Drug metabolism and elimination

 

In general, the metabolism of a drug decreases its therapeutic effect. The majority of drugs are metabolized to increase their water solubility to allow elimination in urine or bile. However some drugs are metabolized into active compounds first before subsequent metabolism to inactive compounds and be excreted.

Most drugs must pass through the liver, which is the primary site for drug metabolism. Once in the liver, enzymes convert prodrugs to active metabolites or convert active drugs to inactive forms. The liver's primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes.

Metabolism is a biotransformation process, where endogenous and exogenous compounds are converted to more polar products to facilitate their elimination from the body. The process of metabolism is divided into 3 phases. Phase I metabolism involves functionalization reactions. Phase II drug metabolism is a conjugation reaction. Phase III refers to transporter-mediated elimination of drug and/or metabolites from body normally via liver, gut, kidney, or lung.

source : https://link.springer.com/chapter/10.1007/978-3-540-93842-2_8

Phase I biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Although Phase I drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Additional metabolism occurs in gastrointestinal epithelial, renal, skin, and lung tissues. Within cells, most phase I enzymes are located in the endoplasmic reticulum and thus are enriched in microsomal preparations.

Phase I reactions are broadly grouped into three categories: oxidation, reduction, and hydrolysis. As most small molecule drugs are lipophilic in nature, drug metabolism converts these hydrophobic compounds into more water soluble compounds that can be excreted. Typically, oxidation is the most common phase I reaction. The hepatic cytochrome P450 system is the most important of the phase I oxidation systems.

 Mono-oxygenase P450 cycle source: Rang & Dale's 7 th edition

For many drugs, metabolism occurs in 2 phases. Phase I reactions involve formation of a new or modified functional group or cleavage (oxidation, reduction, hydrolysis); these reactions are nonsynthetic. Phase II reactions involve conjugation with an endogenous substance (eg, glucuronic acid, sulfate, glycine); these reactions are synthetic. Metabolites formed in synthetic reactions are more polar and thus more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions. Some drugs undergo only phase I or phase II reactions; thus, phase numbers reflect functional rather than sequential classification.

The most important enzyme system of phase I metabolism is cytochrome P-450 (CYP450), a microsomal superfamily of isoenzymes that catalyzes the oxidation of many drugs. The electrons are supplied by NADPH–CYP450 reductase, a flavoprotein that transfers electrons from NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) to CYP450.

CYP450 enzymes can be induced or inhibited by many drugs and substances resulting in drug interactions in which one drug enhances the toxicity or reduces the therapeutic effect of another drug.