Metabolic Stability – Microsomes

Background Drugs are most often eliminated by biotransformation and/or excretion into urine or bile. The liver is the major organ for xenobiotic biotransformation and is thereby important in characterizing the metabolism stability, toxicology, and drug-drug interaction properties of drugs. Drug metabolism is achieved via two major enzyme reactions within the liver, Phase I and Phase II reactions. Phase I enzymes include the cytochrome P450 (CYP) family of enzymes which are located in the smooth endoplasmic reticulum. The basic processes in phase I reactions are oxidation, reduction and/or hydrolysis many of which are catalyzed by the CYP system and require NADPH as a cofactor. Phase II enzymes are located in the cytoplasm and endoplasmic reticulum and are characteristic of conjugation reactions including glucuronic acid, glutathione, sulfate, and glutamine conjugations. Phase II reactions generally inactivate the drug if it is not already therapeutically inactive following Phase I metabolism, and make the drug more water solubleto facilitate its elimination. Some drugs are metabolized by Phase I or Phase II enzymes alone whereas others are metabolized by both Phase I and Phase II enzymes.