Transporter Webinar Series Continue
September 24, 2020
We are delighted to announce the next Webinars in the SOLVO Biotechnology Meet the Experts Transporter Webinar Series:
Vitamin Transport in Clinical Toxicities: Folate and Neural Tube Birth Defects
29 September, 2020
Presenter: Maciej J. Zamek-Gliszczynski. PhD, Senior Fellow and Director, DMPK, GlaxoSmithKline
Time: 8 am (PDT), 11 am (EDT), 4 pm (GMT), 5 pm (CET)
Summary of the presentation: Preliminary analysis of ongoing birth surveillance study identified evidence of potential increased risk for neural-tube defects (NTDs) in newborns associated with exposure to dolutegravir at time of conception (Zash et al. 2008). Folate deficiency is a common cause of NTDs. Folate’s hydrophilic nature results in negligible passive membrane permeability and transport-mediated disposition. Dolutegravir and other HIV integrase inhibitor drugs were evaluated for inhibition of folate transport pathways: proton-coupled folate transporter (PCFT), reduced folate carrier (RFC), and folate receptor α (FRα)-mediated endocytosis (Zamek-Gliszczynski et al., 2019). Inhibition of folate transport was extrapolated to clinic using established approaches for transporters in intestine, distribution tissues, basolateral and apical membranes of renal proximal tubules (2017 FDA Guidance). The present studies showed that dolutegravir is not a clinical inhibitor of folate transport pathways, and it is not predicted to elicit clinical decreases in maternal and fetal folate levels. Furthermore, clinically-relevant HIV integrase inhibitor drug class effect on folate transport pathways was not observed. Consistent with these findings, upon more complete enrollment of the birth surveillance study, dolutegravir no longer exhibited increased risk for NTDs (Zash et al., 2020).
Registration here!
Drug Transporters in Human Stem Cells
8 October, 2020
Presenter: Balázs Sarkadi PhD, MD, Head of Research Group, Research Centre for Natural Sciences, Budapest, Hungary
Time: 8 am (PDT), 11 am (EDT), 4 pm (GMT), 5 pm (CET)
Summary of the presentation: Human stem cells and their tissue derivatives are increasingly applied in advanced medical therapies, as well as in in vitro pharmacological and toxicological studies. Drug development, based on the application of human stem cell preparations may provide more appropriate and less expensive screening systems than animal models, thus are proposed to at least partially replace the use of experimental animals. In this regard, specific human cellular disease models, corresponding to alterations in developmental, metabolic, or signaling pathways, are especially useful in pharmacological studies. Genetically engineered stem cells, expressing fluorescence- or luminescence-based reporter constructs, greatly promote high-content or high-throughput drug screening. The expression of drug transporters is highly variable in the different stem cell preparations, and human pluripotent stem cells practically do not express any of the transporters involved in drug metabolism. However, directed and efficient stem cell differentiation allows the production of specific cardiac, neural, liver, or other cell types, resembling their in vivo human counterparts and allowing a direct examination of the function or drug-sensitivity of selected human drug transporters. In this presentation, examples of human pluripotent stem-cell derived cell preparations, also containing fluorescent reporter constructs to facilitate drug screening, are demonstrated.
Registration here!
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