Current Drug Metabolism - Volume 18, Issue 12, 2017

Background: Salvia is the largest genus of family Lamiaceae and has nearly 1000 species. This genus produces several representative phytometabolites, e.g., diterpenoids and phenolic acids. The traditional uses in ethnomedicine and contemporary experimental studies have corroborated extensive therapeutic efficacy of Salvia plants. Drug metabolism and pharmacokinetic (DMPK) studies of Salvia natural products and their derivatives are indispensable in the optimization of lead compounds. New chemical entity with improved DMPK profiles is preferred. So far, there are few summaries concerning about the DMPK features of Salvia derived medicinal compounds. Tanshinones and Salvianolic acids raise concerns of herb-drug interaction. DMPK studies of various Salvia species, especially Salvia miltiorrhiza, are swiftly increasing. Objective: Here, the latest awareness, as well as the gaps of the DMPK issues in drug development and clinical usage of Salvia compounds, was highlighted. Conclusion: Herb-herb interactions of Salvia-containing traditional Chinese medicine (TCM) medicine pair/formula significantly impact the PK/pharmacodynamic performance of compounds thereof, which may inspire researchers to develop novel herbal formula. While the absorption, distribution, metabolism, elimination and toxicity (ADME/T) of some tanshinones and Salvianolic acids have been outlined, DMPK studies should be extended to more compounds, Salvia species, and Salvia-containing formulations. In the context of systems pharmacology, the DMPK knowledgebase is expected to streamline the Salvia-based drug discovery and development.

Background: Salmonella enterica serovar typhimurium is the most important serotype of Salmonella transmitted from animals to humans in most parts of the world. They are associated with an estimated 1 million deaths annually. Quinolones, an important class of broad-spectrum antimicrobials, have been utilized as a treatment option for salmonellosis for over 40 years. Despite the number of available quinolone agents, many of them failed in the clinical stage and never make it to FDA approval. Despite considerable evidence reveals the importance of different drug discovery process of S. typhimurium, there are no systematic review outlining the pharmacokinetic and pharmacodynamic parameters of quinolones. Keeping this in mind, the present study aims to provide a systematic review on metabolism and pharmacokinetics of different quinolones. Methods: Information from all relevant bibliographic databases was used. Additionally, the recent journal articles and textbooks were searched manually in the preparation of this review article. Results: A total of 136 journal articles and textbooks were included in the preparation of the review. Majority of research articles defines about the metabolism, pharmacodymanics and pharmacokinetics of different quinolones. Twenty eight papers outlined about the mechanism and challenges faced by the quinolones and fluoroquinolones. Finally, information on drug interactions, adverse effects and drug resistance of quinolones and fluoroquinolones were supported with forty two research articles. Note that the importance of computational biology in the field of drug discovery was also addressed with appropriate literatures. Conclusion: Overall, the findings of this review highlight the importance of pharmacokinetic profiling of different quinolones in developing novel drugs to overcome drug resistance in the near future.

Background: Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body's natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes. Methods: We performed a structured search of peer-reviewed literature on P450 (CYP) 3A, with a focus on CYP3A4 and CYP3A5. Results: Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR), CYP3A4 and CYP3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands. Conclusion: Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them.

Background: Absorption, Distribution, Metabolism, Excretion (ADME) properties along with drug induced adverse effects are the major reasons for the late stage failure of drug candidates as well as the cause for the expensive withdrawal of many approved drugs from the market. Considering the adverse effects of drugs, metabolism factor has great importance in medicinal chemistry and clinical pharmacology because it influences the deactivation, activation, detoxification and toxification of drugs. Methods: Computational methods are effective approaches to reduce the number of safety issues by analyzing possible links between chemical structures and metabolism followed by adverse effects, as they serve the integration of information on several levels to enhance the reliability of outcomes. Results and Discussion: In silico profiling of drug metabolism can help progress only those molecules along the discovery chain that is less likely to fail later in the drug discovery process. This positively impacts the very high costs of drug discovery and development. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true influence on drug discovery at different levels. If applied in a scientifically consequential way, computational tools may improve the capability to identify and evaluate potential drug molecules considering pharmacokinetic properties of drugs. Conclusion: Herein, current trends in computational modeling for predicting drug metabolism are reviewed highlighting new computational tools for drug metabolism prediction followed by reporting large and integrated databases of approved drugs associated with diverse metabolism issues.

