Current Drug Metabolism (v.17, #10)

Meet Our Editorial Board Member by Kantharaj Ethirajulu (921-921).

Recent Advances in Understanding of Kinetic Interplay Between Phase II Metabolism and Efflux Transport by Shuai Wang, Huijie Xing, Mengjing Zhao, Danyi Lu, Zhijie Li, Dong Dong, Baojian Wu (922-929).
Background: Mechanistic understanding of the metabolism-transport interplay assumes great importance in pharmaceutical fields because the knowledge can help to interpret drug/xenobiotic metabolism and disposition studies as well as the drug-drug interactions in vivo. About 10 years ago, it started to recognize that cellular phase II metabolism is strongly influenced by the excretion (efflux transport) of generated metabolites, a kinetic phenomenon termed “phase II metabolism-transport interplay”. This interplay is believed to have significant effects on the pharmacokinetics (bioavailability) of drugs/chemicals undergoing phase II metabolism.

Methods: In this article, we review the studies investigating the phase II metabolism-transport interplay using cell models, perfused rat intestine, and intact rats. The potential confounding factors in exploring such interplay is also summarized. Moreover, the mechanism underlying the phase II metabolism-transport interplay is discussed.

Results: Various studies with engineered cells and rodents have demonstrated that there is an interaction (interplay) between phase II enzymes and efflux transporters. This type of interplay mainly refers to the dependence of phase II (conjugative) metabolism on the activities of efflux transporters. In general, inhibiting efflux transporters or decreasing their expression causes the reductions in metabolite excretion, apparent excretion clearance (CLapp) and total metabolism (fmet), as well as an increase in the intracellular level of metabolite (Ci). The deconjugation mediated by hydrolase (acting as a “bridge”) is essential for the interplay to play out based on pharmacokinetic modeling/simulations, cell and animal studies. The hydrolases bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof (a bridging effect). Without the bridge, metabolite formation is independent on its downstream process excretion, thus impact of metabolite excretion on its formation is impossible.

Conclusion: Deconjugation (mediated by hydrolases) plays an essential role in the conjugation-transport interplay.

Metabolism and Toxicological Implications of Commonly Used Chemopreventive Drugs Against Breast Cancer/Carcinogenesis by Aliyu Muhammad, Mohammed Auwal Ibrahim, Ochuko Lucky Erukainure, Ibrahim Malami, Hadiza Sani, Hafsat Abdullahi Mohammed (930-936).
Background: Breast cancer has been reported to be among the frequently diagnosed cancer in women worldwide despite advances in early detection and treatment. Several drugs are currently used for chemoprevention as a result of a number of drawbacks associated with breast cancer therapy.

Aim: This review focuses on the metabolism and toxicological implications of these drugs against breast cancer/ carcinogenesis.

Methodology: Relevant articles on the commonly used anti-breast cancer drugs (raloxifene, tamoxifen, anastrozole, letrozole and exemestane) used in chemoprevention were searched using the major scientific databases including Scopus, Embase, PubMed/ Medline, Sciencedirect and Google Scholar.

Results: The mechanism of action of estrogen receptor modulators are basically mediated via binding to estrogen receptors leading agonistic and antagonistic effects, whereas that of aromatase inhibitors involved the suppression of estrogen concentration in plasma via inhibition or inactivation of aromatase. Both estrogen receptor and aromatase modulators are good candidates for breast cancer chemoprevention, with latter being the most appropriate. However, it has been observed that pharmacodynamics nature of these xenobiotics, often yields some undesirable outcomes after administration which may be linked to resistance and other biological side effects, following phase I/II reactions, bioactivation within and around breast tissue microenvironment vis-a-vis distant tissues. Various findings indicated the manifestation of genotoxicity, organ toxicity and oxidative/nitrosative stress at low, moderate and high doses, thereby complicating the already existing precarious condition. Moreover, interindividual variations were also observed amongst patients, suggesting a critical role of genetic polymorphism. Also, variable side effects including osteoporosis, musculoskeletal events, such as arthralgia and myalgia were found to be predominant.

