Every day, every person is exposed to the negative effects of various chemicals called xenobiotics. They enter the body through the skin, lungs, from the digestive tract along with food, air. Some of these substances do not have a negative effect on the body, but most are able to cause biological responses. As a result, they are neutralized, as well as excreted from the body.
Definition
Biotransformation is a concept that includes the basic chemical changes that occur with drugs in the body.
As a result of this process, a decrease in lipophilicity (solubility of substances in fats) is observed, hydrophilicity increases (solubility in water increases).
Biotransformation of drugs leads to a change in the pharmacological activity of the drug.
A small amount of the drug can be excreted unchanged with the help of the kidneys. Basically, such drugs are "small molecules", or can be in ionized form at pH values close to physiological parameters.
Unfortunately, many drugs do not have such physicochemical properties. Basically, physiologically active molecules of organic compounds are lipophilic, therefore, at physiological parameters, the pH remains in non-ionized form. They are associated with plasma protein, so they are slightly filtered in the renal glomeruli.
Biotransformation is a process aimed at increasing the solubility of drug molecules, accelerating its removal from the body with urine. That is, the conversion of lipophilic drugs to hydrophilic compounds is observed.
Change in drug activity
Biotransformation of substances leads to significant changes in the physiological activity of drugs:
- from the active substance, the drug turns into an inactive form;
- "prodrugs" at the same time acquire pharmacological activity.
The safety of drugs that contain active metabolites is affected not only by the pharmacokinetics of the drug, but also by the performance of active metabolites.
Prodrugs
The purpose of creating such drugs is to increase pharmacological parameters, accelerate and increase the absorption of drugs. For example, ampicillin esters (thalampicin, pivampicin, bicampicin) have been developed, which, unlike the original drug, are absorbed to the maximum extent during administration.
Biotransformation reactions allow hydrolysis of these drugs in the liver. The catalyst in the process is an enzyme - carboxyesterase, which has a high antibacterial activity.
Biotransformation is a process that significantly increases the effectiveness of drugs. The antiviral drug Valaciclovir is bioavailable - more than half of it is converted into acyclovir in the liver. A similar process is explained by the presence in the molecules of amino acid residues - valine.
Of interest is the mechanism of action of inhibitors of the adenosine converting enzyme, which contains carbonyl groups.
These include the following drugs: Perindopril, Hinapril, Enalapril, Spirapril, Thrandolapril, Ramipril.
In this case, biotransformation is the conversion of a drug by hydrolysis to active enalaprilat. The process is carried out thanks to the enzyme - carboxyesterase. If you take the drug itself, then its absorption in the body does not exceed 10 percent.
Improving drug safety
Biotransformation of xenobiotics improves the safety of drugs. For example, scientists managed to develop Sulindak - NSAIDs. At first, this drug does not block the synthesis of prostaglandins, only in the liver during hydrolysis active sulindac sulfide is formed, which has anti-inflammatory activity. At first, scientists believed that the drug has no ulcerogenic effect, but as a result of studies, it was possible to establish a similarity in the number of occurrences of erosive and ulcerative lesions of the digestive organs in the case of taking Sulindak and other NSAIDs.
Action selectivity
Liver biotransformation is a whole complex of biochemical reactions that make it possible to turn drugs into metabolites excreted from the body.
Among the goals of creating prodrugs, one can also note an increase in the selectivity of the action of drugs, which helps to increase the effectiveness and safety of drugs. "Dopamine" is used to increase renal blood flow in renal failure, but the drug has an effect on blood vessels and myocardium. It was also revealed an increase in blood pressure, the development of arrhythmias and tachycardia when using this drug.
After the glutamic acid moiety was attached to dopamine, a new drug was developed called Glutamyl Dopa. When it is hydrolyzed in the kidney, dopamine is formed under the influence of decarboxylase L-aromatic amino acids and glutamyl transpeptidase, without exerting an undesirable effect on central hemodynamics.
Main phases
The figure shows the phases of biotransformation. After the drug enters the body, glucuronidation, sulfotation, acetylation, methylation, conjugation with glutatin, amino acids occur. Further, the drug is excreted from the body.
All major biotransformations are carried out in the liver, but they can also occur in the kidneys, lungs, digestive tract.
How is biotransformation carried out? Metabolism involves two phases: non-synthetic and synthetic.
Non-synthetic reactions
The reactions of the first phase are associated with the transition of drugs to more soluble (hydrophilic) compounds in comparison with the starting material. Changes in the initial physical and chemical parameters of drugs are explained by the process of addition or release of active functional groups: amino groups, sulfhydryl fragments, hydroxyl groups.
In the first stage, oxidation reactions occur. The most common process is hydroxylation, associated with the addition of a radical to the starting material - OH.
It is in this phase of biotransformation that the initial structure of the drug molecule is “hacked”. Enzymes act as accelerators of oxidation processes (catalysts). Their substrate specificity is quite low, which explains their use as accelerators of oxidative interactions.
Synthetic reactions
The reactions of the second phase of biotransformation relate to the processes of compounding (conjugation) of drugs or its metabolites with certain endogenous substances. The products of such interactions are polar conjugates having high solubility in water, quickly excreted from the body by bile or kidney.
In order to enter into the reaction of 2 phases, the molecule must have an active chemical group (radical), to which the conjugating molecule will join. If such groups are initially present in the drug, then the interaction does not imply a first phase.
In some cases, drug molecules acquire active radicals directly in the process of chemical interaction in the first stage.
Passage through the liver
Most biotransformation of drugs occurs in the liver. Those drugs whose metabolism is carried out in the liver are divided into two subgroups: with high and low hepatic clearance.
The drugs of the first subgroup are characterized by a high degree of extraction (extraction) from the blood, which is explained by the high activity of the enzymatic systems that metabolize them. Since they are quickly and easily metabolized in the liver, clearance is associated with the speed of blood flow in the liver.
For the second group, a relationship was found with enzyme activity and the degree of binding of drugs to blood proteins. The capacity of enzyme systems is not a constant, it can be increased with a change in the dose of the drug.
Conclusion
During the administration of drugs having high hepatic clearance, they are absorbed into the small intestine. Through the portal vein they enter the liver. Here they are actively metabolized before they enter the circulatory system. Such a process is called a presystem elimination (“first-pass effect”). As a result, such drugs are characterized by low bioavailability when taken internally, and the absorption in this case is almost one hundred percent. This effect is possessed by such preparations as acetylsalicylic acid, Aminazine, Imipramine, Morphine, Reserpine, Salicylamide.
Genetic factors can have a significant effect on the pharmacokinetics of drugs. Depending on the metabolic rate of drugs in the body, "extensive" and "slow" metabolizers are isolated.
Specialists must take into account the genetic characteristics of the patient when selecting a group of drugs.
Thanks to modern research methods used in modern scientific laboratories, pharmacists are constantly improving the quality of drugs, increasing their absorption rate, and the effectiveness of the effect. As a result of these actions, it is possible to accelerate recovery, reduce the negative impact of drugs on humans.