Background: Metabolism of therapeutic agents in organism is extremely important from a point of view of drug discovery. Unfortunately, experimental estimation of phenomena related to metabolism is available for the limited number of substances. Under such circumstances, the development of computational method to predict endpoints related to metabolism of therapeutic agents becomes an attractive alternative for expensive and timeconsuming experiments. Method: A group of semi-empirical calculations are a convenient compromise between a necessity to carry out experiments and the desire to involve in the practical analysis of a bigger amount of molecular features related to the impact of different substances on metabolism. The practical organization of the investigational analysis may be based on the Monte Carlo technique. Results: The statistical quality of predictive models built up with the Monte Carlo method is usually quite satisfactory. Thus, the semi-empirical calculation using the Monte Carlo method may extend available database, which are related to metabolism of different therapeutic agents. It should be noted that the above approach involves minimal animal testing. The CORAL software has been used for the calculations. Conclusion: The described approach based on the Monte Carlo technique is a tool to predict behavior of therapeutic agents in organism. The approach is flexible: small and large molecules (peptides) can be studied by means of building up models of their endpoints which have impact upon metabolism phenomena.

Background: The study of the mechanisms of liver regeneration is quite an intriguing field that has been extensively modeled. Through the process of compensatory proliferation of the hepatocytes, the liver mass is restored after loss of up to two-thirds of the entire mass. Cyclic nucleotides are intracellular second messengers which are involved in the transduction of a diverse array of stimuli, mediating metabolic and growth regulation. The relationship between cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling and liver regeneration has somehow been elusive to pioneer researchers in the field of liver regeneration. In this review, we will highlight the mechanistic approach involving cyclic nucleotide signaling and its regulation of cell cycle progression in proliferating hepatocytes, highlighting its usefulness to devising therapeutic tools for managing liver diseases. Method: A structured search and review of relevant papers was conducted by the authors. Results: Authors included forty-two peer-reviewed literature in the review which identified possible roles of cyclic nucleotides in hepatocyte proliferation. Conclusion: This review article confirms the biological importance of cyclic nucleotides and the mediatory growth signaling events that could bring about compensatory proliferation of the liver tissues.

Background: Despite major advances in transplant medicine, antibody-mediated rejection (AMR) continues to have severe clinical implications and adversely affect graft survival. Therefore, the search for alternative drugs to treat AMR is widely pursued. The first-in-class proteasome inhibitor bortezomib (BZ) is a selective inhibitor of the 26S proteasome, which was initially approved for the treatment of malignant plasma cell disorders. Methods: This review encompasses how our understanding of inhibiting proteasome pathway created the basis of BZ research and important milestones accomplished in AMR treatment in the transplant setting. It further discusses at length the results of clinical studies, the tolerability profile, drug-drug interactions and the perspectives of BZ use in desensitization protocols. Results: Proteasome inhibition can downregulate NF-ΚB activity; decrease cell proliferation/differentiation; induce apoptosis via cell cycle arrest, endoplasmic reticulum stress and caspase induction due the accumulation of unfolded or misfolded proteins; and downregulate antigen presentation, cell-cell interaction, and cell migration. Proteasome inhibition is more evident in cells with high rate of protein synthesis and secretion, like plasma cells. These cells play a critical role in the production of antibodies during AMR. Conclusions: There is accumulating evidence that the proteasome inhibitor BZ may substantially affect the function and integrity of alloantibody-secreting plasma cells in AMR after organ solid transplant, as well as the activation, proliferation and differentiation of T- and B-lymphocytes. Recent clinical studies have provided evidence that BZ has the capability to downregulate circulating antibodies and treat AMR episodes. Additional randomized-controlled studies are required to assess the impact of BZ during short and long follow-ups.

Background: Lysosomotropic molecules are taken up into lysosomes in vitro and in vivo. Many drugs approved for clinical medicine are lysosomotropic agents, characterized by promoting particular effects including cytoplasmic vacuolization, increase in number and size of lysosomes, inhibition of their enzymes and accumulation of undegraded material, leading mainly to phospholipidosis. Despite lysosomotropism has been extensively described and studied, the pathophysiological significance of this process is still not well understood. Objetive: In this review, we focus on what is known about the effects of lysosomotropic drugs on specific lysosomal functions and their similarities with the phenotypic features of lysosomal storage disorders (LSDs). Conclusion: Some effects of lysosomotropic drugs are very similar to pathologic features of human genetic diseases affecting lysosomal function, and therefore these drugs can be used as tools to understand the mechanisms underlying such patho-pathways as well as to create pharmacologically-induced models of LSDs.