Drug metabolism (or drug biotransformation) is the process of structural transformation of drugs under the catalysis of drug-metabolizing enzymes after absorption and distribution in the body. It is the major elimination route from the body for most drugs. The liver is the most important organ for drug metabolism. The other clearance routes include renal excretion and biliary excretion. About 75% of marketed drugs were reported to be eliminated from the body primarily through the metabolic route . The metabolism of drugs in the body is a very complex process. Research in the metabolic process of drugs is of great significance for improving the in vivo pharmacokinetic properties of drugs, such as reducing the systemic clearance of drugs, increasing the oral bioavailability, addressing the potential metabolism-related issues, and predicting the human dose.
In general, drug-metabolizing enzymes convert lipophilic drug molecules into more hydrophilic metabolites, which the kidneys and bile can readily excrete. The drug metabolic reactions can be classified into two types: phase I and phase II. Phase I metabolism, such as oxidation, involves adding functional groups or exposing the functional groups from a molecule. Phase II metabolism involves conjugation reactions, such as glucuronidation and sulfonation. Drugs can be metabolized by Phase I enzymes, Phase II enzymes, or Phase I, followed by a Phase II enzyme.
In the early stage of drug discovery, the study of in vitro metabolic stability is an important method to analyze drug metabolism. The conversion rate of compounds in the biological matrix can be measured by incubating compounds with a specific biological matrix (e.g., liver microsomes, hepatocytes, etc.) in vitro . in vitro kinetic parameters such as metabolic rate and intrinsic clearance can be obtained, and in vivo clearance can be further predicted by relevant models.
The in vitro experimental models for a metabolic stability study can be classified as cells, subcellular fractions (S9, cytosol, and microsomes), and recombinant enzymes. WuXi AppTec's Metabolic Stability Laboratory can provide stability experiments of microsomes, S9, hepatocytes, and plasma from multiple species and tissues. Details are listed in the following table.
The figure shows the in vitro and in vivo correlation of liver intrinsic clearance of 13 drugs (acetaminophen, midazolam, buspirone, chlorpromazine, diltiazem, promazine, metronolol, propranolol, quinidine, verapamil, diclofenac, tolbutamide, and warfarin). The abscissa is the liver intrinsic clearance measured by an in vitro liver microsomal stability assay. The ordinate is the liver intrinsic clearance calculated from the in vivo clearance reported in the literature . The red, blue, and green lines represent the 2-, 3- and 5-fold error lines, respectively. Sixty-nine percent of compounds were within the range of 2-fold error.
Figure. In Vitro – In Vivo Correlation of Hepatic Intrinsic Clearance for 13 Drugs (Liver microsomal stability assay)