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 etc
  • Permeability: PAMPA, Caco-2, MDR1-MDCK
  • Metabolic stability: microsomes, hepatocytes, S9, plasma, and blood from multiple species; recombinant CYPs; simulated gastric and intestinal fluids
  • 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: chemical inhibitors and/or recombinant CYPs
  • Aldehyde oxidase (AO): identification of AO involvement in drug metabolism
  • Protein binding: different methods such as equilibrium dialysis, untrafiltration, and ultracentrifugation, cold and 14C-labelled compounds
  • Permeability: Caco-2, MDR1-MDCK, cold and 14C-labelled compounds
  • Transporters: BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and OCT2 substrate identification and inhibition, cold and 14C-labelled compounds

In vivo PK

  • Multiple animal species (mouse, rat, hamster, guinea pig, rabbit, mini pig, dog and monkey)
  • All administration routes (PO, IV, SC, SL, IP, IM, topical administration, etc.)
  • All biological matrices (blood, plasma, urine, feces, bile, CSF, lymph fluid and tissues)
  • All kinds of surgery models (Cisterna magana cannulation, bile duct cannulation, portal vein cannulation, intra-duodenal delivery, thoracic duct cannulation, intra-ventricle delivery, in situ liver perfusion, and in situ intestine perfusion, etc.)
  • Experienced veterinarians and strictly executed animal welfare polices

Bioanalysis

Small molecule

  • Rapid turn-around quantitative analysis
    • Fast and sensitive LC-MS/MS systems including UPLCs , LEAP CTC Analytics PAL and Gilson coupled with API 5500, 4000, 3000 Triple Quads, and 4000 Q-Trap
    • Automated sample handling systems including Beckman Biomek FX, Eppendorf epMotion, and Apricot Designs IPB-96-500
    • Dedicated instrument maintenance team
  • High Data Quality
    • Successfully passed data validation from most top 20 pharmaceutical companies
    • Project-dedicated QC team
    • Well-established bioanalytical training system
  • Strong Capability on Challenging Bioanalysis
    • Polar analyte, small molecular biomarker, enzymatic non-stable analyte, peptide drug quantitation
    • Prodrug-drug-metabolite (i.e. Nucleoside triphosphate), chiral analyte separation and quantitation
    • Dry blood spot (DBS) quantitation
  • High Throughput Screening for ADME (2600 samples per day per LC-MS/MS)

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 SFDA or FDA