Hello everyone, today I am going further with Pharmacokinetics, and I will be discussing drug Metabolism. I discussed about drug absorption which takes place after a drug has been taken orally. I mentioned that I would be taken into the Gastrointestinal tract after which it would be absorbed into the bloodstream after which it gets distributed through the circulatory system to various tissues and organs in the body. After the drug has been used up, it needs to be removed from the body through urine, feces, and exhalation but before that occurs, the metabolism of the drug from its active form to its inactive form needs to take place.
When a drug has done its function, it is taken up by the liver. The liver performs certain functions on drugs such as detoxification (turning a toxic substance into a non-toxic one), in the cases of prodrugs, it turns the inactive form of the drug into an active form (an example is Valacyclovir being the prodrug of Acyclovir and the liver breaks the inactive form to the active form of the drug), and it can take an active drug and convert to an inactive drug which can then be removed from the system.
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To turn an active drug into an inactive one, there are two phases that should be considered. The Phase 1 Biotransformation, and the Phase 2 Biotransformation. Depending on the drug, some might undergo either of the phases to become inactive or both phases. To explain this, let's discuss the Hepatocyte a little. The Hepatocyte is made up of the Smooth Endoplasmic Reticulum, the Mitochondrial, and heme-containing enzymes known as the Cytochrome CYP450 system which contains several subtypes that include CYP1A1/2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5/7. The most important subtypes in the pathway are CYP3A4 and CYP2D6. To explain the meaning of such naming, I'll take the CYP3A4. the 3 explains the family of the Cytochrome it belongs to, the A is for the subfamily of the heme-containing enzyme, and the 4 is to identify the isozyme of the Cytochrome CYP450 enzyme.
The CYP450 enzyme takes a drug and utilizes oxidation reactions, reduction reactions, and/or hydrolysis, in other to convert a non-polar drug to a polar drug, and a lipid-soluble drug to a water-soluble one. In other, for the CYP450 enzyme to metabolize the drugs, certain factors are considered such as how fast drugs are metabolized. Rapid metabolizers can quickly convert from an active state to an inactive drug. When the enzyme is a rapid metabolizer, they quickly increase the inactive metabolite concentration and decrease the concentration of the active drug, decreasing the therapeutic effect of the drug. If the drug is a slow metabolizer, it would take a longer time for the CYP450 enzyme to convert the drug from its active state to its inactive state which could lead to toxic side effects as a result of the drug not quickly metabolized.
Another factor that could affect the metabolism of drugs is the liver. Liver diseases such as liver failure, cirrhosis, acute liver failure, and so many other liver conditions can lead to the decrease of Cytochrome CYP450 enzyme in the liver which will reduce the ability to take an active drug and turn it into an inactive drug. This will lead to toxicity after drug intake. This isn't only for people with liver disease, it is also a possibility with infants and the elderly as their Cytochrome P450 is reduced causing drug metabolism to be reduced. The Cytochrome CYP450 enzyme also converts Proddrugs into an active drug, and when there is a case of a decreased Cytochrome CYP450 enzyme, the ability to turn the prodrug to an active one is difficult or impossible.
In phase 2 biotransformation, the Cytochrome CYP450 enzyme is not involved. But in other to convert the drugs from active ones to inactive ones, it will make the drugs polar and water-soluble using transferase enzymes such as UDP–glucuronosyltransferases(glucuronidation) acting on glucuronate, and so on, which act on methyl groups, Acetyl group in the case of acetylation, sulfur molecules in the case of sulfation, and Gluthation molecules. These transferase enzymes act on the drugs to make them more polar, and water-soluble, making them easy to be removed via the biliary system.
Conclusion
Let me do a very quick summary of everything I have been saying since morning, which might look complex a little at first glance. Drug Metabolism has to do with converting a Hydrophilic, non-polar drug to a polar drug so as to enable its elimination from the body. I said that drug metabolism can lead to two types of metabolite, either an active metabolite in the case of converting a prodrug to an active drug (i remembered using an example of Valacyclovir being the prodrug of Acyclovir above), or an inactive metabolite where we convert active drugs to non-active drugs. I explained that the liver is the major place for drug metabolism in the body and has lots of enzymes that metabolize drugs. I also said that the metabolism pathway can be divided into phase 1 and phase 2 where phase one is characterized as a functionalization reaction where the drug polarity is increased so it can be easily excreted. Do you remember I discussed the Cytochrome CYP450 enzyme, it is a superfamily of oxidases, thereby helping with oxidation reactions in drugs. In phase one reaction, reduction reaction and hydrolysis also take place on drugs. Phase 2 reactions are commonly called Conjugation reactions which are done by enzymes known as a transferase. Transferace transfers co-factor to the drug making them polar. The purpose of metabolizing active drugs to inactive metabolites, is to enable the drugs to be excreted from the body and prevent toxicity.