Drug elimination process

Drug Elimination process No. of species Coeffldent Exponent Correlation coefficient ... 

McLachlan AJ, Gross AS, Beal JL, Minns I, and SE Tett (2001). Analytical validation for a series of marker compounds used to assess renal drug elimination processes. Therapeutic Drug Monitoring 23 39 6. 

Garrett and Hunt (12) have shown that the terminal half-life of A -THC in the dog is reached only slowly. They also found that the return of A -THC from the tissues is the rate determining step of the drug elimination process after the initial distribution and metabolism. 

Drug elimination may not be first order at high doses due to saturation of the capacity of the elimination processes. When this occurs, a reduction in the slope of the elimination curve is observed since elimination is governed by the relationship Vmax/(Km- -[conc]), where Vmax is the maximal rate of elimination, Km is the concentration at which the process runs at half maximal speed, and [cone] is the concentration of the drug. However, once the concentration falls below saturating levels first-order kinetics prevail. Once the saturating levels of drugs fall to ones eliminated via first-order kinetics, the half time can be measured from the linear portion of the In pt versus time relationship. Most elimination processes can be estimated by a one compartment model. This compartment can... 

Zero-order kinetics describe the time course of disappearance of drugs from the plasma, which do not follow an exponential pattern, but are initially linear (i.e. the drug is removed at a constant rate that is independent of its concentration in the plasma). This rare time course of elimination is most often caused by saturation of the elimination processes (e.g. a metabolizing enzyme), which occurs even at low drug concentrations. Ethanol or phenytoin are examples of drugs, which are eliminated in a time-dependent manner which follows a zero-order kinetic. 

It was mentioned previously that drug elimination from the body most often displays the characteristics of a first-order process. Thus, if a drug is administered by rapid intravenous (IV) injection, after mixing with the body fluids its rate of elimination from the body is proportional to the amount remaining in the body. 

Equation (35) describes the line in Fig. 10, which is a semilog plot of Cp versus time for an orally administered drug absorbed by a first-order process. The plot begins as a rising curve and becomes a straight line with a negative slope after 6 hours. This behavior is the result of the biexponential nature of Eq. (35). Up to 6 hours, both the absorption process [exp(—kat) and the elimination process [exp( keil)] influence the plasma concentration. After 6 hours, only the elimination process influences the plasma concentration. 

The Wagner-Nelson method of calculation does not require a model assumption concerning the absorption process. It does require the assumption that (a) the body behaves as a single homogeneous compartment and (b) drug elimination obeys first-order kinetics. The working equations for this calculation are developed next. 

The usual goal of an oral sustained-release product is to maintain therapeutic blood levels over an extended period. To achieve this, drug must enter the circulation at approximately the same rate at which it is eliminated. The elimination rate is quantitatively described by the half-life (t /2). Each drug has its own characteristic elimination rate, which is the sum of all elimination processes, including metabolism, urinary excretion, and all other processes that permanently remove drug from the bloodstream. 

Upon absorption, the plasma concentration of the drug continues to rise until it reaches the maximum concentration. Cmax. At Cmax, the rates of elimination processes such as metabolism and excretion, which also begin to operate on the drug as soon as it enters the body, equal the rate at which it is absorbed (Fig. 3.1). Throughout the absorption process, the drug rapidly distributes to the red blood cells, organs, and all intra- and extracellular... 

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. 

The curve crosses the y axis at a value of a. It declines exponentially as t increases. The line is asymptotic to the x axis. This curve is seen in physiological processes such as drug elimination and lung volume during passive expiration. ... 

By combining Figs 5.8 and 5.9, we obtain the situation depicted in Fig. 5.10. After a drug is absorbed, it enters the bloodstream and the concentration builds up until a steady state is reached. As time passes, the elimination process takes over and the concentration of the drug decreases. 

Half-lives estimated after the administration of vinblastine to patients were 4 min, 1.6 hr, and 25 hr, indicating rapid distribution of the drug to most tissues, relatively rapid clearance, and a subsequent slow terminal elimination process. The distribution and initial clearance phase for vincristine are kinetically comparable to those observed for vinblastine half-lives for these phases have been reported to be 4 min and 2.3 hr in studies with vincristine. The terminal elimination phase for vincristine has been reported to be three to four times longer than that estimated for vinblastine, and the slow elimination of vincristine from susceptible neuronal tissue has been suggested to play a role in the neurotoxicity commonly observed in clinical settings with vincristine but not with vinblastine 51). 

The transport mechanisms that operate in distribution and elimination processes of drugs, drug-carrier conjugates and pro-drugs include convective transport (for example, by blood flow), passive diffusion, facilitated diffusion and active transport by carrier proteins, and, in the case of macromolecules, endocytosis. The kinetics of the particular transport processes depend on the mechanism involved. For example, convective transport is governed by fluid flow and passive diffusion is governed by the concentration gradient, whereas facilitated diffusion, active transport and endocytosis obey saturable MichaeUs-Menten kinetics. 

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