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The purpose of drug metabolism is to convert lipophillic compounds to more readily-excreted polar products. Its rate is the primary determinant of the the duration and intensity of the pharmacological action of lipophilic drugs in most instances.
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 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. Phase I reactions may occurs by oxidation, reduction or hydrolysis reactions. 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 — are usually detoxication in nature, and involve the interactions of the polar functional groups of phase I metabolites.
Quantitatively, the liver is the principle organ of drug metabolism, although every 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 very readily and well-metabolized, it is said to show the first pass effect.
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:
- NADPH-cytochrome P450 reductase (very important; Exam)
- Reduced (ferrous) cytochrome P450
A note is 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).
- Epoxide hydrolase (very important; Exam)
- Glutathione S-transferases (very, very important)
- Mercapturic acid biosynthesis
- UDP-Glucoron(os)yltransferases (very important)
- Amino acid N-acyl transferases
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 senescent 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.
- Providing access to knowledge of how organic chemical moieties used as drugs are metabolised
- Describing emerging fields of pharmacogenetics and toxicogenetics
- Understanding age-dependent differences in metabolism of drugs
- Identifying metabolic basis for adverse drug reactions