December 19, 2017
On behalf of all of our employees, we would like to sincerely thank you for working with us in 2017. This year has been our best so far, which is underlined by the items in this newsletter. We wish you a pleasant Christmas break and look forward to working with you again in 2018!
In this issue:
1. New Products and Services Launched
2. First announcement of the Meet the Experts Conference in Budapest, 2018
3. The new Transporter Book – out now!
4. Our peer-reviewed publications in 2017
6. The new FDA draft guidance on in vitro DDI studies
This year we have developed a range of new products and services. In our previous newsletter, you could read about the launches in the first half of the year. In addition, we recently published a science letter on a new set of tools to study species differences in MDR1- and BCRP- mediated transporter activity. The LLC-PK1 and MDCKII cell lines expressing rat, mouse and human MDR1 and BCRP are particularly useful when predicting brain penetration in various species. Continuing along this path we developed an MDCKII cell line expressing cynomolgous monkey Bcrp as well. A cell line for cynomolgous monkey Mdr1 will follow soon.
Species differences are of interest in transport of bile salt and liver toxicity as well. In addition to our existing portfolio of BSEP membranes we have now developed a set of new tools to study bile salt transport in depth in various species:
HEK293-ratAsbt cell line
HEK293-rOstalpha/beta cell line
HEK293-OSTalpha/beta cell line
HEK293-ASBT cell line
cynomolgous monkey-Bsep-HEK293 vesicles
All of these cell lines and vesicles will be launched in the first couple of weeks of 2018. Closely related to these is our planned launch of in vitro hepatotoxicity assays on HepatoPac ®. We will announce this in a separate newsletter in Q1 of 2018.
Contact us through our website or through your local Account Manager to find out more about these newly developed models!
Mark your calendar: April 25-28, 2018 - Budapest
We are happy to announce that the Meet the Experts conference series returns to where it all started from: Budapest! This will be the 8th Meet the Experts Transporter conference and the 3rd meeting in Budapest. Since 2014 hundreds of people have participated in these events in Budapest, Boston, San-Francisco and Tokyo, enjoying lectures from the best transporter scientists around the world.
The 2018 meeting in Budapest will kick-off with technical lectures and a lab demonstration on transporter assays on Wednesday the 25th of April, followed by two days of conference on Thursday 26th and 27th of April.
Registration for the meeting will open early January, a separate newsletter on this will follow. Stay tuned!
The brand new, 3rd edition of our Transporter Book – Experts Only – is out now! Since its first publication close to 3000 copies of this book have been distributed and it is becoming The Transporter Book for Transporter scientists. Why? Because it’s a comprehensive reference work of almost 300 pages including:
- references to 1585 research papers on transporters
- detailed information on the function, localization and clinical relevance of more than 50 transporters
- an entirely new chapter on when you should study transporters by Dr. Ayman El-Kattan (Pfizer)
- descriptions of a wide range of methods to study transporters
- regulatory requirements, pharmacological barriers and much more
Contact your Sales representative or register on our website to receive a copy, free of charge - because at SOLVO we think Transporters are important.
3T – transport, toxicity, technology – contribution of Solvo scientists to scientific exploration in year 2017
Influx and efflux transporters play different roles. Tissues with barrier function working against a concentration gradient are dominated by apically expressed efflux transporters. One of the classical examples is P-glycoprotein (P-gp) expressed in microvascular brain endothelial cells. It protects brain from xenobiotics such as seliciclib a CDK inhibitor anti-cancer agent. Using in vitro and in vivo techniques we were able to show that P-gp is behind the limited brain penetration of seliciclib in adult mice (Erdo 2017 Brain Res Bull).
Influx transporters play a decisive role in cell types/tissues with secretory function such as the hepatocytes of liver. This holds for homeostasis of physiological substrates. Homeostasis of bile salts/acids is supported by a complex transport pathway. Sodium-taurocholate co-transporting polypeptide (NTCP) is a key influx transporter responsible for uptake of bile salts. The substrate profile of NTCP, however, has not been thoroughly investigated. We have shown that NTCP has a preference for amidated bile salts and it transports glycochenodeoxycholate (GCDC), the most abundant monovalent bile salt in humans with particular efficiency (Jani 2017 Toxicol In Vitro).
