Non-Clinical ADME: Mass Balance, Tissue Distribution and Metabolism
According to Guideline ICH M3, the non-clinical safety assessment of a new drug – including all major metabolites – needs to be completed prior to the initiation of Phase III trials. Understanding the role of metabolites in the overall pharmacology and safety profile of a new drug is an essential part of this.
Following exploratory metabolism studies in vitro in microsomes, hepatocytes, and in some cases in vivo, the definitive metabolite pathway is typically investigated with radiolabeled drug. This allows a mass balance and thus a detailed picture of absorption, distribution, metabolism and excretion from studies in vitro, in animals or in humans.
We offer a complete range of techniques to help you plan and execute your metabolism program.
- Planning and consulting of the radioactive study program (labeling position and isotope, quantities needed, specific activity, radiochemical purity etc.)
- Radio-synthesis of 3H or 14C-labelled compounds
- In vitro metabolism studies in microsomes or hepatocytes with labelled drug
- Reactive metabolite and intermediate trapping (GSH)
- Other absorption and transporter studies, e.g. hepatocyte uptake, plasma protein binding.
- Mass balance or ADME studies with radiolabeled test item in rodents, dogs and monkeys.
- Determination of excretion kinetics in urine, feces, expired air, and bile
- Determination of residual radioactivity in the animals
- Pharmacokinetics of parent and total radioactivity (= total drug mass)
- Extraction, profiling, and identification of metabolites in plasma, urine, feces, bile, and tissues
- Tissue distribution by quantitative tissue dissection (QTD), or quantitative whole body autoradiography (QWBA)
- Isolation, purification, identification of metabolites by LC-accurate mass, and 1D and 2D NMR
- Dosimetry calculations prior to human mass balance studies
- Liquid scintillation counters, TopCount, beta-counters
- Thermo Scientific Q ExactiveTM Plus LTQ OrbiTrap (cold studies)
- Waters Xevo G2 Q-TOF (cold studies)
- LTQ Orbitrap (cold and hot studies)
- API 4000 Q-Trap (cold and hot studies)
- Q ExactiveTM Plus LTQ OrbiTrap, 6500 Q-trap (hot and cold studies