Conclusion: The aromatase inhibitors seem to be most appropriate when it comes to application by virtue of their metabolic functions and fates. The reason is that raloxifene and tamoxifen are not the ideal drugs to reduce the incidence of primary invasive breast cancer because their safety and efficacy don't reach the desired optimal agent level. However, adequate care should be taken while prescribing, as well as during and after treatment with constant close monitoring of patients for any possible biochemical and clinical manifestations vis-a-vis the issue of pharmacogenetics.

Metabolic Inhibitors as Antiparasitic Drugs: Pharmacological, Biochemical and Molecular Perspectives by Suprabhat Mukherjee, Niladri Mukherjee, Prajna Gayen, Priya Roy, Santi P. Sinha Babu (937-970).
Background: Human diseases caused by the infectious parasites have been one of the major problems throughout the evolutionary journey. Protozoan and metazoan parasitic infections result in a large number of deaths, disabilities and socio-economic loss worldwide to date. Despite the best efforts for developing suitable antiparasitics, these infections take a massive toll on human health. The prevalence of emerging resistance to the existing drugs, lack of efficacy and toxic side effects are as added complications. Being enlisted under 'neglected' category, serious diseases like leishmaniasis, filariasis, trypanosomiasis etc. have failed to draw attention of the governments as well as the pharmaceutical companies. Thus, target specific as well as cost-convenient therapy needs to be employed for the treatment of these diseases and selective targeting of metabolic pathways appears to be the most promising mean.

Methods: In this context, quality works have been explored for screening either anti-metabolic drugs or selective targets in different groups of parasites. Moreover, complete genome sequencing and metabolomic profiling have provided the initiatives to search for new lethal targets in parasites.

Results: New metabolic targets are being reported from different organelles and other sub-cellular compartments of parasites such as mitochondrion, kinetoplast, apicoplast, glycosome, hydrogenosome, acidocalcisome, plasma membrane, cytoskeleton, etc. Herein, unique findings achieved in identifying new antimetabolic drugs or targets and studying their molecular mode of actions have been reviewed by incorporating existing and upcoming approaches.

Conclusion: Considering the alarming scenario of diseases caused by parasites globally, this paper provides a comprehensive review to the scientific community on the development of novel interventions based on metabolic targets to combat the challenges posed by parasites.

Background: The adverse drug reactions and poisoning events associated with the use of herbal medicines, especially the potential damaging effects of them on the liver organs, have increasingly been reported worldwide. Some herbal ingredients in medicinal plants carry the risk of herb-induced liver injury with a severe or potentially lethal clinical course, but the hepatotoxicity mechanisms and risk factors of them are not well characterized until now. Xenobiotics are converted by cytochrome P450 enzymes into highly reactive metabolites that covalently bind to the catalytic site of the enzyme itself, subsequently causing mechanism-based inhibition (MBI). Compared to reversible inhibition, MBI more frequently results in unfavorable acute and/or immune system-mediated idiosyncratic toxicities and drug/herb-drug interactions (DDI/HDIs).

Methods: We searched PubMed databases (1980-2015) for articles published in the English language to identify publications on mechanism-based inhibitors from phytomedicine and herbal ingredients hepatotoxicity.

Results: 43 mechanism-based inhibitors from phytomedicine were summarized. Twelve of these inhibitors could cause hepatotoxicity, whereas the rest have no related reports. Among them, six hepatotoxic mechanism-based inhibitors are proven to induce hepatotoxicity via their reactive metabolites (RMs). The possible mechanism for this hepatotoxicity is that RMs react with cellular components such as proteins, DNA, and membranes, resulting in ROS overproduction, respiratory chain dysfunction, and cell stress. Moreover, the amine and furan heterocycle groups might be the most potential substructures in mechanism-based inhibitors which can cause hepatotoxicity.

Conclusion: These results suggest that when mechanism-based inhibitors from phytomedicine containing amine or furan heterocycle substructures are used alone or with other drugs, in vivo hepatotoxicity screening or its clinical implications for herb-drug interactions are needed to attention.

