Current Drug Metabolism - Volume 20, Issue 4, 2019

Background: As part of an integrated and innovative approach to accelerate the clinical development of the dual receptor antagonist ACT-541468, 6 healthy subjects in one cohort in a first-in-humans (FIH) study received an oral dose of 50 mg non-labeled ACT-541468 together with a microtracer amount of 250 nCi of 14C-labeled ACT- 541468 to investigate its absorption, distribution, metabolism, and excretion (ADME). Methods: Using accelerator mass spectrometry (AMS), radiochromatograms were constructed for fractionated plasma, urine, and feces samples. Subsequently, the structures of the metabolites were elucidated using high performance liquid chromatography (HPLC) coupled with high resolution mass spectrometry. Results: In total 77 metabolites have been identified of which 30, 28, and 60 were present in plasma, urine, and feces, respectively. In plasma, the major metabolites were the mono-oxidized benzylic alcohol M3, the ACT-541468 aldehyde M1, formed by further oxidation of M3 in the benzylic position, and the doubly oxidized M10, formed by (1) benzylic oxidation of M3 (loss of one molecule of water and one molecule of ammonia) and (2) additional loss of water from the oxidized pyrrolidine ring of M5. Transformation of the pyrrolidine to a 6-membered ring was detected. Metabolites that accounted for more than 5% of total radioactivity in excreta were M2, which is also formed by oxidation at the benzylic position, M4, formed by demethylation of the methoxy-group, M7 and A6, both formed by oxidation of M4, and M10, the only major metabolite detected in urine. Conclusion: In conclusion, ACT-541468 is extensively metabolized predominantly by oxidative transformations.

Objective: The purpose of this systematic review and meta-analysis was to summarize the potential impact of CYP2C8 and SLCO1B1 genetic polymorphisms on repaglinide pharmacokinetics. Methods: A systematic search was conducted using electronic databases. Eligible studies reported data from pharmacokinetic evaluations of repaglinide in healthy adults according to different categories of CYP2C8 and SLCO1B1 genetic polymorphisms. Results: Six studies including a total of 191 participants met the inclusion criteria. We noted that CYP2C8 *1/*3 carriers exhibited lower AUC(0-∞) (SMD: -0.77; 95%CI: -1.23 to -0.30; P=0.001) and Cmax (SMD: -0.94; 95%CI: - 1.41 to -0.47; P<0.001) than CYP2C8 *1/*1 carriers. There were no significant differences in AUC(0-∞), Cmax, t1/2 and mean change in blood glucose concentration between *1/*4 and *1/*1 carriers. Further, *3/*3 carriers had lower Cmax (SMD: -1.42; 95%CI: -2.66 to -0.17; P=0.026) than *1/*1 carriers. Additionally, *3/*3 carriers had lower Cmax than *1/*3 carriers (SMD: -1.20; 95%CI: -2.40 to -0.00; P=0.050). Finally, we noted that repaglinide pharmacokinetics did not differ by SLCO1B1 genotype. Conclusion: The current systematic review and meta-analysis indicated that the genotype of CYP2C8, but not SLCO1B1, may affect repaglinide pharmacokinetics. However, because of the comparatively insufficient number of published studies included, our conclusions require support from additional studies.

Background: In recent times, herbals or phytomedicines have become very popular due to their global acceptance as a complementary and alternative remedy. While modern drugs are commercially available only after laboratory validations, clinical trials, as well as approval from drug regulatory authorities, majority of the marketed herbal products lack such scientific evidence of efficacy and safety. This results in herb or herb-drug interaction induced unfavorable clinical outcomes without crucial documentation on their temporal relations and concomitant use. Methods: An online literature search for peer-reviewed articles was conducted on the PubMed, Europe PMC, Medline and Google Scholar portals, using the phrases: complementary & alternative medicine, traditional Chinese medicine, herb-drug interaction, mechanisms of herb-drug interaction, herb-induced toxicity, herbal hepatotoxicity and causality, traditional medicine, viral hepatitis, etc. Results: The retrieved data showed that globally, patients are attracted to herbal remedies with the misconception that these are completely safe and therefore, use them simultaneously with prescription drugs. Notably, there exists a potential risk of herb-drug interactions leading to some adverse side effects, including hepatotoxicity. The toxicological effect of a drug or herb is due to the inhibition of drug metabolizing enzymes (e.g., cytochrome P450), including interactions with certain prescription drugs through various mechanisms. Several cases of hepatotoxicity due to use of herbals in viral hepatitis-related liver diseases have been recently reported. However, limited experimental data and clinical evidence on herbal pharmacokinetics hamper the evaluation and reporting of adverse reactions and the underlying mechanisms. Conclusion: Herb-drug interaction related morbidity is thus an emerging serious public health issue with broad implications for clinicians, pharmaceutical industries and health authorities. Nonetheless, despite increasing recognition of herb-drug interaction, a standard system for interaction prediction and evaluation is still nonexistent. This review article discusses the herb-drug interactions related hepatotoxicity and underlying mechanisms, including drug metabolizing enzymes and their regulation.

