Why does the body need drug metabolism?
Any administered drug is perceived by the body as a foreign compound (xenobiotic) that must be eliminated. Most drugs are initially lipophilic—a property that allows them to easily cross cell membranes and effectively absorb into the bloodstream.
However, lipophilicity becomes a major obstacle to elimination: once in the kidneys, such substances easily cross the membranes of renal tubules and are reabsorbed back into the blood. The task of biotransformation is to change the molecule structure by increasing its polarity (polaritas) and hydrophilicity. Water-soluble (polar) metabolites cannot be reabsorbed in the tubules and reliably leave the body with urine or bile.
Phases of biotransformation
The metabolic process of most drugs proceeds in two consecutive stages, each of which performs its own chemical task.
Phase I. Non-synthetic reactions (Metabolic transformation) This is the primary stage resulting in the formation of reactive metabolites. The main types of chemical transformations:
- Oxidation (oxidatio) — the introduction of oxygen atoms into the molecule.
- Reduction (reductio) — the addition of a hydrogen atom or the removal of oxygen.
- Hydrolysis (hydrolysis) — the cleavage of ester, amide, or phosphate bonds by adding water (catalyzed by esterases, amidases, and phosphatases).
Phase II. Biosynthetic reactions (Conjugation) Follows the first phase. The essence of the process is the addition of endogenous chemical groups to the drug or its metabolite. This is carried out by transferase enzymes. The most frequent reaction is glucuronidation (addition of glucuronic acid residues). The molecule can also be conjugated with glutathione, glycine, sulfuric acid, or methyl groups. Conjugation products are highly polar, inactive, and rapidly excreted by the kidneys or intestines.
Cytochrome P-450 system
Microsomal enzymes located on the membranes of the smooth endoplasmic reticulum of hepatocytes play a key role in the first phase of metabolism.
The main component of this system is cytochrome P-450 (Cytochromum P-450), a mixed-function oxidase. This is a hemoprotein that binds the drug molecule and oxygen. With the participation of the NADPH cofactor (electron donor), the oxygen molecule is cleaved: one atom is incorporated into the drug, forming an oxidized metabolite, and the second atom goes into forming a water molecule ($H_2O$).
Oxidases have low substrate specificity. The most important isoenzyme is CYP3A4, which is involved in the metabolism of a vast number of different drugs. The activity of cytochrome P-450 isoenzymes can change under the action of other substances:
- Induction (acceleration): certain drugs (phenobarbital, rifampicin) or environmental factors (St. John's wort, tobacco smoke components) cause enzymes to work faster. Because of this, other drugs are broken down too quickly, and their therapeutic effect drops.
- Inhibition (slowdown): substances like macrolides, ketoconazole, or grapefruit juice block enzymes. The metabolism of substrates slows down, which leads to the risk of their accumulation and the development of toxic reactions.
Extrahepatic metabolism and presystemic elimination
Although the liver (hepar) performs the bulk of the work, enzyme systems are also localized in other tissues: the intestinal wall, kidneys (renes), lungs (pulmones), skin, and blood plasma. Some reactions occur outside the endoplasmic reticulum—in the cytosol or mitochondria (non-microsomal enzymes with high substrate specificity).
The enzymatic activity of the intestines (intestinum) is of immense clinical importance. About 70% of all cytochrome P-450 isoenzymes (predominantly CYP3A4) are located in its wall. Together with the P-glycoprotein transport protein, they ensure presystemic elimination—breaking down a significant part of the ingested drug before it can enter the systemic circulation. This significantly reduces the bioavailability of many drugs.
Bioactivation and toxification
The result of biotransformation does not always boil down to the safe destruction of the drug. Alternative scenarios are possible:
- Preservation of activity. Metabolites can work just as well as the original substance (e.g., in diazepam or codeine), which prolongs the therapeutic effect. Even phase II products can retain activity—thus, morphine-6-glucuronide has a pronounced analgesic effect.
- Activation of prodrugs. The substance is administered inactive and begins to work only after the cleavage of part of the molecule during metabolism.
- Toxification. Sometimes intermediate products turn out to be cellular poisons. For example, paracetamol (Paracetamolum) is oxidized by the CYP2E1 isoenzyme to a highly toxic metabolite. Normally, it is instantly neutralized by conjugation with glutathione. But when glutathione stores are depleted (overdose) or enzyme activity is excessive (chronic alcoholism), this poison destroys liver and kidney cells.
