Current Drug Metabolism - Volume 20, Issue 11, 2019

Background: Monocarboxylate Transporter 1 (MCT1), an important membrane transport protein, mediates the translocation of monocarboxylates together with protons across biological membranes. Due to its pathological significance, MCT1 plays an important role in the progression of some diseases, such as brain diseases and cancers. Methods: We summarize the general description of MCT1 and provide a comprehensive understanding of the role of MCT1 in brain diseases and cancers. Furthermore, this review discusses the opportunities and challenges of MCT1- targeting drug-delivery systems in the treatment of brain diseases and cancers. Results: In the brain, loss of MCT1 function is associated with pathologies of degeneration and injury of the nervous system. In tumors, MCT1 regulates the activity of signaling pathways and controls the exchange of monocarboxylates in aerobic glycolysis to affect tumor metabolism, proliferation and invasion. Meanwhile, MCT1 also acts as a good biomarker for the prediction and diagnosis of cancer progressions. Conclusion: MCT1 is an attractive transporter in brain diseases and cancers. Moreover, the development of MCT1- based small molecule drugs and MCT1 inhibitors in the clinic is promising. This review systematically summarizes the basic characteristics of MCT1 and its role in brain diseases and cancers, laying the foundation for further research on MCT1.

Background: Liver injury induced by drugs has become a primary reason for acute liver disease and therefore posed a potential regulatory and clinical challenge over the past few decades and has gained much attention. It also remains the most common cause of failure of drugs during clinical trials. In 50% of all acute liver failure cases, drug-induced hepatoxicity is the primary factor and 5% of all hospital admissions. Methods: The various hepatotoxins used to induce hepatotoxicity in experimental animals include paracetamol, CCl4, isoniazid, thioacetamide, erythromycin, diclofenac, alcohol, etc. Among the various models used to induce hepatotoxicity in rats, every hepatotoxin causes toxicity by different mechanisms. Results: The drug-induced hepatotoxicity caused by paracetamol accounts for 39% of the cases and 13% hepatotoxicity is triggered by other hepatotoxic inducing agents. Conclusion: Research carried out and the published papers revealed that hepatotoxins such as paracetamol and carbon- tetrachloride are widely used for experimental induction of hepatotoxicity in rats.

Background: Prevention is the primary strategy to avoid the occurrence and mortality of colorectal cancer. Generally, the concentrations of tumor markers tested during the diagnosis and believed to assist the detection of disease in the early stages of cancer. Some of the biomarkers are also important during treatment and real-time monitoring of the progress of treatment. Methods: We considered a rationale search of key references from the database of peer-reviewed research and review literatures of colorectal cancer. The topic of search was focused on the novel methods and modern techniques of Screening, Diagnosis, and Treatment of colorectal cancer. The screened publications were critically analysed using a deductive content analysis and the matter was put in separate headings and sub headings. Results: It was found that endoscopic examination, early detection, and surgery are some of the common strategies to manage colorectal cancer because late stages are difficult to treat due to the high-cost requirement and fewer chances of survival. As far as chemotherapy is concerned, systemic chemotherapy has been shown to offer the maximum benefit to patients with cancer metastasis. Among different chemotherapy measures, primary colorectal cancer prevention agents involve pharmaceuticals, phytochemicals, and dietary supplements are some of the standard options. Conclusion: In this review article, we have provided a comprehensive analysis of different biomarkers for the detection of colorectal cancer as well as different formulations developed for efficient treatment of the disease. The use of dietary supplements, the combinatorial approach, and nanotechnology-based strategies for colorectal cancer diagnosis and treatment are some of the recent and modern methods of cancer management.

Background: Inflammatory Bowel Disease (IBD) is a common disease affecting many patients. This disease is treated by azathioprine and TPMT genetic polymorphism affecting the patient’s tolerance. The aim of this study is to investigate the importance of TMPT genotyping in reducing the incidence of adverse effects of azathioprine. Methods: One hundred and forty-one IBD patients were followed for azathioprine Adverse Drug Reaction (ADR). Patients were genotyped for TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C. Results: The frequency of Azathioprine adverse effect was about 35.5%. An association between TPMT genotypes 1/3A and 3B/3B and azathioprine related bone marrow suppression was found (P value ≤ 0.05). Conclusion: The findings suggest that there was a significant association between TPMT genotypes 1/3A and 3B/3B and azathioprine related bone marrow suppression.

Background: Cotrimoxazole (TMP-SMX) is concomitantly used as a primary prophylaxis of opportunistic infections with antiretroviral agents, such as Atazanavir (ATV). Results from an ex vivo study showed changes in intestinal absorption of ATV when rats were pretreated with TMP-SMX. The objective of this in vivo study is to determine the effect of TMP-SMX on the pharmacokinetics of ATV in rats. We also studied changes in gut microbiota induced by TMP-SMX. Methods: We used the non-compartment analysis to compare the pharmacokinetics of ATV in a parallel group of rats treated with a low or therapeutic dose of TMP-SMX for nine days to untreated control rats. Gut microbiota was characterized using qPCR and High Throughput Sequencing of 16S rDNA. Results: Rats treated with TMP-SMX showed a much broader exposure to ATV compared to the control group (AUC0-8h (ng.mL-1.h), 25975.9±4048.7 versus 2587.6±546.9, p=0.001). The main observation regarding the gut microbiota was a lower proportion of enterobacteria related to the administration of TMP-SMX. Moreover, the Total Gastrointestinal Transit Time (TGTT) was longer in the TMP-SMX treated group. Conclusion: Concomitant administration of TMP-SMX and ATV significantly increased ATV exposure in rats. This increase could be the result of a prolonged TGTT leading to an increase in the intestinal residence time of ATV favoring its absorption. Gut microbiota changes induced by TMP-SMX could be at the origin of this prolonged TGTT. If demonstrated in humans, this potential interaction could be accompanied by an increase in the adverse effects of ATV.

