Importance of studying drug metabolism
- A drug candidate encounters a large variety of enzymes in the liver such as p450s and UGTs
- These enzymes transform the drug into active or inactive metabolites
- It is crucial to study the impact of the drug on these enzymes and the impact of the enzymes on the drug to understand the risks of DDIs
- The USFDA guidance prescribes studies on enzyme inhibition, induction and phenotyping to determine enzyme responsible for metabolism
Metabolism is the enzymatic modification of drugs and other xenobiotics, usually to increase clearance. It is a determinant of oral bioavailability, clearance, and half-life in vivo. Metabolism occurs predominantly in the liver and may also occur in the intestine or other organs.
Evaluation of an NME’s drug-drug interaction potential is an integral part of drug development and regulatory review prior to market approval. Many metabolic routes of elimination, including most of those occurring through the cytochrome P450 family of enzymes, can be inhibited or induced by concomitant drug treatment. An NME must be characterized both in terms of the enzymatic pathway(s) by which it is metabolized and in terms of the effects it may have on the metabolism of other drugs. If positive, the latter is an example of a pharmacokinetic drug-drug interaction.
Observed changes arising from metabolic drug-drug interactions can be substantial — an order of magnitude or more decrease or increase in the blood or tissue concentrations of a drug or metabolite — and can include increased formation of toxic and/or active metabolites or elevated exposure to a toxic parent compound such that toxic levels are achieved. For this reason, in vitro metabolic assessment plays a key role in early drug discovery with ExpressPlus™ screening assays as well as in advanced stages of development.
Absorption Systems offers comprehensive p450 enzyme inhibition panel testing (reversible and IC50 determination), as prescribed by the USFDA in their latest guidance.
*Note: Our tests are currently done only in liver microsomes
Certain drugs can induce the expression of CYP enzymes, increasing the possibility of DDIs. FDA recommended endpoint is the change in mRNA expression level of the target gene.
What is the importance of CYP phenotyping?
Drugs that exhibit a propensity for a particular enzymatic metabolism pathway can increase the likelihood of toxicity through DDIs