Current Drug Metabolism - Volume 19, Issue 1, 2018

Background: The present work describes development of offline and web-searchable metabolism databases for drugs, other chemicals, and physiological compounds using human and model species, prompted by the large amount of data published after year 1990. The intent was to provide a rapid and accurate approach to published data to be applied both in science and to assist therapy. Methods: Searches for the data were done using the Pub Med database, accessing the Medline database of references and abstracts. In addition, data presented at scientific conferences (e.g., ISSX conferences) are included covering the publishing period beginning with the year 1976. Results: Application of the data is illustrated by the properties of benzo[a]pyrene (B[a]P) and its metabolites. Analysis show higher activity of P450 1A1 for activation of the (-)- isomer of trans-B[a]P-7,8-diol, while P4501B1 exerts higher activity for the (+)- isomer. P450 1A2 showed equally low activity in the metabolic activation of both isomers. Conclusion: The information collected in the databases is applicable in prediction of metabolic drug-drug and/or drug-chemical interactions in clinical and environmental studies. The data on the metabolism of searched compound (exemplified by benzo[a]pyrene and its metabolites) also indicate toxicological properties of the products of specific reactions. The offline and web-searchable databases had wide range of applications (e.g. computer assisted drug design and development, optimization of clinical therapy, toxicological applications) and adjustment in everyday life styles.

Background: Even though chemotherapeutic regimens show considerable importance, it may cause progressive, continuing and sometimes irreversible peripheral neuropathy. Chemotherapy induced peripheral neuropathy (CIPN) is comprised of sensory abnormalities that are most distressing issues. The mechanism associated with CIPN pathogenesis is not completely revealed and its treatment is still questionable. The purpose of this review was to investigate the role of mitochondria in CIPN. Methods: This review is literature based that describes the mitochondrial mechanism underlying CIPN and the neuropathic complications associated with different antineoplastic agents. Results: For severe pain, a modification towards less efficient chemotherapeutic drugs could possibly be needed and/or patients perhaps prefer to withdrawal therapeutic regimen. The epidemiology of CIPN is still debatable. The major recurrent molecules causing CIPN are platinum based drugs including cisplatin and oxaliplatin, thalidomide, bortezomib, vinka alkaloids and taxanes. Neuropathic pain is one of the symptoms of CIPN. Various neuropathic disorders as well as CIPN are due to mitochondrial impairment, relevant impairment of Ca2+ signalling pathways and reactive oxygen species (ROS) that ultimately leads to apoptosis. Conclusion: The pathophysiology of CIPN is complicated as chemotherapeutic medications often involve combination of drugs. With these combinatorial therapies cancer survivors develop continuing effects of CIPN which require rehabilitation strategies for the recovery of patient's condition and quality of life.

Background: Anthracyclines in combination with cytarabine have been the standard therapy for acute myeloid leukemia (AML) for decades with high efficacy. However, the majority of patients will show initial resistance or will relapse after initial complete remission. Genetic variability in genes involved in anthracyclines metabolic pathway could be one of the causes of the interindividual differences in clinical outcomes. Methods: A systematic review of published studies in AML cohorts was carried out in order to analyze the influence of polymorphisms in genes of anthracycline metabolism on efficacy and toxicity. Results: Polymorphisms in the main enzymes of anthracyclines metabolism (CBR, AKR, NQO1, NOS3) have been related to lower enzymatic activity and higher cardiotoxicity. Moreover, variant alleles in the genes of carcinogens and chemotherapy neutralizing enzymes (GST, SULT, NADP(H) oxidase) have been associated with ROS generation and drug efficacy, influencing the survival rates and cardiac toxicities. In addition, genetic variability in the transporters of anthracyclines could affect the intake in cells, including influx (SLC28A3, SLC22A12, SLCO1B1) and efflux transporters (ABCB1, ABCC1, ABCC3, ABCG2). Conclusion: The knowledge of the role of pharmacogenetics in anthracyclines metabolism could explain the differences observed in their disposition in leukemic cells. These genetic variants are proposed biomarkers in clinical practice in order to individualize chemotherapy schemes, potentially increasing the effectiveness and reducing the toxicities.

Background: Nanomedicine, which is defined as application of nanoparticles in medicine, has offered new hopes for overcoming the drawbacks appeared in traditional chemotherapy. The size of nanomedicine normally in the range from 1 to 200 nm endows its potential applications in cancer therapy. But in clinics, there is still a gap between the in vitro physicochemical properties and the cellular level performance. Method: The physicochemical properties include size, shape, surface chemistry, surface topology, and surface properties strongly affect nanomedicine inter-/intra-cellular efficiency. Herein, this article reviews effects of physicochemical properties of nanomedicine on the cellular endocytosis and intracellular route. And strategies of nanomedicine optimization are also discussed from different perspectives. Results: On the one hand, not as that of the traditional small molecular agents, the cellular endocytosis pathway and efficiency of nanomedicine is related to its size, structure and surface properties. On the other hand, the intracellular conditions also affect the intracellular route of nanomedicine. Conclusion: Nanomedicine of different scale size is internalized through different pathways. While different sensitivities to intracellular conditions determined by physicochemical properties of nanomedicine will lead to different cellular consumption. So, both the properties of nanomedicine and the intracellular conditions play important roles in cellular metabolism. Consequently, nanocarriers finely engineered as the above principles can provide practical solution to the problems appeared in cellular level for promoting traditional cancer therapy.