Drug metabolism mainly takes place in the liver, where along with metabolism of the drugs, the excretion and thus the clearance of the drugs takes place. Drug metabolism mainly takes place in two phases – Phase I and Phase II. The Phase I reactions mainly result in functionalization of the drugs whereas the Phase II reactions result in the increased polarity of the drugs due to the conjugation of a polar group on the drug, thereby increasing their solubility which helps in their excretion from the body. The Phase I reactions mainly involve the action of Cytochrome P450 enzymes, Flavin Monoxygenases, etc, while the Phase II reactions mainly involve the action of UDP glucuronyl transferases (UGTs, sulfotransferases, etc.).
The Cytochrome P450s play a very important role in drug metabolism as they help in the addition or unmasking of functional groups so that the Phase II enzymes act upon them. Cytochrome P450s are heme- containing isoenzymes present in the lipid bilayer of the endoplasmic reticulum of the hepatocytes. Since, they have a colored pigment, which absorbs light of wavelength 450nm, hence the name. Many isoenzymes of cytochrome P450s are expressed within the human body, which act upon different substrates, and of them, some play important roles in drug metabolism. The main metabolic reaction that takes place is the mixed oxidation function whereby the drug undergoes oxidation reaction with the formation of NADP in the reaction. The metabolic studies of the prospective drugs is carried out using in-vitro models like: a) microsomes (human, rat, mouse, etc) derived from the SER (Smooth Endoplasmic reticulum) of the cells; b) S9 fraction obtained from the differential centrifugation of the liver homogenate; c) fresh and cryo preserved hepatocytes; d) tissue slices; e) recombinant expressed enzymes. During the metabolic studies, cytochrome P450s have been extensively studied as Phase I reactions are greatly affected during co-administration of more than one drug. This phenomenon is known as drug – drug interaction. In the co-administration of more than one drug, either inhibition or induction of the cytochrome P450s takes place due to which the metabolism of the drugs is affected. When the metabolism of the drugs is affected, it hinders the proper action of the drugs as the drugs are either easily eliminated from the body due to faster metabolism or they remain in the cells for longer period due to inhibited metabolism producing toxic effects. Hence, drug-drug interaction study has become a part of the metabolic stability study of a prospective drug.
Drug metabolism has an important role in the determination of the pharmacokinetic (PK) parameters like oral bioavailability, clearance and the half-life of the entity within the cell. The drug metabolic studies help to screen the compounds based on their metabolic rate and thereby help to proceed with the in-vivo studies using rat, mouse, etc. The determination of the metabolite structure with the help of LC/MS-MS and the metabolic phenotyping i.e. the particular enzyme responsible for the metabolism of the prospective drug, which can be done using recombinant enzymes, gives a much clearer idea about the metabolism of the compounds and the information derived can be used for further drug-drug interaction studies. However, the metabolic phenotyping of a prospective drug is quite difficult, long-drawn and expensive process. High-throughput screening of the prospective drugs based on their metabolic stability is carried out mainly using liver microsomes in a drug research lab.
Drug metabolism is very essential in the toxicity studies too. The persistence of the compounds in the systemic circulation for long period causes toxicity and the nature of the metabolites and the reaction of the metabolites within the body, must be studied thoroughly before the compounds progress to the next stage of screening in drug discovery process. In this way, it is seen that drug metabolic studies form an integral part in drug discovery.