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phase 1 drug metabolism

directory of Chem Help ASAP videos: https://www.chemhelpasap.com/youtube/ Metabolic reactions are extremely important in drug discovery. We'll normally break these up into two types. There are phase 1 metabolic reactions, which include oxidations, normally performed by the cytochrome P450 enzymes. There are reductions and hydrolytic reactions. There are also phase 2 reactions, and those will be covered in the next video. Sometimes people talk about phase 3, but that's more about drug transport rather than metabolism. Okay, Let's race through a number of reactions. On the top... These are all oxidation reactions. The first involves a molecule losartan. Losartan gets oxidized. Notice that it has this primary alcohol, and that alcohol is oxidized to a carboxylic acid. Carbamazepine, the middle structure... Carbamazepine has an alkene. Alkenes are potential sites for oxidation. In this case, we form an epoxide off of that alkene. And then finally, in the bottom structure, we have dapsone. Sometimes oxidations occur on atoms (to add oxygens) like nitrogens and even sulfur. So here we have an NH2 and we get a hydroxylamine out as a product. All these reactions, notice in the middle, are performed by different isoforms of the cytochrome P450s. Here are some dealkylation reactions. Technically these are oxidations, but we're losing parts of the molecule -- carbon parts of the molecule. So the first reaction starts with codeine. There's an OCH3 group. Notice that the OCH3 is gone in the product. That is an oxidative process on carbon, and as a result, you break the C-O bond. Fluoxetine has an NCH3, and in the product that NCH3 is gone. Again, since these are oxidations, they are mediated by our cytochrome P450 enzymes. After seeing two slides of oxidations, you might think all phase 1 reactions are oxidations. They're not. You can also get reductions. So our first structure, in the upper left, this is chloramphenicol. It has a nitro group, and that nitro group can be reduced to an NH2 group. In the second line, nabumetone, it contains a ketone, and this ketone can be reduced to the corresponding alcohol. These are not typically performed by the cytochrome P450s, but they're just a whole family of reducing enzymes found in the body that can perform these types of reactions. Phase 1 reactions include oxidations, reductions, and hydrolyses or hydrolytic reactions. One example we're showing here is enalapril. Enalapril contains an ester, and esters can be hydrolyzed in the body to form acids. And there are many enzymes that perform these reactions. There are esterases found in the plasma. There are lipases that break down fats, which are esters. So this is a common type of reaction to see... hydrolysis of esters or amides in the body.