Introduction
Biotransformation is an endogenous pharmacokinetic process that leads to a change in the chemical structure of active pharmaceutical ingredients. The organism’s general goal in doing so is to make the foreign substances more hydrophilic and to direct them to excretion via the urine or stool. Otherwise, they could be deposited in the body and exert harmful effects. The drug, which enters the body, can be metabolized into dozens of substances during biotransformation. This sheds new light on drug therapy and our picture of active ingredients. Thus, the drug is actually a potential mixture of active ingredients. The new compounds may differ in their pharmacokinetic and pharmacodynamic properties from the parent compound. Sometimes they even have a completely different pharmacological effect than the original active substance. Biotransformation, of course, has not been specifically adopted by the body for drug substances. All exogenous substances without physiological function, the so-called xenobiotics, are subject to it. The central organ for biotransformation is the liver. In addition, however, numerous other organs are involved, including the intestine or the blood.
Significance for drug therapy
Most drugs are partially or completely metabolized, and only a minority remain unchanged and are excreted identically (e.g., atovaquone). Metabolism is relevant to drug therapy for the following reasons: The so-called prodrugs are activated only by a metabolic conversion step. Examples include the ACE inhibitors. The metabolite has a lower pharmacological activity than the parent substance. Biotransformation is important for the elimination of active ingredients. Metabolites of active substances can also be toxic, which contradicts the actual goal of biotransformation. A typical example is NAPQI, the liver toxic metabolite of paracetamol. At therapeutic doses it can be neutralized, but an overdose is acutely life-threatening because detoxification is overloaded. Substrates of metabolic enzymes are susceptible to drug-drug interactions. When an enzyme is inhibited or induced by another drug, the concentration of substrates and active or inactive metabolites changes. This may influence the effect and increase undesirable effects. Enzyme activity varies interindividually. If metabolic activity is very high in a patient, the effect of a drug may be absent because the dose is rapidly degraded.
Functionalization (Phase I)
Functionalization is the introduction or exposure of functional groups in the drug molecule. Chemically, it mainly involves oxidations, reductions, or hydrolyses. The enzyme family of cytochromes P450 (CYP) is of central importance for drug metabolism. Important members are for example CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A. In addition to the cytochromes, other enzymes exist, such as alcohol dehydrogenase (ADH) and monoamine oxidases (MAO). Example: oxidation of celecoxib to 4′-hydroxycelecoxib.
Conjugation (phase II).
Conjugation involves the enzymatic and covalent linkage of a drug or metabolite to a molecule. The most important conjugation reaction is glucuronidation. In this process, an active substance or a drug metabolite is linked to glucuronic acid. This usually makes the substance more water-soluble and it can be eliminated in the urine. The enzymes that catalyze this conjugation are the UDP-glucuronosyltransferases (UGT). Other conjugation reactions include methylation, sulfation, and acetylation. All reactions are catalyzed by transferases. Example: glucuronidation of morphine.
Phase I and phase II
Functionalization may precede conjugation. For example, an aromatic is first hydroxylated and then conjugated to a glucuronic acid. However, this sequence is not necessary. If the drug already carries a corresponding functional group, direct conjugation is also possible, and after phase I, the metabolite can be excreted directly.
First-pass metabolism
During peroral administration, a drug enters the bloodstream from the intestine and subsequently passes through the liver until it reaches its site of action from the bloodstream.In the intestine and liver, a significant proportion of the amount of active ingredient can already be metabolized away. This effect is referred to as first-pass metabolism. High first-pass metabolism makes a drug susceptible to drug-drug interactions, adverse effects, and intra- and interindividual differences in efficacy. In some circumstances, oral administration may not be possible at all. Alternative dosage forms can be used to circumvent first-pass. These include, for example, suppositories, sublingual tablets, transdermal patches, nasal sprays, and injectables.