Drug metabolism in the liver

Phase 1

The major drug metabolizing system is located in the microsomal fraction of hepatocytes (in the smooth endoplasmic reticulum). It includes mixed-function monooxygenases, cytochrome C reductase, and cytochrome P450. The cofactor is reduced NADP in the cytosol. Drugs undergo hydroxylation or oxidation, which enhances their polarization. An alternative phase 1 reaction is the conversion of ethanol to acetaldehyde by alcohol dehydrogenases, found mainly in the cytosol.

Enzyme induction is caused by barbiturates, alcohol, anesthetics, hypoglycemic and anticonvulsant drugs (griseofulvin, rifampicin, glutethimide), phenylbutazone and meprobamate. Enzyme induction may be the cause of liver enlargement after initiation of drug therapy.

Phase 2

Biotransformation, which drugs or their metabolites undergo, consists of their conjugation with small endogenous molecules. The enzymes that ensure this are not specific to the liver, but are found in it in high concentrations.

Active transport

This system is located at the biliary pole of the hepatocyte. Transport is carried out with energy consumption and depends on the degree of saturation with the transported substance.

Excretion with bile or urine. The products of drug biotransformation can be excreted with bile or urine; the method of excretion is determined by many factors, some of which have not yet been studied. Highly polar substances, as well as metabolites that have become more polar after conjugation, are excreted unchanged with bile. Substances with a molecular weight of over 200 kDa are also excreted with bile. The lower the molecular weight of the substance, the more of it is excreted with urine.

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Cytochrome P450 system

The P450 hemoprotein system, located in the endoplasmic reticulum of hepatocytes, metabolizes drugs, producing toxic metabolites. At least 50 isoenzymes of the P450 system have been identified, and there are undoubtedly more. Each of these enzymes is encoded by a separate gene. In humans, drug metabolism is provided by cytochromes belonging to three families: P450-I, P450-II, and P450-III. Each cytochrome P450 molecule has a unique substrate site that can bind drugs (but not all). Each cytochrome is capable of metabolizing several drugs. Genetic differences in the catalytic activity of the enzyme may cause the development of idiosyncrasy to the drug. For example, with abnormal expression of the P450-I I-D6 isoenzyme, deterioration of the metabolism of debrisoquine (an antiarrhythmic drug) is observed. The same enzyme system metabolizes most beta-blockers and neuroleptics. Impaired debrisoquine metabolism can be identified by detecting regions of mutant cytochrome P450-II-D6 genes using polymerase chain reaction (PCR), raising hopes that in the future it will be possible to predict pathological reactions to drugs.

The P450-II-E1 isoenzyme is involved in the formation of electrophilic products of paracetamol metabolism.

The P450-III-A isoenzyme is involved in the metabolism of cyclosporine, as well as other drugs, especially erythromycin, steroids, and ketoconazole. Polymorphism of the P450-II-C isoenzyme affects the metabolism of mephenytoin, diazepam, and many other drugs.

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Enzyme induction and drug interactions

An increase in the content of cytochrome P450 enzymes as a result of induction leads to an increase in the production of toxic metabolites. It was found that in the transplanted liver, the expression of P450 enzymes and its induction by phenobarbital are preserved in hepatocytes regardless of their position in the acinus or the state of the sinusoids.

When two active drugs compete for the same binding site on an enzyme, the metabolism of the drug with the lower affinity is slowed and its duration of action is prolonged.

Ethanol induces the synthesis of P450-II-E1 and thereby increases the toxicity of paracetamol. The toxicity of paracetamol also increases with treatment with isoniazid, which also induces the synthesis of P450-II-E1.

Rifampicin and steroids induce P450-III-A, which metabolizes cyclosporine. This explains the decrease in the blood level of cyclosporine when taken in combination with these drugs. Cyclosporine, FK506, erythromycin, and ketoconazole compete for the binding site of the P450-III-A isoenzyme, so when these drugs are prescribed, the blood level of cyclosporine increases.

Omeprazole induces P450-IA. This isoenzyme plays an important role in the biotransformation of procarcinogens, carcinogens and many drugs. It is possible that taking omeprazole increases the risk of developing tumors.

In the future, it will be possible to determine P450 profiles and identify individuals at high risk of adverse drug reactions. Selective inhibitors or inducers can be used to change the P450 profile.

Immune hepatotoxicity

The metabolite may be a hapten for liver cell proteins and cause immune damage to them. Enzymes of the P450 system may participate in this process. There are several P450 isoenzymes on the hepatocyte membrane, the induction of which may lead to the formation of specific antibodies and immune damage to the hepatocyte.

In hepatitis caused by halothane, antibodies to liver microsomal proteins damaged by this drug are detected in the serum of patients.

Idiosyncrasy to diuretics and thienylic acid is accompanied by the appearance of autoantibodies that interact with liver and kidney microsomes (anti-LKM II). The antigen to which these antibodies are directed belongs to the P450-II-C family, which is also involved in the metabolization of thienylic acid.