ADME-Tox Studies services brochure
The following is a summary of the comprehensive ADME-Tox drug development services that Celsis Development Services offers. These studies provide comprehensive understanding of the metabolism, toxicity and absorption of drug molecules.
CYP Inhibition
The key enzymes of drug metabolism are the isoforms of the cytochrome P450 (CYP) family. Human liver microsomes or cryopreserved human hepatocytes and CYP isoform-specific substrates are used to evaluate the potential of an existing or new molecular entity (NME) to inhibit CYP-dependent enzyme activities. IC50 values are calculated where applicable and follow-up studies may be conducted to determine inhibition constants (Ki).
CYP Induction
Human hepatocytes (freshly isolated or plateable cryopreserved) and CYP isoform-specific substrates are used to evaluate the potential of an existing or NME to induce CYP-dependent enzyme activities. The induction of CYP expression can also be evaluated using real-time polymerase chain reaction (RT-PCR).
Ex-Vivo Induction
Microsomes prepared from liver tissue of animals treated with an existing or NME in vivo are used to evaluate dose-dependent changes in protein content, total CYP levels and specific CYP-dependent enzyme activities.
Metabolic Stability
Cryopreserved human hepatocytes or human liver microsomes are used to evaluate the metabolic rate for an existing or NME. Hepatic intrinsic clearance values or half-life values are calculated where applicable.
Metabolite Profiling and Identification
Hepatocytes from human and various animal species are used to generate a metabolite profile for an existing or NME. Information regarding the metabolic transformation and additional structural elucidation can be provided. Human metabolite profiles can be compared with animal metabolite profiles to aid in selecting the species most suitable for toxicology and ADME studies.
CYP Pathway Identification
Recombinant CYPs or human liver microsomes with CYP isoform-specific inhibitors are used to determine which CYP isoforms are responsible for the metabolism of an existing or NME.
Cytotoxicity
Human hepatocytes in suspensions or cultures are used to evaluate an existing or NME-related toxicity or apoptosis. TD50 values are calculated where possible.
Intestinal Absorption
Caco-2 cells are used as a model to study the absorption of an existing or NME across the intestinal epithelium. The potential interaction of the drug molecule with transporters, such as P-glycoprotein, can also be studied.
Dermal Absorption and Dermal Metabolism
Split-thickness human skin is used in a flow-through diffusion cell system to study percutaneous absorption of an existing or NME, as well as its disposition within various skin layers. Metabolism of molecular entities can also be evaluated using freshly excised skin, skin cytosol or microsomes and human keratinocytes.
Protein Binding
Equilibrium dialysis and ultrafiltration techniques are used to understand the binding of the existing or NME to plasma proteins and to quantify the amount of free drug. Sophisticated analytical instruments are employed by experienced metabolism scientists to facilitate structure modifications and to help design appropriate toxicokinetic and pharmacokinetic studies.
