Why Does the Body Metabolize Drugs?
Any administered drug is treated 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 absorb efficiently into the bloodstream.
However, lipophilicity becomes a major obstacle during excretion: once in the kidneys, such substances easily traverse renal tubular membranes and undergo passive reabsorption back into the blood. The task of biotransformation is to modify the molecular structure by increasing its polarity (polaritas) and hydrophilicity. Water-soluble (polar) metabolites cannot be reabsorbed in the tubules and are reliably excreted from the body in urine or bile.
Phases of Biotransformation
The metabolism of most drugs occurs in two sequential stages, each fulfilling a specific chemical objective.
Phase I: Non-Synthetic Reactions (Metabolic Transformation) This is the initial stage resulting in the formation of reactive metabolites. The main types of chemical alterations include:
- Oxidation (oxidatio) — the introduction of oxygen atoms into the molecule.
- Reduction (reductio) — the addition of hydrogen atoms or removal of oxygen.
- Hydrolysis (hydrolysis) — the cleavage of ester, amide, or phosphate bonds by the addition of water (catalyzed by esterases, amidases, and phosphatases).
Phase II: Biosynthetic Reactions (Conjugation) Following Phase I, this process involves attaching endogenous chemical groups to the drug or its metabolite. This is carried out by transferase enzymes. The most common reaction is glucuronidation (attachment of glucuronic acid residues). Molecules may also be conjugated with glutathione, glycine, sulfuric acid, or methyl groups. Conjugation products are highly polar, pharmacologically inactive, and rapidly excreted by the kidneys or biliary system.
Cytochrome P450 System
Microsomal enzymes located on the membranes of the smooth endoplasmic reticulum of hepatocytes play a key role in Phase I metabolism.
Central to this system is Cytochrome P450 (Cytochromum P-450), a mixed-function oxidase. It is a hemoprotein that binds the drug molecule and oxygen. With the participation of NADPH (an electron donor), the oxygen molecule is split: one atom is incorporated into the drug to form an oxidized metabolite, while the other forms a water molecule ($H_2O$).
These oxidases exhibit low substrate specificity. The most important isoenzyme is CYP3A4, which metabolizes a vast number of diverse drugs. The activity of Cytochrome P450 isoenzymes can be altered by other substances:
- Induction (acceleration): Certain drugs (e.g., phenobarbital, rifampin) or environmental factors (e.g., St. John's wort, tobacco smoke components) cause enzymes to work faster. Consequently, co-administered drugs are degraded too quickly, dropping their therapeutic efficacy.
- Inhibition (slowdown): Substances such as macrolides, ketoconazole, or grapefruit juice block the enzymes. Substrate metabolism slows down, leading to a risk of drug accumulation and toxic adverse effects.
Extrahepatic Metabolism and Presystemic Elimination
Although the liver (hepar) performs the bulk of the metabolic workload, 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 intestine (intestinum) is of immense clinical significance. Approximately 70% of all Cytochrome P450 isoenzymes (predominantly CYP3A4) reside in the intestinal wall. Working alongside the transport protein P-glycoprotein, they mediate presystemic elimination (first-pass metabolism), breaking down a significant portion of an orally administered drug before it reaches systemic circulation. This substantially reduces the bioavailability of many drugs.
Bioactivation and Toxification
The outcome of biotransformation is not always the safe destruction of a drug. Alternative scenarios include:
- Retention of Activity: Metabolites may retain activity comparable to the parent drug (e.g., diazepam or codeine), prolonging the therapeutic effect. Even Phase II products can remain active; for instance, morphine-6-glucuronide possesses potent analgesic activity.
- Prodrug Activation: The substance is administered in an inactive form and becomes active only after a portion of the molecule is cleaved during metabolism.
- Toxification: Intermediate products can occasionally act as cellular poisons. For example, paracetamol (Paracetamolum) is oxidized by the CYP2E1 isoenzyme into a highly toxic metabolite. Normally, this metabolite is instantly detoxified via conjugation with glutathione. However, when glutathione stores are depleted (overdose) or the enzyme is overactive (chronic alcoholism), this toxin destroys liver and kidney cells.