Background: Nanotechnology-based therapies are emerging as a promising new anticancer approach. Early clinical studies suggest that nanoparticle-based therapeutics can show enhanced efficacy while reducing side effects minimal, owing to targeted delivery and active intracellular uptake. Methods: To overcome the problems of gene and drug delivery, nanotechnology based delivery system gained interest in the last two decades. Encouraging results from Nano formulation based drug delivery systems revealed that these emerging restoratives can efficiently lead to more effective, targeted, selective and efficacious delivery of chemotherapeutic agents to the affected target cells. Results: Nanotechnology not only inhibits targeted gene products in patients with cancer, but also taught us valuable lessons regarding appropriate dosages and route of administrations. Besides, nanotechnology based therapeutics holds remarkable potential as an effective drug delivery system. We critically highlight the recent findings on nanotechnology mediated therapeutics strategies to combat hepatocellular carcinoma and discuss how nanotechnology platform can have enhanced anticancer effects compared with the parent therapeutic agents they contain. Conclusion: In this review, we discussed the key challenges, recent findings and future perspective in the development of effective nanotechnology-based cancer therapeutics. The emphasis here is focused on nanotechnology-based therapies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with hepatocellular carcinoma.

Background: The progression of liver disease causes metabolic transformation in vivo and thus affects corresponding endogenous small molecular compounds. Metabonomics is a powerful technology which is able to assess global low-molecular-weight endogenous metabolites in a biological system. This review is intended to provide an overview of a metabonomics approach to the drug toxicology of diseases of the liver. Methods: The regulation of, and relationship between, endogenous metabolites and diseases of the liver is discussed in detail. Furthermore, the metabolic pathways involved in drug interventions of liver diseases are reviewed. Evaluation of the protective mechanisms of traditional Chinese medicine in liver diseases using metabonomics is also reviewed. Examples of applications of metabolite profiling concerning biomarker discovery are highlighted. In addition, new developments and future prospects are described. Results: Metabonomics can measure changes in metabolism relating to different stages of liver disease, so metabolic differences can provide a basis for the diagnosis, treatment and prognosis of various diseases. Conclusion: Metabonomics has great advantages in all aspects of the therapy of liver diseases, with good prospects for clinical application.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a systematic inflammatory disease, and smoking is an important risk factor for COPD. Macrolide can reduce COPD inflammation. However, the inflammatory mechanism of COPD remains unclear and the anti-inflammatory mechanism of Macrolide is complex and not exactly known. Methods: We read and analysed thirty-eight articles, including original articles and reviews. Results: The expression of Nrf2 was lower in COPD patients and might have a protective role against apoptosis caused by CSE-induced oxidative stress. Nrf2 may play an important role in COPD inflammation. Nrf2 is a key factor in downstream of PI3K/Akt and is involved in the regulation of oxidative stress and inflammatory response. Therefore, PI3K/Akt pathway may play an important role in the activation of Nrf2 and COPD inflammation. Macrolide reduces lung and systemic inflammation of COPD by regulating PI3K/Akt pathway. Conclusion: This review indicates that PI3K/Ak-Nrf2 may play an important role in COPD inflammation and macrolides may reduce lung and systemic inflammation of COPD by regulating PI3K/Akt-Nrf2 pathway. However, many crucial and essential questions remain to be answered. Further understanding of the mechanisms of macrolide efficacy and PI3K/Akt-Nrf2-mediated inflammatory responses may provide a new clue for exploring COPD treatment in the future.

Background: Research of biomarkers in genitourinary tumors goes along with the development of complex emerging techniques ranging from next generation sequencing platforms, applied to archival pathology specimens, cytological samples, liquid biopsies, and to patient-derived tumor models. Methods: This contribution is an update on molecular biomarkers for diagnosis, prognosis and prediction of response to therapy in genitourinary tumors. The following major topics are dealt with: Immunological biomarkers, including the microbiome, and their potential role and caveats in renal cell carcinoma, bladder and prostate cancers and testicular germ cell tumors; Tissue biomarkers for imaging and therapy, with emphasis on Prostate-specific membrane antigen in prostate cancer; Liquid biomarkers in prostate cancer, including circulating tumor cell isolation and characterization in renal cell carcinoma, bladder cancer with emphasis on biomarkers detectable in the urine and testicular germ cell tumors; and Biomarkers and economic sustainability. Conclusion: The identification of effective biomarkers has become a major focus in cancer research, mainly due to the necessity of selecting potentially responsive patients in order to improve their outcomes, as well as to reduce the toxicity and costs related to ineffective treatments.

Background: In the past two decades, a great body of research has been published regarding the effects of genetic polymorphisms on methotrexate (MTX)-induced toxicity and efficacy. Of particular interest is the role of this compound in childhood acute lymphoblastic leukaemia (ALL), where it is a pivotal drug in the different treatment protocols, both at low and high doses. MTX acts on a variety of target enzymes in the folates cycle, as well as being transported out and into of the cell by several transmembrane proteins. Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. Results: This review has intended to summarize the current knowledge concerning the clinical impact of polymorphisms in enzymes and transporters involved in MTX disposition and mechanism of action on paediatric patients with ALL. Conclusion: In this work, we describe why, in spite of the significant research efforts, pharmacogenetics findings in this setting have not yet found their way into routine clinical practice.