Briefly: answers to topical questions
What main cytochrome P-450 isoenzymes, in addition to CYP3A4 and CYP2E1, are involved in drug metabolism?
In addition to CYP3A4 and CYP2E1, the following cytochrome P-450 isoenzymes are mentioned in sources:
- CYP1A2 — metabolizes xanthines, paracetamol, warfarin, clomipramine, and tamoxifen.
- CYP2D6 — metabolizes codeine, psychotropic and cardiac drugs, as well as omeprazole.
- CYP2C19 — participates in the bioactivation of clopidogrel.
- CYP2C9 and CYP2B6 — also participate in the second bioactivation reaction of clopidogrel.
- CYP3A5 — is mentioned together with CYP3A4 as part of the extensive group metabolizing most drugs.
- CYP1A1, CYP2A1, and CYP1B1 — are listed among the cytochrome P450 isoenzymes present in the skin.
Which specific enzymes belong to non-microsomal biotransformation enzymes?
Non-microsomal biotransformation enzymes include enzymes of the cytosol, mitochondria, lysosomes, cytoplasmic membranes, and blood plasma:
- Monoamine oxidase type A (MAO-A) — performs oxidative deamination of catecholamines and biogenic amines.
- Alcohol dehydrogenase — catalyzes the oxidation of ethanol (Spiritus aethylicus).
- Xanthine oxidase — is responsible for the hydroxylation of purine compounds.
- Reductases — participate in reduction reactions (including those produced by the intestinal microflora).
- Esterases, amidases, and phosphatases — catalyze hydrolysis reactions of esters, amides, and phosphate bonds.
What clinical examples of prodrugs exist?
In clinical practice, a number of prodrugs are used that are activated only during metabolism:
- Clopidogrel — requires activation by cytochrome P-450 isoenzymes to manifest its antiplatelet effect.
- Ciclesonide — an esterified steroid that turns into active desciclesonide in the lungs.
- Tibolone — is metabolized to form substances with estrogenic, gestagenic, and androgenic activity.
- Enalapril (Enalaprilum) — is hydrolyzed to active enalaprilat, which improves absorption.
- Valacyclovir — a substrate for the oligopeptide transporter, turning into an active compound in the liver.
- Levodopa (Levodopa) — crosses the blood-brain barrier and is decarboxylated into dopamine (Dopaminum).
- Gabapentin (Gabapentin) — modified to increase lipophilicity and penetration into the central nervous system.
What functions does the P-glycoprotein transport protein perform, in addition to participating in presystemic elimination in the intestine?
In addition to participating in presystemic elimination, the P-glycoprotein transport protein acts as an efflux pump in various tissues:
- Central nervous system protection — prevents lipophilic substances from penetrating the blood-brain barrier by pumping them out of brain tissue back into the bloodstream.
- Tumor resistance development — determines cellular resistance to antitumor agents (e.g., vinca alkaloids) by actively pumping the drug out of the tumor cell.
- Limitation of tissue distribution — reduces the tissue concentration of drugs by acting as an ATP-dependent transporter that prevents their accumulation.
Class and exam questions
Why do lipophilic substances need to become hydrophilic?
If a lipophilic substance enters the kidneys, it will easily pass through the cell membranes of the renal tubules and be reabsorbed back into the bloodstream (reabsorption). Hydrophilic substances cannot cross membranes and are therefore reliably excreted in the urine.
What is the essence of conjugation reactions?
This is the second phase of biotransformation, in which an endogenous molecule (e.g., a glucuronic acid residue) attaches to the drug. A large, polar, inactive complex is formed that leaves the body very quickly.
Why is it dangerous to drink alcohol while taking paracetamol?
Chronic ethanol intake induces (accelerates the activity of) the hepatic isoenzyme CYP2E1. As a result, paracetamol is converted too rapidly into a toxic metabolite, which depletes internal glutathione stores and leads to liver damage.
What else to study on this topic
- Principles of cytochrome P-450 nomenclature nomenclature system (families, subfamilies, and isoenzymes).
- Specific substrates, inducers, and inhibitors of the CYP1A2, CYP2C, CYP2D6, and CYP3A4 isoenzymes.
- Non-microsomal oxidation: the role of MAO-A, alcohol dehydrogenase, and xanthine oxidase.
- Features of prodrug metabolism and the formation of pharmacologically active metabolites.
- The role of enterohepatic circulation (enterohepatic re-circulation) in the elimination of glucuronides.
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