Discovery in vitro ADMET
Discovery in vitro ADMET Services
Pharmaron’s Discovery in vitro ADMET services support the characterization of DMPK properties for molecules discovered and invented, including hits, leads, and potential preclinical candidates. In vitro ADMET assays are designed to meet the specific needs of each drug discovery program. Pharmaron’s broad spectrum of in vitro ADMET services provides critical insight into a drug’s absorption, distribution, metabolism, and excretion attributes.
Capabilities
Solution Properties
- Aqueous solubility (kinetic and thermodynamic solubility)
- pKa using Sirius T3 with solid material or DMSO stock
- Distribution/partition coefficient (LogD/P)
- Protein binding/tissue binding (plasma, blood, brain, kidney, skin, lung, liver microsomes and hepatocytes)
- Blood partitioning
- Chemical stability
Drug Absorption and Transport
- Permeability evaluation (PAMPA, Caco-2, MDCK, and MDCKIIko cells transfected with different species of MDR1)
- Transporter investigation on substrate and inhibitor evaluation (P-gp, BCRP, BSEP, MRP2/3/4, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, OATP2B1, OATP1A2, MATE1, MATE2, PEPT1, NTCP, ASBT)
- Hepatic uptake using media-loss method
Metabolic Stability and Identification
- Metabolic stability in the liver, intestine, lung, and colon using subcellular fractions
- Long-term hepatocyte culture and micro liver systems for low clearance
- compounds
- After change
- Plasma/blood stability
- Metabolite profiling and identification
- GSH/CN/Methoxyamine trapping
- Reactivity and stability of Acyl Glucuronides (Ags)
Drug-drug Interactions
- Substrate evaluation & isoform ID (CYP, FMO, MAO, AO, XO, CES, ADH, ALDH, UGT, SULT, NAT1, NAT2, GST)
- Enzyme inhibition (CYP, UGT, and non-CYP enzymes) – direct inhibition and time-dependent inhibition
- KI/kinact determination
- CYP induction (human hepatocytes; HepaRG cells; PXR activation using DPX2 cells from PuraCYP)
in vitro Toxicity
- Liver toxicity package (general and mechanistic toxicity evaluation)
- Phototoxicity (3T3 NRU)
- Cardiotoxicity
- Genotoxicity