Expert Opinion on Drug Metabolism & Toxicology

Höcht, Christian; Bertera, Facundo M.; Santander Plantamura, Yanina; Parola, Luciano; Del Mauro, Julieta S.; Polizio, Ariel H.

doi: 10.1080/17425255.2019.1558204pmid: 30582386

Introduction: Although main antihypertensive drugs are able to efficiently reduce blood pressure, only a third of treated hypertensive patients achieve optimal blood pressure control. Extensive interpatient variability on drug metabolism and oral disposition of blood pressure lowering drugs can contribute to this failure in hypertension management.Areas covered: The aim of the present review is to update the knowledge on the features of hepatic metabolism of the main antihypertensive agents, including β-blockers, calcium channel blockers, angiotensin receptor blockers, and angiotensin converting enzyme inhibitors. The factors that contribute to the large interindividual variability of main antihypertensive drugs are also covered.Expert opinion: The variability of plasma concentration of antihypertensive drugs due to the involvement of hepatic metabolism can contribute to the inadequate control of blood pressure in the daily clinical practice. Genotype screening of specific hepatic drug-metabolizing enzymes may contribute to optimize dose selection and to increase the rate of blood pressure control in patients treated with specific β-blockers, calcium channel blockers, and angiotensin receptor blockers.

Hamilton, Gerhard; Rath, Barbara

doi: 10.1080/17425255.2019.1554055pmid: 30484335

Introduction: Drug screening assays employing two-dimensional (2D) cultures of cancer cells have been largely replaced by three-dimensional (3D) multicellular tumor spheroid (MCTS) models which more closely represent patient’s tumors. The predictive power of the different MCTSs depends on source of the cells, techniques of preparation, and characteristics of the aggregates.Areas covered: The preparation of MCTSs and a comparison of the spheroids assembled from permanent cancer and patient-derived cell lines in respect to the correlation of their chemosensitivity to clinical responses are discussed. Spheroids formed in in vivo in pleural effusion and blood of cancer patients are presented as interesting sources for drug screening.Expert opinion: 3D tumor models for drug screening were adopted to increase the predictive power of assays for success in clinical trials. Cell lines which form dense spheroids differ in physical properties, gene expression, and chemosensitivity from 2D cultures. Still, most of these MCTS models lack characteristics of complex tumor tissues and have not been validated for their adequacy to select clinically useful drugs. Patient-derived spheroids from pleural effusion or blood, namely tumorospheres of circulating tumor cells, are MCTS models most similar to patient’s tumors.

Smits, Anne; De Cock, Pieter; Vermeulen, An; Allegaert, Karel

doi: 10.1080/17425255.2019.1558205pmid: 30554542

Introduction: Legal initiatives to stimulate neonatal drug development should be accompanied by development of valid research tools. Physiologically based (PB)-pharmacokinetic (PK) modeling and simulation are established tools, accepted by regulatory authorities. Consequently, PBPK holds promise to be a strong research tool to support neonatal drug development.Area covered: The currently available PBPK models still have poor predictive performance in neonates. Using an illustrative approach on distinct PK processes of absorption, distribution, metabolism, excretion, and real-world data in neonates, we provide evidence on the need to further refine available PBPK system parameters through generation and integration of new knowledge. This necessitates cross talk between clinicians and modelers to integrate knowledge (PK datasets, system knowledge, maturational physiology) or test and refine PBPK models.Expert opinion: Besides refining these models for ‘small molecules’, PBPK model development should also be more widely applied for therapeutic proteins and to determine exposure through breastfeeding. Researchers should also be aware that PBPK modeling in combination with clinical observations can also be used to elucidate age-related changes that are almost impossible to study based on in vivo or in vitro data. This approach has been explored for hepatic biliary excretion, renal tubular activity, and central nervous system exposure.

Dubovsky, Steven L.

doi: 10.1080/17425255.2019.1558206pmid: 30558453

Introduction: Calcium channel blockers (CCBs) comprise a heterogeneous group of medications that reduce calcium influx and attenuate cellular hyperactivity. Evidence of hyperactive intracellular calcium ion signaling in multiple peripheral cells of patients with bipolar disorder, calcium antagonist actions of established mood stabilizers, and a relative dearth of treatments have prompted research into potential uses of CCBs for this common and disabling condition.Areas covered: This review provides a comprehensive overview of intracellular calcium signaling in bipolar disorder, structure and function of calcium channels, pharmacology of CCBs, evidence of efficacy of CCBs in bipolar disorder, clinical applications, and directions for future research.Expert opinion: Despite mixed evidence of efficacy, CCBs are a promising novel approach to a demonstrated cellular abnormality in both poles of bipolar disorder. Potential advantages include low potential for sedation and weight gain, and possible usefulness for pregnant and neurologically impaired patients. Further research should focus on markers of a preferential response, studies in specific bipolar subtypes, development of CCBs acting preferentially in the central nervous system and on calcium channels that are primarily involved in neuronal signaling and plasticity.

