Drug Metabolism and Pharmacokinetics

DMPK

Overview

  • Complete ADME/PK technology platform in supporting drug discovery and development
  • AAALAC accredited animal facilities
  • State-of-the-art instrumentations
  • Best animal surgery teams in China
  • GLP-like working environment

In vitro ADME

Early ADME

  • Physicochemical properties: kinetic and thermodynamic solubility, logD, pKa
  • Permeability: PAMPA, Caco-2, MDR1-MDCK
  • Solution-phase stability
  • Metabolic stability: microsomes, hepatocytes, S9, recombinant CYPs, plasma from multiple species
  • CYP inhibition: 5-in-1 cocktail or discrete substrates, %inhibition or IC50 determinations
  • CYP induction: PXR-luciferase reporter gene assay for CYP3A
  • Protein binding: plasma, brain or tissue homogenate from multiple species
  • Blood-plasma partition: multiple species

Definitive ADME

  • CYP inhibition: 8 CYP isoforms, multiple substrates for CYP3A4, IC50, Ki, Kinact, reversible/irreversible inhibitor identification, time-dependent inhibition
  • CYP induction: human cryopreserved hepatocytes, enzyme activity and/or mRNA determinations
  • CYP phenotyping: multiple species
  • Aldehyde oxidase (AO): identification of AO involvement in drug metabolism
  • Protein binding: equilibrium dialysis, ultrafiltration, and ultracentrifugation
  • Transporters: MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2 and BCRP (currently undergoing validation)

In vivo PK

Multiple Animal Species

  • Mouse, rat, hamster, guinea pig, rabbit, mini pig, beagle, cynomolgus monkey

All Administration Routes

  • PO, IV, SC, SL, IP, IM, topical administration

All Biological Matrices

  • Whole blood, plasma, urine, feces, bile, CSF, lymph fluid, tissue homogenate

Myriad Surgery Models and Techniques

  • Cisterna magna cannulation
  • Bile duct cannulation
  • Portal vein cannulation
  • Thoracic duct cannulation
  • Intraduodenal administration

Mass Balance

  • Biliary versus urinary excretion rates
  • Tissue distribution

Experienced Veterinarians and Strictly Executed Animal Welfare Policies

Metabolite ID

In Vitro

  • Hepatocytes, S9 fractions, microsomes

In Vivo

  • Plasma, urine, bile, feces

Reactive Metabolite and Intermediate Trapping

  • GSH, CN

Instruments

  • API 4000 Q-TRAP LC-MS/MS systems coupled with HPLC and UPLC
  • Waters Xevo G2 Q-TOF UPLC-MS/MS system
  • PE Model 307 sample oxidizer
  • PE Tri-Carb 2900 TR liquid scintillation analyzer
  • PE Radiomatic 610 TR flow scintillation analyzer
  • PE Microbeta Trilux 1450 reader

Large molecule

  • Instrumentation
    • Microplate readers including SpectraMax M2e, MSD SECTOR imager 6000 and EnVision 2103
    • Microplate Washer, Bio-Tek ELx405R
    • PCR instruments including ABI7500, ABI7900 and ABI9700
    • Others: FACS Calibur flow cytometer, BioRobot Universal and ChemiDoc XRS System
  • Assay Developed or Validated
    • Methodologies of more than 30 analytes (protein, modified protein, peptide, antibody, anti-drug antibody, hormone, specific gene, etc.) were developed, including ELISA, MSD, RT-PCR, flowcytometry and western blot.

Metabolite Identification & Mass Balance

  • Metabolite identification and profiling in in vitro systems (hepatoctes, S9 fraction, microsomes, etc.)
  • Metabolite identification and profiling in in vivo systems (plasma, urine, bile, feces, etc.)
  • Reactive metabolite and intermediate trapping (GSH, CN)
  • Mass balance in rodents
  • Biliary versus urinary excretion rate and pathways
  • Tissue distribution
  • Major metabolite determination for safety testing
  • Bulk metabolite isolation and purification for definite structural elucidation
  • Instrument
    • API 4000 Q-TRAP LC-MS/MS systems coupled with HPLC and UPLC
    • Waters Xevo G2 Q-TOF UPLC-MS/MS system
    • PE Model 307 sample oxidizer
    • PE Tri-Carb 2900 TR liquid scintillation analyzer
    • PE Radiomatic 610 TR flow scintillation analyzer
    • PE Microbeta Trilux 1450 reader

IND Package Service

  • Investigational New Drug (IND) filing for the CFDA and FDA