Background: Due to the potential advantages of Gadolinium Nanoparticles (NPs) over gadolinium elements, gadolinium based NPs are currently being explored in the field of MRI. Either in elemental form or nanoparticulate form, gadolinium toxicity is believed to occur due to the deposition of gadolinium ion (designated as Gd3+ ion or simply G ion). Objective: There is a serious lack of literature on the mechanisms of toxicity caused by either gadolinium-based NPs or ions. Breast cancer tumors are often subjected to MRIs, therefore, human breast cancer (MCF-7) cells could serve as an appropriate in vitro model for the study of Gadolinium Oxide (GO) NP and G ion. Methods: Cytotoxicity and oxidative damage was determined by quantifying cell viability, cell membrane damage, and Reactive Oxygen Species (ROS). Intracellular Glutathione (GSH) was measured along with cellular Total Antioxidant Capacity (TAC). Autophagy was determined by using Monodansylcadaverine (MDC) and Lysotracker Red (LTR) dyes in tandem. Mitochondrial Membrane Potential (MMP) was measured by JC-1 fluorescence. Physicochemical properties of GO NPs were characterized by field emission transmission electron microscopy, X-ray diffraction, and energy dispersive spectrum. Results: A time- and concentration-dependent toxicity and oxidative damage was observed due to GO NPs and G ions. Bax/Bcl2 ratios, FITC-7AAD double staining, and cell membrane blebbing in phase-contrast images all suggested different modes of cell death induced by NPs and ions. Conclusion: In summary, cell death induced by GO NPs with high aspect ratio favored apoptosis-independent cell death, whereas G ions favored apoptosis-dependent cell death.

Background: Mouse Udp-glucuronosyl Transferase (UGT) 2b1 is equivalent to the human UGT2B7 enzyme, which is a phase II drug-metabolising enzyme and plays a major role in the metabolism of xenobiotic and endogenous compounds. This study aimed to find the relative expression of the mouse ugt2b1 gene in the liver, kidney, and heart organs and the influence of Nonsteroidal Anti-inflammatory Drug (NSAID) administration. Methods: Thirty-five Blab/c mice were divided into 5 groups and treated with different commonly-used NSAIDs; diclofenac, ibuprofen, meloxicam, and mefenamic acid for 14 days. The livers, kidneys, and hearts were isolated, while the expression of ugt2b1 gene was analysed with a quantitative real-time polymerase chain reaction technique. Results: It was found that the ugt2b1 gene is highly expressed in the liver, and then in the heart and the kidneys. NSAIDs significantly upregulated (ANOVA, p < 0.05) the expression of ugt2b1 in the heart, while they downregulated its expression (ANOVA, p < 0.05) in the liver and kidneys. The level of NSAIDs’ effect on ugt2b1 gene expression was strongly correlated (Spearman’s Rho correlation, p < 0.05) with NSAID’s lipophilicity in the liver and its elimination half-life in the heart. Conclusion: This study concluded that the mouse ugt2b1 gene was mainly expressed in the liver, as 14-day administration of different NSAIDs caused alterations in the expression of this gene, which may influence the metabolism of xenobiotic and endogenous compounds.

Background: Metoclopramide is mainly metabolized by CYP2D6, CYP3A4, CYP2C19, and CYP1A2 enzymes, while cilostazol is also metabolized by CYP3A4, CYP2C19, and CYP1A2 enzymes. Aim: This study evaluates the effect of cilostazol on the pharmacokinetics of oral metoclopramide. Methods: This was a randomized, two-phase cross-over pharmacokinetic study separated by a 4-week wash-out time period, 12 healthy non-smoking volunteers received metoclopramide 20 mg as a single oral dose and after 4 weeks, cilostazol 100 mg twice daily for 4 days then with metoclopramide 20 mg on test day. Serial blood samples were analyzed by using a validated high-performance liquid chromatography-ultraviolet method to determine maximum plasma drug concentration (Cmax), time to reach (Tmax), and area under the curve (AUC0-∞) of metoclopramide. Results: Cilostazol increased the mean Cmax, AUC0-∞ and half-life (T1/2) of metoclopramide by 6%, 27% and by 0.79 %, respectively. In addition, Tmax of metoclopramide was delayed by cilostazol. Conclusion: The results showed delayed Tmax of metoclopramide by cilostazol, which could lead to the conclusion that cilostazol affects the absorption of metoclopramide. Both drugs when necessary to administer together must not be administered at the same time especially when given in gastroparesis patients.