Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET)
- Experienced team with holistic Drug Discovery experience to delineate the druggability issues early in the discovery programs
- Capability to develop fit for purpose ADME and in vivo pharmacokinetic studies to scientifically support client requirements
- Expertise in developing quantitative LC-MS/MS methods for complex biomarkers in bio-fluids and tissue samples
Aqueous Solubility
- Kinetic
- Thermodynamic
- Biorelevant media (FaSSIF and FeSSIF)
Lipophilicity (Log D and Log P)
- Octanol-water/phosphate buffer partitioning
Stability
- Simulated Gastro Intestinal fluids (SGF, SIF)
- Biorelevant media (FaSSIF and FeSSIF)
- Aqueous buffers at different pH
- Plasma and blood stability
- Dosing formulation
Pre-formulation
- Topical formulations
- Creams/ointment/gel
- Metabolic stability/ intrinsic clearance
- Liver and intestinal microsomes
- S9 fractions
- Hepatocytes
- Direct glucuronidation in liver microsomes using UDPGA
- Reactive metabolites identification using GSH trapping assay
- Metabolite finger printing analysis in liver microsomes
- Metabolism based drug-drug Interactions
- CYP inhibition (single point, IC50) using human liver microsomes (HLM)
- Time dependent CYP inhibition in HLM (IC50 shift, Ki and Kinact)
- CYP reaction phenotyping (purified rCYPs/microsomes)
- CYP induction in plateable human hepatocytes
- 1A2, 2B6 and 3A4 enzyme activity
- mRNA analysis
- Cytotoxicity
-
- Intrinsic permeability-PAMPA
- Mono and bi-directional transport: CaCo-2 and MDCK cells
- In presence and absence of efflux drug transport inhibitors (P-gp, BCRP and MRP)
-
- Definitive plasma protein binding
- Microsomal protein binding
- Brain tissue binding
- Blood-to-plasma concentration ratio (RBC partitioning)
Cytotoxicity
-
- HepG2 cell line
- Hepatocytes
Rodents and non-rodents
-
- Rats (multiple strains) : healthy and disease models
- Mouse (multiple strains) : healthy and disease models
- Beagle dogs: preferred vendor
- Various routes of administration
- Single, multiple and cassette dosing
- Dose proportionality studies
- Routes ( urine and feces) of excretion
Tissue exposure kinetics in rodents
-
- Exposure kinetics in skin, plasma and other organs (liver, spleen, thymus etc., ) of choice
- Partitioning into brain (frontal cortex, striatum, hippocampus and cerebellum)
- Cerebrospinal fluid collection
- Partitioning into ocular and related parts (vitreous humor, retina and sclera)-rat
Dermal pharmacokinetics in rodents
-
- Healthy and disease models
- Assistance in selection of right animal model
Mechanistic pharmacokinetics models in rodents
- Chronic bile duct cannulated rats
- Chronic portal vein cannulated Rats
- ABT treated mouse and rat pharmacokinetics to delineate involvement of CYP enzymes
PK-PD, modelling and simulations (WinNonlin approach)
-
- PK-PD/efficacy correlation – exposure or Cmax based
- PK modelling and simulations (fit for purpose)
- Scaling of preclinical PK to predict human PK – allometry approach
- Prediction of starting and efficacious human doses
High-throughput bio-analysis
- Fit for purpose methods
- 96 well plate analysis
- Cassette analysis
Quantitation of biomarkers
- Quantitative determination for biomarker modulations in plasma and tissues
- Expertise in quantitation of neurotransmitters and endogenous compounds
- Expertise in chemical derivatisation techniques to improve chromatographic behaviour and enhance ionization efficiencies
Biotransformation
- Soft spot analysis to drive structure-activity relationship (SAR) and facilitate in design of metabolically stable analogues
- Metabolite finger printing analysis
- Reactive metabolite screening (glutathione conjugation)
Trouble shooting expertise / assessment of matrix effects
- Evaluation of formulation excipients
- Evaluation of extraction methods
- Protein precipitation
- Liquid-liquid extraction
- Solid phase extraction
- Evaluation of ionization polarity (positive/negative)
- Evaluation of ionization source (ESI/APCI) technique of analysis (LC-MS/HPLC)
Miscellaneous
LC-MS/MS based in vitro primary and secondary activity screening
- Biological assays
- Complex lipid based assays