Drug metabolism

Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, 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.

Phases

Phase I

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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). Simple hydrolysis in the stomach transforms , 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 products that often contains the Phase I metabolites. As an example, the major metabolite of the pharmaceutical trimebutine, desmethyltrimebutine (nor-trimebutine), can be efficiently produced by in vitro oxidation of the commercially available drug. Hydroxylation of an N-methyl group leads to expulsion of a molecule of formaldehyde, while oxidation of the O-methyl groups takes place to a lesser extent.

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

Cytochrome P450 reductase also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR, is a membrane-bound enzyme required for electron transfer to cytochrome P450 in the microsome of the eukaryotic cell from a FAD- and FMN-containing enzyme NADPH:cytochrome P450 reductase The general scheme of electron flow in the POR/P450 system is: NADPH → FAD → FMN → P450 → O2

• Reduced (ferrous) cytochrome P450

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 Amidase
• Epoxide hydrolase

Phase II

Phase II reactions — usually known as conjugation reactions (e.g., with glucuronic acid, sulfonates (commonly known as sulfation), glutathione or amino acids) — are usually detoxicating 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.

Mechanism	Involved enzyme	Co-factor	Location
Methylation	Methyltransferase	S-adenosyl-L-methionine	Liver, kidney, lung, CNS
Sulphation	Sulfotransferases	3'-phosphoadenosine-5'-phosphosulfate	Liver, kidney, intestine
Acetylation	N-acetyltransferases Bile acid-CoA:amino acid N-acyltransferases	Acetyl coenzyme A	Liver, lung, spleen, gastric mucosa, RBCs, lymphocytes
Glucuronidation	UDP-glucuronosyltransferases	UDP-glucuronic acid	Liver, kidney, intestine, lung, skin, prostate, brain
Glutathione conjugation	Glutathione S-transferases	Glutathione	Liver, kidney

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.

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). However, in cases where an enzyme is responsible for metabolizing a pro-drug into a drug, enzyme induction can speed up this conversion and increase drug levels, potentially causing toxicity.

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.