Medicinal Chemistry Services
- Metabolic Stability
- CYP Interaction
- Permeability & Transporters
- Physicochemical Properties
- Protein Binding
Discovery PK and Toxicology
At Frontage, we have extensive experience in drug transporter research. We offer comprehensive transporter services to support projects from discovery to development including screening, and full characterization of both uptake and efflux transporters.
Hepatic transporters help facilitate bile production by exporting bile salts and phosphatidylcholine (PC) from hepatocytes. In humans, inhibition of bile salt export protein (BSEP, ABCB11) and/or multidrug resistance protein 3 (MDR3, ABCB4) transporters can lead to potentially serious DILI.
Drug candidates can be screened for inhibition of BSEP and/or MDR3 to assess DILI risk. BSEPcyte® and MDR3cyte® assays detect the potential of drug candidates to inhibit BSEP and MDR3, respectively. Both approaches utilize a hepatocyte suspension platform, which offers several advantages over other in vitro techniques:
BSEP is responsible for the biliary secretion of bile salts, which is the primary driving force for enterohepatic recirculation of bile salts and maintaining bile flow. Inhibition of BSEP by a diverse range of drugs or therapeutic agents is associated with DILI. At Frontage, we have developed a novel assay, BSEPcyte®, that accurately measures BSEP inhibition.
MDR3 is primarily expressed in the canalicular membrane of hepatocytes and is responsible for the biliary secretion of PC. PC combined with bile salts forms mixed micelles in bile that solubilize cholesterol and prevent highly concentrated bile salts from damaging biliary canaliculi epithelial cells. Mutations in the human MDR3 gene are associated with progressive familial intrahepatic cholestasis, primary biliary cirrhosis, cholangiocarcinoma, and DILI. The novel MDR3cyte® assay platform at Frontage can provide an accurate assessment of MDR3 inhibition by drug candidates and new chemical entities.