Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. 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 xenobiotics, 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 precede 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 the enzymatic addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a cytochrome P450 monooxygenase (often abbreviated CYP), 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.

A common Phase I oxidation involves conversion of a C-H bond to a C-OH.

This reaction sometimes converts a pharmacologically inactive compound (a prodrug) to a pharmacologically active one.

By the same token, Phase I can turn a nontoxic molecule into a poisonous one (toxification).

A famous example is acetonitrile, CH₃CN.

Simple hydrolysis in the stomach transforms acetonitrile into acetate and ammonia, which are comparatively innocuous.

But Phase I metabolism converts acetonitrile to HOCH₂CN, which rapidly dissociates into formaldehyde and hydrogen cyanide, both of which are toxic.

Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts.

This example of a biomimetic reaction tends to give a mixture of products that often contains the Phase I metabolites, and Alpha Chimica's approach to preparing prospective drug candidates makes use of this in vitro chemistry.

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 on drugs where conjugation reactions occur include carboxyl (-COOH), hydroxyl (-OH), amino (NH₂), and sulfhydryl (-SH) groups. Products of conjugation reactions have increased molecular weight and are usually inactive unlike Phase I reactions which often produce active 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 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

Methylation

• methyltransferase

Sulphation

• Glutathione S-transferases
• Sulfotransferases

Acetylation

• N-acetyltransferases
• Amino acid N-acyl transferases

Glucuronidation

• UDP-glucuronosyltransferases
  • Mercapturic acid biosynthesis

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.

In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects. This can be used to identify individuals most at risk from adverse reaction.

See also

• Drug design
• Xenobiotic metabolism
• Active metabolite
• Drug reaction testing
• SPORCalc, an example process for exploring drug metabolism databases
• Simcyp Simulator
• Simulations Plus

References

• Basic and Clinical Pharmacology (9th Edition; Katzung): 1.4. Drug Biotransformation

External links

• University of Minnesota Biocatalysis/Biodegradation Database
• Drug Metabolism Database