/kg/h). Postoperative pain scores, anesthesia outcomes, hemodynamic parameters, the time of the post-anesthesia care unit (PACU) discharge and intra and postoperative complications were comparatively assessed in both groups. Results: The baseline characteristics of the patients (age, gender, BMI, and ASA physical status) showed no differences between the two groups (P>0.05). Although the duration of surgery and recovery time showed no differences between the groups, the duration of anesthesia and extubation time was remarkably lower in the RA group than in the GA group (P<0.01). Administration of nerve blocks demonstrated less pain and longer sleep time in the postoperative phase as compared to the GA group. Heart rate and mean arterial blood pressure were significantly less in the RA group at the end of the loading dose of DEX and incision time (P<0.05). SpO2, respiration rate and Ramsay sedation scale did not exhibit any significant differences between the two groups at all-time points (P>0.05). No significant differences were observed with regard to the adverse events between the two groups (P>0.05). Conclusions: Although our findings revealed that both methods are suitable and safe methods for maxillofacial surgery, the outcomes of anesthesia with regional block and sedation include less pain in the postoperative phase, shorter extubation time and earlier discharge from the PACU demonstrated that this method is more reliable for maxillofacial surgery. Further controlled studies are needed to compare the effectiveness and safety profiles of two RA and GA techniques and also to compare DEX with other anesthetic agents to achieve optimum outcomes in maxillofacial surgeries.

Background: Butaselen is an ebselen analog that is under clinical trials for treating hepatic and pulmonary fibrosis. Our previous studies showed that butaselen is mainly present in human plasma in the form of M2, a free Se-methylated metabolite. Objective: This study aimed to investigate the metabolic mechanisms of butaselen. Methods and Results: Butaselen was incubated with human plasma. Butaselen immediately disappeared, and the butaselen-HSA (human serum albumin) adduct was detected by HPLC-HRMS, showing that butaselen covalently binds to HSA. The butaselen-HSA adduct was precipitated using acetonitrile and then incubated with PBS, Cys, and GSH for 1 hour. The product was M1, a reduced form of butaselen. The results indicated that HSA, Cys, and GSH can reduce the butaselen-HSA covalent bond. The binding site for butaselen could be the cysteine-34 residue of HSA through pronase and trypsin hydrolysis. Incubating butaselen with cysteine, butaselen-Cys, butaselen-2Cys, and M1 were generated, indicating the covalent binding and reduction of butaselen by cysteine. We incubated liver microsomes and cytosol with butaselen, 6.22 and 246 nM M2 were generated, respectively. The results demonstrated that cytosolic enzymes are mainly involved in M2 production. The amount of M2 in the liver cytosol decreased from 246 nM to 2.21 nM when 10 mM m-anisic acid (a specific TPMT enzyme inhibitor) was added, showing that TPMT is responsible for M2 formation. Conclusion: Butaselen was covalently bound to HSA, and the binding site was the cysteine-34 residue of HSA. The butaselen-HSA adduct was reduced by free thiol compounds to generate M1. M1 was further metabolized to M2 by cytosolic TPMT. This study provides a basis for studying the pharmacokinetics of selenium-containing drugs.