Drug metabolism


Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are organic compounds that are foreign to an organism's normal biochemistry, such as any drug, pollutant, or poison. These pathways are a form of biotransformation that are present in all major groups of organisms, a fact which may allude to an . These reactions often act to detoxify poisonous compounds. The study of drug metabolism is one of the tenets of pharmacokinetics as metabolism, the fourth stage of LADME, involves the enzymatic biotransformation and non-enzymatic biotransformation of a drug, thereby leading to the fifth stage, excretion.
The metabolism of pharmaceutical drugs is an important aspect of pharmacology and medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects multidrug resistance in infectious diseases and in chemotherapy for cancer, and the actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions. These pathways are also important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down during bioremediation, or persist in the environment. The enzymes of xenobiotic metabolism, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides.
Drug metabolism is divided into three phases. In phase I, enzymes such as Cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalyzed by transferase enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognized by efflux transporters and pumped out of cells. Drug metabolism often converts lipophilic compounds into hydrophilic products that are more readily excreted.

Permeability barriers and detoxification

The exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time; these are major characteristics of xenobiotic toxic stress. The major challenge faced by xenobiotic detoxification systems is that they must be able to remove the almost-limitless number of xenobiotic compounds from the complex mixture of chemicals involved in normal metabolism. The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity enzymatic systems.
All organisms use cell membranes as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these cell membranes, and the uptake of useful molecules is mediated through transport proteins that specifically select substrates from the extracellular mixture. This selective uptake means that most hydrophilic molecules cannot enter cells, since they are not recognized by any specific transporters. In contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-soluble xenobiotics using membrane barriers.
However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolize almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general contain one or more charged groups.
The detoxification of the reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are the glyoxalase system, which removes the reactive aldehyde methylglyoxal, and the various antioxidant systems that eliminate reactive oxygen species.

Phases of detoxification

The metabolism of xenobiotics is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells.

Phase I – modification

In phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalyzed by the cytochrome P-450-dependent mixed-function oxidase system. These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates. The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and the generation of a highly-reactive oxyferryl species, according to the following scheme:
Phase I reactions may occur by oxidation, reduction, hydrolysis, cyclization, decyclization, and 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, 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 to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one. Simple hydrolysis in the stomach is normally an innocuous reaction, however there are exceptions. For example, phase I metabolism converts acetonitrile to glycolonitrile, which rapidly dissociates into formaldehyde and hydrogen cyanide.
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, 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 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 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.

Hydrolysis

In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione, sulfate, glycine, or glucuronic acid. Sites on drugs where conjugation reactions occur include carboxy, hydroxy, amino, and thiol groups. Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produce active metabolites. The addition of large anionic groups detoxifies reactive electrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.
These reactions are catalyzed by a large group of broad-specificity transferases, which in combination can metabolize almost any hydrophobic compound that contains nucleophilic or electrophilic groups. One of the most important classes of this group is that of the glutathione S-transferases.
MechanismInvolved enzymeCo-factorLocationSources
methylationmethyltransferaseS-adenosyl-L-methionineliver, kidney, lung, CNS
sulfationsulfotransferases3'-phosphoadenosine-5'-phosphosulfateliver, kidney, intestine
acetylation
  • N-acetyltransferases
  • bile acid-CoA:amino acid N-acyltransferases
acetyl coenzyme Aliver, lung, spleen, gastric mucosa, RBCs, lymphocytes
glucuronidationUDP-glucuronosyltransferasesUDP-glucuronic acidliver, kidney, intestine, lung, skin, prostate, brain
glutathione conjugationglutathione S-transferasesglutathioneliver, kidney
glycine conjugationTwo step process:
  1. XM-ligase
  2. Glycine N-acyltransferase
glycineliver, kidney