[The pharmacokinetic process: is the drug getting to its site of action?: Drug metabolism]

In general, drug biotransformation reactions are classified as either phase 1 functionalization (mainly oxidative) reactions or phase 2 conjugation (biosynthetic) reactions. Phase 1 reactions introduce or expose a functional group on the parent compound and generally result in the loss of pharmacological activity. Phase 2 reactions lead to the formation of a covalent linkage between a functional group on the parent compound with glucuronic acid, sultate, glutathione, amino acids, or acetate. These highly polar conjugates are generally inactive and are excreted rapidly in the urine and feces. The metabolic conversion of drugs is enzymatic in nature. The enzyme systems involved in the biotransformation of drugs are localized in the liver although every tissue examined has some metabolic activity The enzymes involved in phase 7 reactions are located primarily in the endoplasmic reticulum while the phase 2 conjugation enzymes are mainly cytosolic. The cytochrome P450 monooxigenase system is the cornerstone and the major catalyst of drug biotransformation reactions. The CYP superfamily is divided into families and subfamilies of enzymes that are defined on the basis of similarities in the amino acid sequence. Currently, no doubt exists that the CYP-mediated reactions typically show pronounced interindividual variability that is evaluated under the scope of the pharmacogenetic discipline. In addition, therapeutic outcome may be influenced by a number of factors such as concomitant drug administration, diet or smoking, among others. It may regulate drug metabolism through modulation (induction or inhibition) of the activities of CYPs and hence, it may provoke the occurrence of severe adverse drug reactions.