Carnitine is also an important physiological substrate as it is of low permeability and it needs to get into all cells as carnitine plays a key role in intracellular fatty acid transport. Our recent species specificity study has shown that the human and rat orthologs of the main cation/carnitine transporter organic cataion/carnitine transporter novel 2 (OCTN2/Octn2) have overlapping but somewhat different substrate specificity when expressed on the same cellular background (Szabo 2017 DMPK).
The herb of Ambrosia artemisiifolia is becoming a popular medicinal plant. Yet, its toxicity has not been carefully characterized. Thus, in collaboration with scientists at the University of Szeged an in vivo study pointed out some potential toxicity of A. artemisiifolia in rats. This study was supported by our Bioanalytical group, headed by Dr. Zoltán Tímár. (Kiss 2017 PloS One).
Proteomics is becoming a key method to aid in vitro – in vivo extrapolation (IVIVE). It helped the prediction of in vivo hepatobiliary clearance of rosuvastatin from sandwich cultured rat hepatocyte data and transporter overexpressing cell line data in a collaborative effort of the laboratory of Professor Jash Unadkat at the University of Washington, F.Hoffman-La Roche Ltd. (Basel, Switzerland) and SOLVO (Ishida 2017 DMD). A research study led by U Washington scientists paved the way to effective isolation of plasma membrane proteins via biotinylation and neutravidin binding (Kumar 2017 AAPS J). This novel method will improve proteomic quantitation of the plasma membrane fraction of membrane proteins.
A multi institutional collaboration led by Semmelweis University scientists generated an immortalized adipose tissue derived mesenchymal stem-cell line overexpressing SS18-SSX, a chimeric protein unique to synovial sarcoma (Mihaly 2017 Cancer Genet). This novel reagent will be of great help to address the question if SS18-SSX1 is sufficient to trigger formation of synovial sarcoma. This project was conceived and partly executed by our Senior Scientist, Dr. Péter Tátrai.
To listen to our previous webinars, visit our website.
On October 25th, Dr. Mary Paine from Washington State University presented on the emerging topic of Natural Product-Drug Interactions, introducing case studies from the NAPDI center. She presented various novel in vitro Natural Product-Drug interactions due to inhibition of either drug metabolizing enzymes of transporters. As this is work in progress and partly unpublished the webinar is not available for download.
On the 5th of December, Dr. Nicole A. Kratochwil – Senior research scientist at F. Hoffman-La Roche, Basel - gave an excellent talk in a webinar organized by SOLVO and Ascendance titled: “ In Vitro PK Studies in Long-Term Liver Models to Assess DDI Potentials and Major Clearance Pathways of Drug Candidates ”. The interest in this topic was well reflected by the high number of registrations and attendees, as well as the many questions asked and answered in a Q&A session following the presentation. In the webinar, Nicole presented her experience with long-term liver models and the clear benefits such models have over more conventional techniques. Applications discussed were that of metabolic clearance, MetID, as well as transporter studies.
For learning more about HepatoPac® and the applications, please visit our website where previous webinars explained the model, or contact your SOLVO account manager.
In October FDA released an update to their draft guidance on drug interactions. In a departure from the previous guidance document, the new publication is split into two separate documents: one outlining clinical drug interaction studies, and one covering in vitro metabolism and transporter-mediated drug-drug interaction studies.
The new draft guidance on in vitro transporter-mediated drug interactions does contain some significant changes to the previous version, reflecting the progress made by the field towards a greater understanding and appreciation of the role that drug transporters play in drug disposition. One key change is the inclusion of Multidrug and Toxin Extrusion proteins, MATE1 and MATE2-K. These poly specific transporters are expressed in the kidney, with MATE1 additionally found in the liver, and mediate the elimination of organic cations. They are now recommended for inhibition studies, and also for substrate assessment for investigational drugs with ≥ 25% active renal secretion. Other changes to the draft guidance include modifications to the cutoffs for triggering clinical drug interaction studies, inclusion of time-dependent inhibition for OATPs, suggestions on in-house calibration of in vitro transporter assay systems, and a greater emphasis on in vitro study design, with additional recommendations covering solubility, non-specific binding, choice and concentration of probe substrate, and solvent effects.
We have complied a summary of take-home messages from the latest FDA draft guidance here. You can also contact us today to schedule a discussion with our scientific team and ensure that your in vitro transporter studies are fully compliant with the latest regulatory guidance from FDA, EMA and PMDA.