In vitro metabolism

In vitro metabolism studies now comprise an essential component of the registration package for any new drug. Quotient Bioresearch offers a full range of both discovery and development support studies.

Modern in vitro techniques are increasingly used to support both drug discovery and development programmes. Quotient Bioresearch’s in vitro department has an experienced team of specialists providing in vitro metabolism and cell culture with complete dedicated analytical support (UPLC-MS/MS, radio-HPLC).

Studies include:

• Reaction phenotyping (enzymology) – an assessment of the enzymes responsible for metabolising a potential new drug in human liver provides integral information. Reaction phenotyping studies are often conducted using radiolabelled (14C/3H) compounds so that the full metabolic profile is known
• CYP450 inhibition – inhibition of cytochrome P450 enzymes is the major cause of clinically relevant metabolically based drug-drug interactions in vivo and therefore an assessment of the CYP450 inhibition potential for compound development
• CYP450 induction – some compounds can induce levels of drug metabolism enzymes following prolonged exposure. This can lead to decreased efficacy and possible formulation of toxic metabolites. In line with FDA recommended practices, the assessment of enzyme induction at Quotient Bioresearch is conducted using cultured human hepatocytes. After exposure the effect of the test compound can be assessed using RT-PCR
• P-gp interactions – transporter based drug-drug interactions in vivo are being increasingly reported in the scientific literature. These interactions can affect permeability and distribution of compounds. Quotient Bioresearch can assess interactions with P-gp (as both substrate and inhibitor) using Caco-2 human adenocarcinoma cell lines, as recommended by the FDA.

Other in vitro drug development studies conducted at Quotient Bioresearch include:

• Species comparison of metabolism – Provides essential metabolic information early in the development process. The rate and metabolic route(s) of metabolism for a new compound can be readily compared between species and compared with human to aid in the selection of appropriate animal models for the safety assessment of the compound in development. In particular, we are expert at isolating hepatocytes and using the freshly isolated hepatocyte model for studies of this type which is the preferred model
• Plasma protein binding – required to aid in the interpretation of pharmacokinetic and toxicokinetic information. Quotient Bioresearch can assess plasma protein binding across a range of species including human using either equilibrium dialysis, ultrafiltration or ultracentriguation.

Contact us for more information and to discuss your specific needs.