Drug metabolism

# Overview
Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products. Its rate is an important determinant of the duration and intensity of the pharmacological action of drugs.
Drug metabolism can result in toxication or detoxication - the activation or deactivation of the chemical.
While both occur, the major metabolites of most drugs are detoxication products.
Drugs are almost all xenobiotics.
Other commonly used organic chemicals are also drugs, and are metabolized by the same enzymes as drugs.
This provides the opportunity for drug-drug and drug-chemical interactions or reactions.

# Phase I vs. Phase II
Phase I and Phase II reactions are biotransformations of chemicals that occur during drug metabolism.
Phase I reactions usually precedes Phase II, though not necessarily.
During these reactions, polar bodies are either introduced or unmasked, which results in (more) polar metabolites of the original chemicals.  In the case of pharmaceutical drugs, Phase I reactions can lead either to activation or inactivation of the drug.
Phase I reactions (also termed Nonsynthetic reactions) may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization reactions.  Oxidation involves addition of oxygen (forming a negatively charged radical) or removal of hydrogen (forming a positively charged radical).  The process of oxidation takes place in the presence of mixed function oxidases and mono-oxygenases in the liver.  These oxidative reactions typically involve a cytochrome p-450 haemoprotein, NADPH and oxygen.  The classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines, paracetamol, and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate.
Phase II reactions  usually known as conjugation reactions (e.g., with 
glucuronic acid, sulfonates (commonly known as sulfation)
, glutathione or amino acids)  are usually detoxication in nature, and involve the interactions of the polar functional groups of phase I metabolites.

# Sites
Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal organ of drug metabolism, although every biological tissue has some ability to metabolize drugs.
Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the gut, and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs.
If a drug is taken into the GI tract, where it enters hepatic circulation through the portal vein, it becomes well-metabolized and is said to show the first pass effect.
Other sites of drug metabolism include epithelial cells of the gastrointestinal tract, lungs, kidneys, and the skin.
These sites are usually responsible for localized toxicity reactions.

# Major enzymes and pathways
Several major enzymes and pathways are involved in drug metabolism, and can be divided into Phase I and Phase II reactions:

## Phase I

### Oxidation
- Cytochrome P450 monooxygenase system
- Flavin-containing monooxygenase system
- Alcohol dehydrogenase and aldehyde dehydrogenase
- Monoamine oxidase
- Co-oxidation by peroxidases

### Reduction
- NADPH-cytochrome P450 reductase
- Reduced (ferrous) cytochrome P450
It should be noted that during reduction reactions, a chemical can enter futile cycling, in which it gains a free-radical electron, then promptly loses it to oxygen (to form a superoxide anion).

### Hydrolysis
- Esterases and amidases
- Epoxide hydrolase

## Phase II
- Glutathione S-transferases
Mercapturic acid biosynthesis
- Mercapturic acid biosynthesis
- UDP-glucuronosyltransferases
- N-acetyltransferases
- Amino acid N-acyl transferases
- Sulfotransferases

# Factors that affect drug metabolism
The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products.
The Cytochrome P450 monooxygenase system is the most important pathway in this regard.
In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action.
The opposite is also true (e.g., enzyme inhibition).
Various physiological and pathological factors can also affect drug metabolism.
Physiological factors that can influence drug metabolism include age, individual variation (e.g., pharmacogenetics), enterohepatic circulation, nutrition, intestinal flora, or sex differences.
In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults.
Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs.
With N-acetyltransferases (involved in Phase II reactions), individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly, split roughly 50:50 in the population of Canada.
This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity.
Cytochrome P450 monooxygenase system enzymes can also vary across individuals, with deficiencies occurring in 1 - 30% of people, depending on their ethnic background.
Pathological factors can also influence drug metabolism, including liver, kidney, or heart diseases.