Drug elimination biotransformation

A second area of drug discovery and development in which enzyme reactions play a critical role is in the study of drug metabolism and pharmacokinetics. The elimination of xenobiotics, including drug molecules, from systemic circulation is driven by metabolic transformations that are entirely catalyzed by enzymes. Table 1.2 lists some of the enzyme-catalyzed transformations of xenobiotics that commonly contribute to drug molecule elimination. These biotransformation reactions... 

Renton KW. Alteration of drug biotransformation and elimination during infection and inflammation. Pharmacol Ther 2001 92 147-163. 

Genetic differences. Patients show a wide variation in both the extent of liver biotransformation and the range of metabolic pathways used to eliminate drugs. Differences in the metabolism of the drug can lead to a smaller clinical effect than desired, a greater clinical effect than desired (e.g., an antihypertensive causing hypotension), or a more toxic effect than desired. 

Relatively innocuous factors can also sometimes influence liver enzyme activity. For example, the metabolic elimination of the bronchodilator theophylline has been reported to be prolonged in patients with influenza A or adenovirus infections. In 1990, an influenza epidemic in Seattle resulted in the admission of 11 children with high serum levels of theophylline and confirmed drug toxicity. These effects appear to be confined to cytochrome P450-based drug biotransformation. They may be related to the generation of interferons as a result of these infections, which, presumably, are causally related to the inhibitory effect on hydroxylases and demethylases. 

Drugs are most often eliminated by biotransformation and/or excretion into the urine or bile. The liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues. [Note Some agents are initially administered as inactive compounds (prodrugs) and must be metabolized to their active forms.]... 

A human ADME study conducted using radiolabeled form of the NCE (usually referred to as 14C-human ADME) is a study that in most cases is required prior to start of the Phase III clinical trials and the data from the human ADME study are important components of the nonclinical sections of the NDA submission and drug label. The objectives of 14C-human ADME studies are to determine the total disposition of the NCE, encompassing mass balance, routes of NCE/metabolite elimination, and biotransformation pathways. 

Modes of drug elimination are biotransformation, renal excretion, and excretion by other routes (e.g., bile, sweat, lungs, etc.). Most drugs follow first-order elimination rates. Figures l-MOa and 1-1-lOb compare zero- and first-order elimination, and Figure 1-1-11 demonstrates how the t, and the theoretical zero time plasma concentration (C°) can be graphically determined. Two important relationships are dose = x C° and t, = 0.7/k (k = the first-order rate constant of elimination). 

The terminator of drug action is, of course, elimination. Elimination is a composite of excretion (kidney, etc.) and biotransformation (metabolism). The primary measure of drug elimination from the whole body is clearance, CLt, defined as the volume of plasma fluid removed of drug per unit time. It is a direct measure of the loss of the drug from the system and can be calculated from Eq. (3.5) after IV administration of a dose of the drug. 

Identification of metabolic reactions at an early phase can significantly affect the drug discovery process, because bioavailability, activity, toxicity, distribution and final elimination all depend on metabolic biotransformations [1], Once obtained, this information can help researchers judge whether or not a potential candidate should be eliminated from the pipeline or modified to reduce the affinity for CYP antitarget enzymes. 

---