DMPK

The Drug Metabolism and Pharmacokinetics (DMPK) group at the Piramal Healthcare Research Centre plays a vital role in conducting absorption, distribution, metabolism and excretion (ADME) studies to identify candidates for clinical development. Some of the properties determined are bioavailability, pharmacokinetics, drug exposure analysis and metabolic fate. Other DMPK measurements include tissue distribution of the drug, the potential for changes in drug exposure upon repeated dosing, and excretion of the drug. The laboratory has trained scientists having extensive experience in designing and implementing in vitro, in vivo, and tissue culture based studies as well as with data analysis and interpretation. The laboratory is well equipped with HPLC’s and LC-MS/MS systems to support bioanalysis.

During the drug discovery phase, studies are carried out to assess the in vitro ADME and pharmacokinetic profile of compounds in rodents, thereby enabling selection of lead candidates from different compound series. Some studies that are carried out in this phase include:

• Stability studies (plasma, biologically simulated fluids, sub-cellular fractions, hepatocytes)
• CYP450 inhibition screening (fluorescence)
• Protein binding
• PAMPA
• Caco-2 or MDCK permeability
• Plasma kinetics (p.o., i.p., s.c., i.m., i.v., in rodents) to provide information on the absorption bioavailability and elimination of the test compound.

During the lead optimization and pre-clinical development phase, the DMPK group conducts in-depth IND-enabling studies of selected lead candidates to support IND submissions, which include:

• CYP inhibition and induction (LC-MS/MS)
• CYP phenotyping
• P-gp interaction potential
• Blood cell partitioning
• Formulation and salt screening for pharmacokinetic optimization
• Dose proportionality studies
• Metabolite identification and inter-species comparisons
• Toxicokinetics

Selected publications:

1. Subash Sandhya, Seervi Madhav, Iyer Krishna, Damre Anagha. Assessment of Rat Hepatic Cytochrome P450 Induction and Inhibition Potential of Chlorogenic Acid. Indian Journal of Pharmaceutical Education and Research, 2011, 45(1): 32-39.
2. Anand G. Patil, Russell D’Souza, Neeta Dixit, Anagha Damre. Validation of Quinidine as a Probe Substrate For The in vitro P-glycoprotein Inhibition Assay In Caco-2 Cell Monolayer. Eur J Drug Metab Pharmacokinet, 2011, 36: 115-119.
3. Anand G. Patil, Dilip Reddy, Russell D’Souza, Anagha Damre. Development and Validation of RP-HPLC-Fluorescence Method for Quantitative Determination of Quinidine, a Probe Substrate for P-glycoprotein Inhibition Assay Using Caco-2 Cell Monolayer. Biomedical Chromatography, 2010, 24(6): 620-5.
4. Patil AG, Raheja V, Damre A. Simultaneous Analysis of Intestinal Permeability Markers, Caffeine, Paracetamol and Sulfasalazine by Reverse Phase Liquid Chromatography: A Tool for the Standardization of Everted Gut Sac Model for Intestinal Permeability Assessment in Rats. Asian Journal of Pharmaceutical and Clinical Research, 2010, 3(3): 204-207.