Medicine Lecture Note - Biotransformation

Biotransformation The process of changing the chemical structure of drugs that occurs in the body and is catalyzed by enzymes is called biontransformation or drug metabolism. It works by changed the drug molecules in the body to become more polar. Apart from that, in general drugs become inactive so that biotransformation plays a very important role in ending the drug's action. Biotransformation reactions are classified into: 1. Phase I metabolism Phase I metabolic reactions include conjugation/biosynthesis reactions. Reactions in this phase usually result in the loss of the drug's pharmacological activity. However, there are also those that continue to show continued activity or increased activity. In a few cases, metabolism is associated with changes in pharmacological activity. Prodrug is a compound that pharmacologically inactive, designed to maximize the number of active species reaching their site of action. Inactive prodrugs are immediately converted to biologically active metabolites, often via hydrolysis of ester or amide bonds. If it is not excreted quickly into the urine, the results of the phase I biotransformation reaction will react with endogenous compounds to form conjugates that are highly soluble in water. 2. Phase II metabolism Phase II conjugation reactions cause the formation of covalent bonds between functional groups in the parent compound or phase I metabolite and endogenous derivatives of glucuronic acid, sulfate, glutathione, amino acids, or acetate. This highly polar conjugate is generally inactive and is rapidly excreted in urine and feces. An example of an active conjugate is the morphine metabolite, namely glucuronide which has a stronger analgesic effect compared to its parent compound. Biotransformation Site Metabolic conversion of drugs is generally enzymatic. The drug system involved in drug biotransformation is located in the liver, although each tissue examined also has metabolic activity. After administration of drugs via the nonparenteral route, a number of drugs can undergo metabolic inactivation in the epithelium of the small intestine or in the liver before the drug reaches the bloodstream. This first-pass metabolism significantly limits the oral availability of highly metabolizing drugs. In certain cells, most of the drug metabolism activity occurs in the endoplasmic reticulum and in the cytosol, although drug biotransformation can also occur in the mitochondria, cell nuclear membrane, plasma membrane. Factors affecting Drug Metabolism : - Genetic variation Advances in molecular biology show that genetic diversity must occur for all proteins without exception, including enzymes that catalyze drugmetabolism reactions. - Environmental Influence The activity of drug metabolizing enzymes may be modulated by exposure to certain exogenous compounds. In some cases, this may occur with drugs that, if given simultaneously with a second substance, cause drug-drug interactions. In addition, dietary micronutrients and other environmental factors can increase enzyme action, which is called induction, or decrease enzyme action, which is called inhibition. - Disease factors The liver is the main site of enzymatic drug metabolism. Disorders of the function of this organ in patients with hepatitis, alcohol-induced liver disease, biliary cirrhosis, fatty liver and liver cancer have the potential to interfere with drug metabolism. - Age and Gender Cytochrome P450 isoforms and to a lesser extent phase II drug-metabolizing enzymes develop earlier in fetal development, but their levels, even at birth, are lower than after birth. Both phase I and gase II enzymes begin to mature gradually starting from the second to fourth week after birth, although the development pattern is different for each enzyme. Therefore, babies and newborns are able to metabolize drugs relatively more efficiently but more slowly than adults. The exception to this is impaired bilirubin gglucoronidation at birth, which causes hyperbilirubinemia in newborn babies. Full maturity occurs after reaching the age of 20 years and then declines slowly with age. A number of examples show that drug administration and/or reactions in women and men can be different for certain drugs. Some differences in activity in drug metabolism due to sex differences, especially those catalyzed by CYP3A, have also been identified. In pregnant women there is induction of certain drug metabolizing enzymes during the second and third trimesters of pregnancy. This results in larger doses of medication having to be given during this period and returning to the previous dose after delivery. For example, for the use of phenytoin.