Background: Allergic rhinitis is a global health problem, and its prevalence rate and socioeconomic burden continue to increase. Intranasal steroid (INS) is the first treatment choice in the majority of patients, because of its ability to effectively control allergic symptoms. However, patients and clinicians are concerned about the potential adverse effects of prolonged INS use.

Methods: We performed to review for evaluating systemic and local safety of INS use, by searching MEDLINE, EMBASE, and Cochrane Library database for identification of relevant articles.

Results: In the present study, the systemic bioavailabilities of several commercially available INSs were researched, and then systemic safeties were reviewed with focus on suppression of the hypothalamus-pituitary-adrenal axis and their effects on pediatric growth. In addition, local adverse effects, such as, epistaxis and nasal septal perforation, were investigated. Finally, the authors proposed some techniques in order to avoid these complications.

Conclusion: INSs offer a safe, effective means of treating allergic rhinitis in the short- and long-term with no or minimal adverse systemic and local effects.

Immunotherapy in Liver Diseases: A Balance Between Immunity and Tolerance by Alaknanda Mishra, Pramod K. Upadhyay, Perumal Nagarajan (997-1005).
Background: In today's context when liver diseases have spread across countries and people of all ages, it is of high importance to consider novel methods of non-toxic and long lived therapeutics. Among various therapies, immunotherapy for acute and chronic liver diseases is rapidly moving to the forefront among treatment options in hepatology medicine.

Objective: The present review covers the recent advances in immunotherapy of hepatocellular carcinoma (HCC), viral hepatitis, cirrhosis, obesity induced inflammation, non alcoholic fatty liver diseases (NAFLD), and drug induced liver injury (DILI) and disease pertaining to autoimmunity in liver.

Methods: A Literature search pertaining to liver immune tolerance and various immunotherapies using the major scientific databases on preclinical studies as well as clinical trials and meta-analysis were analyzed to know about the tolerance and immunotherapy of liver diseases.

Results: Immunotherapy in liver might be problematic owing to the immune tolerance property of liver. The key to therapeutic approach by utilizing this immune biology of liver is based on harnessing the immunomodulatory techniques to achieve immune activity or inhibition. Therefore, it is a necessity to overcome this immune tolerance for effective immunotherapeutic strategies. Immunotherapy may also help to boost and enhance the immunity of patients against liver diseases in combination with conventional treatment methods, or more than one method in immunotherapy may produce synergistic effect and prove to be better than when applied alone.

Conclusion: Liver has a unique immuno- biological advantage which is utilized to maintain a balance between immunity and tolerance. This intricate balance of hepatic immune cells can be modulated to effect treatments in various liver diseases. However it is important to maintain a balance between the immunity of the liver and its modulation to provide protection against hepatic disease. The key to successful curing of these conditions lies along this fine line of manipulating liver immune cells for our own benefit.

Background: Allometric scaling is regularly used for the prediction of human pharmacokinetic (PK) parameters from animal PK studies. The predicted human PK parameters can also be used for the prediction of plasma concentration-time profiles in humans.

Objectives: The main objective of this work is to predict human concentration-time profiles of drugs (one-compartment model) following oral administration using animal oral pharmacokinetic parameters.

Methods: Six drugs from the literature were chosen that were described by one-compartment model in both humans and animals following oral administration. Pharmacokinetic parameters such as oral clearance, oral volume of distribution of the central compartment, time to reach maximum plasma concentration, absorption rate constant, and half-life in humans were predicted from animals using allometric scaling. These predicted human pharmacokinetic parameters were then used to predict human plasma concentrations-time profiles of drugs.

Results: The results of this study indicate that the proposed method can be used to predict human plasma concentrations- time profiles of drugs with reasonable accuracy (≤50% prediction error).

Conclusions: Given the complexity in the pharmacokinetics of oral drugs there remains some uncertainty in this entire exercise. One can minimize the prediction error by experience in allometric scaling, scientific judgment, and unconventional or innovative thinking.