Current Drug Metabolism - Volume 21, Issue 14, 2020

Childhood obesity has assumed epidemic proportions and is currently one of the most widespread public health problems. Many are the factors involved in the pathogenesis of excess weight with interactions between genetic, environmental and biological factors and therefore, also the therapeutic approach must be multidisciplinary and multidimensional. In this review of the literature, we report the contiguity of childhood obesity with eating disorders and the importance of involving the family context in order to induce stable lifestyle changes, both in relation to dietary and nutritional habits, but also in increasing physical activity. Finally, among the therapeutic options, although for selected cases, pharmacotherapy and bariatric surgery can be used as treatment strategies.

Natural products, an infinite reserve of bioactive molecules, will continue to serve humans as an important source of therapeutic agents. Germacrone is a bioactive natural compound found in the traditional medicinal plants of family Zingiberaceae. This multifaceted chemical entity has become a point of focus during recent years due to its numerous pharmacological applications, e.g., anticancer, anti-inflammatory, antiviral, antioxidant, anti-adipogenic, anti-androgenic, antimicrobial, insecticidal, and neuroprotective. Germacrone is an effective inducer of cell cycle arrest and apoptosis in various cancers (breast, brain, liver, skin, prostate, gastric, and esophageal) via modulation of different cell signaling molecules and pathways involved in cancer proliferation. This is the first report highlighting the wide spectrum of pharmacological activities exhibited by germacrone. The reported data collected from various shreds of evidences recommend that this multifaceted compound could serve as a potential drug candidate in the near future.

Background: Aldol reductase (AR) is the polyol pathway's main enzyme that portrays a crucial part in developing ‘complications of diabetes’ involving cataract, retinopathy, nephropathy, and neuropathy. These diabetic abnormalities are triggered tremendously via aggregation of sorbitol formation (catalyzed by AR) in the polyol pathway. Consequently, it represents an admirable therapeutic target and vast research was done for the discovery of novel molecules as potential AR inhibitors for diabetic complications. Objective: This review article has been planned to discuss an outline of diabetic complications, AR and its role in diabetic complications, natural compounds reported as AR inhibitors, and benefits of natural/plant derived AR inhibitors for the management of diabetic abnormalities. Results: The goal of AR inhibition remedy is to stabilize the increased flux of blood glucose and sorbitol via the ‘polyol pathway’ in the affected tissues. A variety of synthetic inhibitors of AR have been established such as tolrestat and sorbinil, but both of these face limitations including low permeability and health problems. Pharmaceutical industries and other scientists were also undertaking work to develop newer, active, and ‘safe’ AR inhibitors from natural sources. Therefore, several naturally found molecules were documented to possess a potent inhibitory action on AR activity. Conclusion: Natural inhibitors of AR appeared as harmless pharmacological agents for controlling diabetic complications. The detailed literature throughout this article shows the significance of herbal extracts and phytochemicals as prospective useful AR inhibitors in treating diabetic complications.

Background: Cancer is a major problem that threatens human survival and has a high mortality rate. The traditional chemotherapy methods are mainly intravenous injection and oral administration, but have obvious toxic and side effects. Anti-tumor drugs for pulmonary administration can enhance drug targeting, increase local drug concentration, and reduce the damage to systemic organs, especially for the treatment of lung cancer. Methods: The articles on the pharmacokinetics of anti-tumor drugs targeting pulmonary administration were retrieved from the Pub Med database. This article mainly took lung cancer as an example and summarized the pharmacokinetic characteristics of anti-tumor drugs targeting for pulmonary administration contained in nanoparticles, dendrimers, liposomes and micelles. Results: The review shows that the pharmacokinetics process of pulmonary administration is associated with a drug carrier by increasing the deposition and release of drugs in the lung, and retarding the lung clearance rate. Among them, the surface of dendrimers could be readily modified, and polymer micelles have favorable loading efficiency. In the case of inhalation administration, liposomes exhibit more excellent lung retention properties compared to other non-lipid carriers. Therefore, the appropriate drug carrier is instrumental to increase the curative effect of anti-tumor drugs and reduce the toxic effect on surrounding healthy tissues or organs. Conclusion: In the process of pulmonary administration, the carrier-embedded antitumor drugs have the characteristics of targeted and sustained release compared with non-packaging drugs, which provides a theoretical basis for the clinical rational formulation of chemotherapy regimens. However, there is currently a lack of comparative research between drug packaging materials, and more importantly, the development of safe and effective anti-tumor drugs targeting for pulmonary administration requires more data.

Background: In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients. Methods: Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/) and the ADME database (https://life-science.kyushu.fujitsu.com/admedb/). Results: Chloroquine and hydroxychloroquine are metabolized by P450 1A2, 2C8, 2C19, 2D6, and 3A4/5 in vitro and by P450s 2C8 and 3A4/5 in vivo by N-deethylation. Chloroquine effectively inhibited P450 2D6 in vitro; however, in vivo inhibition was not apparent except in individuals with limited P450 2D6 activity. Chloroquine is both an inhibitor and inducer of the transporter MRP1 and is also a substrate of the Mate and MRP1 transport systems. Hydroxychloroquine also inhibited P450 2D6 and the transporter OATP1A2. Conclusions: Chloroquine caused a statistically significant decrease in P450 2D6 activity in vitro and in vivo, also inhibiting its own metabolism by the enzyme. The inhibition indicates a potential for clinical drug-drug interactions when taken with other drugs that are predominant substrates of the P450 2D6. When chloroquine and hydroxychloroquine are used clinically with other drugs, substrates of P450 2D6 enzyme, attention should be given to substrate-specific metabolism by P450 2D6 alleles present in individuals taking the drugs.