Pejčić, Ana; Janković, Slobodan M.; Opančina, Valentina; Babić, Goran; Milosavljević, Miloš

doi: 10.1080/17425255.2019.1552256pmid: 30479183

Introduction: Recipients of hematopoietic stem cell transplantation (HSCT) are exposed to numerous drugs in both pre- and post-transplantation period, which creates an opportunity for drug–drug interactions (DDIs); if clinically relevant DDIs happen, the risk of adverse treatment outcomes is increased.Areas covered: This review is focused on DDIs in recipients of HSCT that were observed and published as clinical trials, case series or case reports. Relevant publications were found by the systematic search of the following online databases: MEDLINE, SCOPUS, EBSCO, and SCINDEX.Expert opinion: The most important DDIs involve cytostatic or immunosuppressant drug on one side, and antimicrobial drugs on the other. The majority of clinically relevant interactions have pharmacokinetic character, involving drug metabolizing enzymes in the liver. Antifungal azoles inhibit metabolism of many cytostatic and immunosuppressant drugs at cytochromes and increase their plasma concentrations. Macrolide antibiotics and fluoroqunolones should be avoided in HSCT recipients, as they have much larger potential for DDIs than other antibiotic groups. HSCT recipients increasingly receive new immunomodulating drugs, and further observational studies are needed to reveal unsuspected DDIs with clinical relevance.

Apáti, Ágota; Varga, Nóra; Berecz, Tünde; Erdei, Zsuzsa; Homolya, László; Sarkadi, Balázs

doi: 10.1080/17425255.2019.1558207pmid: 30526128

Introduction: Human pluripotent stem cells (hPSCs) are capable of differentiating into all types of cells in the body and so provide suitable toxicology screening systems even for hard-to-obtain human tissues. Since hPSCs can also be generated from differentiated cells and current gene editing technologies allow targeted genome modifications, hPSCs can be applied for drug toxicity screening both in normal and disease-specific models. Targeted hPSC differentiation is still a challenge but cardiac, neuronal or liver cells, and complex cellular models are already available for practical applications.Areas covered: The authors review new gene-editing and cell-biology technologies to generate sensitive toxicity screening systems based on hPSCs. Then the authors present the use of undifferentiated hPSCs for examining embryonic toxicity and discuss drug screening possibilities in hPSC-derived models. The authors focus on the application of human cardiomyocytes, hepatocytes, and neural cultures in toxicity testing, and discuss the recent possibilities for drug screening in a ‘body-on-a-chip’ model system.Expert opinion: hPSCs and their genetically engineered derivatives provide new possibilities to investigate drug toxicity in human tissues. The key issues in this regard are still the selection and generation of proper model systems, and the interpretation of the results in understanding in vivo drug effects.

Zhou, Wenli; Graham, Karen; Lucendo-Villarin, Baltasar; Flint, Oliver; Hay, David C.; Bagnaninchi, Pierre

doi: 10.1080/17425255.2019.1558208pmid: 30572740

Background: The liver plays a central role in human drug metabolism. To model drug metabolism, the major cell type of the liver, the hepatocyte, is commonly used. Hepatocytes can be derived from human and animal sources, including pluripotent stem cells. Cell-based models have shown promise in modeling human drug exposure. The assays used in those studies are normally ‘snap-shot’ in nature, and do not provide the complete picture of human drug exposure.Research design and methods: In this study, we employ stem cell-derived hepatocytes and impedance sensing to model human drug toxicity. This impedance-based stem cell assay reports hepatotoxicity in real time after treatment with compounds provided by industry.Results: Using electric cell-substrate impedance Sensing (ECIS), we were able to accurately measure drug toxicity post-drug exposure in real time and more quickly than gold standard biochemical assays.Conclusions: ECIS is robust and non-destructive methodology capable of monitoring human drug exposure with superior performance to current gold standard ‘snapshot’ assays. We believe that the methodology presented within this article could prove valuable in the quest to better predict off-target effects of drugs in humans.