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Optivia Transporter Assay Services
Uptake of a representative substrate in MDCK-II cells expressing a
single human transporter is shown in open bars. Uptake in matched
mock control cells (black bars) directly accounts for passive diffusion
and transport from endogenous MDCK-II transporters allowing for the
direct determination of uptake mediated
exclusively by the
expressed human transporter.
Representative data for OCT1 inhibition screening. Metformin
uptake in MDCK-II cells expressing the human OCT1 transporter
is monitored in the presence of vehicle and known inhibitors
quinidine, MPP+ and cimetidine (open bars). OCT1 substrates
and non-competitive inhibitors are expected to reduce
metoformin uptake. Direct transport assays also available.
Metformin is used as a marker substrate to assess OCT2 inhibition by
MPP+.
Inititial metformin concentration is held constant and
challenged with increasing concentrations of MPP+ allowing for IC50
determination.
Cellular accumulation of metformin is measured in MDCK-II cells
expressing human OCT2. Uptake is also monitored in matched
control cells without human OCT2 (mock) to account for diffusion
and endogenous MDCK-II transport allowing for Km and Vmax
determination for human OCT2 mediated uptake.
Optivia Biotechnology Inc.
115 Constitution Drive, Menlo Park #7, CA 94025, USA
Toll Free: 888-OPTIVIA (888-678-4842) Tel: 650-324-3177 Fax: 650-324-1855
Email: [email protected] Web: www.optiviabio.com
The Optivia Advantage
Optivia transporter assays are designed with human biology in mind.
We strive to provide in vitro assays most likely to predict results in humans. Our assays are used to
discover drugs with improved bioavailability, tissue selectivity and fewer drug-drug interactions.
Human
Transporters
Mammalian
Cells
Optivia assays use human transporters.
Significant interspecies differences in transporter affinities have been shown.1
Optivia assays are performed in polarized mammalian cell monolayers.
Mammalian cells are a better overall model for human biology than insect vesicles or frog
oocytes. Non-mammalian systems have been shown to produce low molecular weight, underglycosylated versions of human transporter proteins. Under-glycosylated P-gp, for instance, is
less stable and has been shown to have lower function.2
Functional
Efflux and
Uptake Assays
Optivia assays always measure functional cellular efflux or uptake.
Improved
Bioavailability
and PK
Optivia assays enable you to optimize human bioavailability and PK.
Tissue
Selectivity and
Targeted Tissue
Delivery
Drug-Drug
Interaction
Assessment
Continuing
Innovation
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Functional flux transporter assays have been shown to have fewer false negatives, fewer false
positives and better correlation with human clinical results than receptor binding, ATP-ase and
calcein inhibition assays.3
Uptake and efflux transporters mediating absorption and elimination are expressed in the GI
tract, kidney and liver and can greatly affect bioavailability and pharmacokinetic profiles4.
Optivia assays enable you discover drugs with tissue selectivity.
Drugs must reach target tissues needed for efficacy and avoid those where they may cause
undesirable or unsafe effects. Many transporters are expressed only in specific tissues5 allowing
for strategies to discover tissue selective drugs6.
Optivia assays enable you to avoid transporter mediated drug-drug interactions (DDI).
The FDA identified 25 important human transporters in the draft DDI guidance7 and is expected
to release specific decision trees for a number of these in 2009 or 2010.
Optivia performs custom model development including novel transporters, siRNA knockdown of
endogenous transporters in Caco-2 cells, dual transporter systems, transporter polymorphisms
and more.
Suzuyama et al. “Species differences of inhibitory effects on P-glycoprotein-mediated drug transport”, J Pharm Sci. 2007 Jun;96(6):1609-18.
Zhang et al. “Regulation of the Stability of P-Glycoprotein by Ubiquitination”, Mol Pharmacol 2004 66(3) 395-403.
Polli et al. “Rational Use of in Vitro P-glycoprotein Assays in Drug Discovery”, J Pharmacol Exp Ther. 2001 Nov;299(2):620-8.
Cundy et al. “XP13512, A Novel Gabapentin Prodrug: I. Design, Synthesis, Enzymatic Conversion to Gabapentin, and Transport by Intestinal Solute Transporters “, JPET 2004
311(1), 315-323.
Sugiyama et al. “Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport”, Pharm Res. 2005 Oct;22(10):1559-77.
Erion et al. “Targeting thyroid hormone receptor- agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index”, PNAS 2007 104(39), 15490-15495.
US FDA, “Guidance for Industry Drug Interaction Studies —Study Design, Data Analysis, and Implications for Dosing and Labeling (Draft), Sept. 2006.
Optivia Biotechnology Inc.
115 Constitution Drive, Menlo Park #7, CA 94025, USA
Toll Free: 888-OPTIVIA (888-678-4842) Tel: 650-324-3177 Fax: 650-324-1855
Email: [email protected] Web: www.optiviabio.com