Background: Nanostructured lipid carriers (NLCs) are in high demand in the existing pharmaceutical domain due to its high versatility. It is the newer generation of lipid nanoparticulate systems having a solid matrix and greater stability at room temperature. Objective: To review the evidence related to the current state of the art of the NLCs system and its drug delivery perspectives to the brain. Methods: Scientific data search, review of the current state of the art and drug delivery perspectives to the brain for NLCs were undertaken to assess the applicability of NLCs in the management of neurological disorders through an intranasal route of drug administration. Results: NLCs are designed to fulfill all the industrial needs like simple technology, low cost, scalability, and quantifications. Biodegradable and biocompatible lipids and surfactants used for NLCs have rendered them acceptable from regulatory perspectives as well. Apart from these, NLCs have unique properties of high drug payload, modulation of drug release profile, minimum drug expulsion during storage, and incorporation in various dosage forms like gel, creams, granules, pellets, powders for reconstitution and colloidal dispersion. Ease of surface- modification of NLCs enhances targeting efficiency and reduces systemic toxicity by providing site-specific delivery to the brain through the intranasal route of drug administration. Conclusion: The present review encompasses the in-depth discussion over the current state of the art of NLCs, nose-to-brain drug delivery perspectives, and its theranostic application as useful tools for better management of various neurological disorders. Further, pharmacokinetic consideration and toxicity concern is also discussed specifically for the NLCs system exploited in nose-to-brain delivery.

A amyloid-β (Aβ) plaque formation in the brain is known to be the root cause of Alzheimer’s disease (AD), which affects the behavior, memory, and cognitive ability in humans. The brain starts undergoing changes several years before the actual appearance of the symptoms. Nanotechnology could prove to be an alternative strategy for treating the disease effectively. It encompasses the diagnosis as well as the therapeutic aspect using validated biomarkers and nano-based drug delivery systems, respectively. A nano-based therapy may provide an alternate strategy, wherein one targets the protofibrillar amyloid-β (Aβ) structures, and this is followed by their disaggregation as random coils. Conventional/routine drug therapies are inefficient in crossing the blood-brain barrier; however, this hurdle can be overcome with the aid of nanoparticles. The present review highlights the various challenges in the diagnosis and treatment of AD. Meticulous and collaborative research using nanotherapeutic systems could provide remarkable breakthroughs in the early-stage diagnosis and therapy of AD.

Background: Cytochrome P450s (CYPs) are drug-metabolizing enzymes catalyzing the metabolism of about 75% of drug in clinical use. CYP2C9 represents 20% CYP proteins in liver cells and is a crucial member of CYPs superfamily. CYP2C19 metabolizes very important drugs such as antiulcer drug omeprazole, the antiplatelet drug clopidogrel and anticonvulsant mephenytoin. Single nucleotide polymorphisms (SNPs) of CYP genes have been associated with unexpected drug reactions and diseases in different populations. Objective: We examined the associations of CYP2C9*3 (rs1057910) and CYP2C19*3 (rs4986893) with T2D in Saudi population. Methods: We used the allele-specific PCR (AS-PCR) and DNA sequencing in 111 cases and 104 controls for rs1057910, and in 119 cases and 110 controls for rs4986893. Results: It is indicated that the genotype distribution of rs1057910 in cases and controls were not significantly different (P=0.0001). The genotypes of rs1057910 were not associated with type 2 diabetes (T2D) (P>0.05). Whereas the genotype distribution of rs4986893 in cases and controls was significantly different (P=0.049). The AA genotype of rs4986893 may be associated in increased risk to T2D with OR=17.25 (2.06-143.8), RR=6.14(0.96-39.20), P=0.008. Conclusion: The CYP2C9*3 (rs1057910) may not be associated with T2D, while CYP2C19*3 (rs4986893) is probably associated with T2D. These findings need to be validated in follow-up studies with larger sample sizes and different populations.

Background: The relationships between lifestyle-related diseases and polymorphic drug-metabolizing enzyme activities in the general population in Japan remain unclear. Objective: In this study, the relationships between an index of arteriosclerosis and the phenotypic activities of flavin-containing monooxygenase 3 (FMO3) and cytochrome P450 (P450) 2A6 were analysed. Methods: Subjects in a general population in Japan (age range 35-97 years, 640 men and 795 women, 12% were current smokers) who took part in a health check program were recruited. Results: Subjects were divided into two groups using the median ankle-brachial pressure index (ABI) score. Subjects harbouring P450 2A6 wild-type allele had a significant age-adjusted odds ratio of 1.3 (95% CI, 1.0-1.6) of having a lower than median ABI score compared with subjects for mutant P450 2A6. For subjects with wild-type FMO3, the odds ratio of 0.89 was not significant. The proportions of P450 2A6 extensive metabolizers varied significantly across the inter-quartile ranges of the ABI scores (p = 0.008). Furthermore, the proportion of subjects with low ABI scores was also dependent on the phenotypic P450 2A6 activity (p = 0.025) as estimated from the P450 2A6 genotype. These results suggest that in a general population in Japan, the ABI score, as a risk index for arteriosclerosis, is associated with the predicted P450 2A6 phenotype but is not associated with FMO3 function. Conclusion: The P450 2A6 wild-type allele may be a possible candidate biomarker for arteriosclerosis in a general population in Japan with a variety of dietary habits.