drug interactions

directory of Chem Help ASAP videos: https://www.chemhelpasap.com/youtube/ During lead optimization, the toxicity of the lead is always a concern, and one indication of toxicity is when a drug interacts with another drug. So this is called a drug interaction. Sometimes these are called drug-drug interactions, and you'll even see people call these DDIs for drug-drug interactions. Drug interactions can arise for many reasons. Perhaps the most common is related to metabolism. Most drugs are metabolized by the CYP enzymes, the cytochrome P450s. Drugs can also inhibit these enzymes. Of the approximately 50 different CYP enzymes, only a few are involved in drug metabolism. The most important (by far) is 3A4, and it metabolizes about half of all small molecule drugs. Other important ones include 2C9 and 2D6, and there are a handful of others. Let's see how these drug interactions affect drug behavior. So assume that drug A is metabolized by CYP2D6. Furthermore drug B inhibits 2D6. The two Cp-time curves are both for drug A. The blue curve is drug A alone, and the red curve is drug A with drug B. So to be clear, the red curve is drug A also, but it's drug A in the presence of drug B. Notice that with B around, A has a very different curve. And this is a problem! So let's think about drug A, and let's assume it operates within its therapeutic window. Well, with B present, we are now inhibiting the hepatic clearance of drug A, and if hepatic clearance goes down, then half-life for drug A will increase. and we will see the AUC for drug A increase. So therefore, the exposure of drug A increases and Cp for drug A now exceeds the therapeutic window. We're going to see increased adverse drug reactions of A if the patient is taking both A and B together. So these are... This is a real safety problem. Metabolic drug reactions can be anticipated because CYP isoform inhibition can be tested with assays involving extracts of liver cells. During lead optimization, CYP inhibition of new leads will be regularly checked. Inhibition of CYP3A4 would raise a huge red flag because CYP3A4 metabolizes so many different drugs. If a lead is an inhibitor of 3A4, then the med chem team will either try to modify the lead to minimize inhibition or switch to a completely different lead from the hits identified by the screening program.