According to FDA, drug is any substance aimed to diagnose, cure, relieve symptoms, treat or prevent a disease and which affect the structure as well as function of body.Though such a definition may serve the legal requirements, a more general approach can be used for the actual metabolic processes within the body. Simply put, it is any chemical substance which affects the living body or the processes.
We are all exposed to a wide variety of chemicals everyday. These are generally termed as xenobiotics. They are substances which are absorbed through the body surface or ingested into the body. Some of these chemicals are harmless in its native forms, but elicits toxic responses once they are metabolized inside the body.
Whatever may be the effects, these substances must be eliminated from the body. Biotransformation mechanisms help in conversion of these toxic chemicals into harmless substances which can be easily eliminated from the system.
Need for biotransformation
Most drugs do not have the physiochemical characteristics to be eliminated readily from the system. They are mostly lipophilic, remain un ionized or partially ionized at the physiological parameters of pH and temperature making them difficult to be excreted via the renal tubules. Hence if the body depends solely on renal excretion to eliminate the drugs, it would result in longer retention times and consequently higher biological activity.
An alternative method to this is metabolizing the drugs to less toxic or less active forms in the system. Generally, these biotransformation aims to convert the lipophilic molecules to lipophobic compounds or molecules for elimination.
Most of the metabolic products are less pharmacodynamically active than the parent drug and sometimes inactive. A few has enhanced activity after biotransformation processes. Such drugs are identified and are the basis of prodrugs. These are ingested in inactive forms which on getting metabolized in the body changes to biologically active forms.
The reverse can also occur. Less toxic chemicals can become more toxic, carcinogenic or teratogenic on being metabolized in the body.
Most of the biotransformation processes occur between the absorption of drug into the blood stream and its elimination from the body. A few of them occur at the intestinal wall. These reactions can be generally classified into Phase I and Phase II reactions.
Phase I metabolic reactions aim to enhance or decrease the biological activity of the drug molecule whereas Phase II reactions help to eliminate the molecule from the body.
Phase I reactions
Phase I reactions usually transform the parent drug molecule to polar metabolite. A functional group like -OH, -NH2, or -SH is introduced or unmasked in the drug molecule either making them inactive or changing their biological activity.
Phase II reactions
Usually these changes are not enough to make them sufficiently polar for a rapid elimination. Additional conjugation with highly polar molecules such as acetate, glucuronate, amino acids etc result in easy elimination. These reactions constitute the phase II reactions.
In a few cases, the parent drug may already possess an ionizable or functional group which can readily form the conjugates. The conjugate thus formed may undergo a Phase I reaction afterwards. Thus phase II can precede phase I reactions. One common example is the isoniazid molecule.
First pass effect
Drug metabolism in its large part occurs in liver tissues. It can also take place in the lungs, skin, gastrointestinal tract or the kidneys. Orally administered drugs find their way into the portal circulation via absorption and enter the liver.
The liver tissues metabolize these drug molecules. This is called as the 'first pass effect'. Some drugs may be readily metabolized in the intestine before they enter into liver thus making the process easier. The bioavailability of the drugs is greatly reduced by this hepatic first pass effect and hence other modes of drug administration should be employed to overcome this.
An intravenous mode of administration therefore has greater bioavailability than the oral administration of drugs. The microbial community of small intestine carries out some of these transformations. Some drugs are metabolized by the digestive enzymes such as trypsin or gastric acid. Majority of the drug biotransformation are specifically catalyzed by enzymatic actions.
At the subcellular level, these reactions are found to occur in the microsomal enzymes such as mixed function oxidases and cytochrome P450. The CYP450 is the terminal oxidase in the reaction and therefore this step is essentially the rate limiting step of hepatic drug oxidation reactions.
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