Elimination processes plasma half-lives

The introduction of fluorine atoms in a molecule can be used to modify the processes and the rates of metabolism of the drug, in order to extend the plasma half-life or avoid the formation of toxic metabolites. Due to the properties of the fluorine atom, in particular its electronic effects, it may interact differently during the biotransformation steps, according to the type of processes involved (oxidative, reductive, hydrolytic, etc), which allow the clearance of the exogen molecule (i.e., the elimination of the active substance from the organism). 

The half-life will be independent of the dose, provided that the elimination is first order and therefore should remain constant. Changes in the half-life, therefore, may indicate alteration of elimination processes due to toxic effects because the half-life of a compound reflects the ability of the animal to metabolize and excrete that compound. When this ability is impaired, for example, by saturation of enzymic or active transport processes, or if the liver or kidneys are damaged, the half-life may be prolonged. For example, after overdoses of paracetamol, the plasma half-life increases severalfold as the liver damage reduces the metabolic capacity, and in some cases, kidney damage may reduce excretion (see chap. 7). 

The hyperbolic relationship be tween plasma concentration and effect explains why the time course of the effect, unlike that of the plasma concentration, cannot be described in terms of a simple exponential function. A half-life can be given for the processes of drug absorption and elimination, hence for the change in plasma levels, but generally not for the onset or decline of the effect... 

Absorption/Distribution - Following IV administration, distribution is essentially confined to extracellular fluids and is characterized by an initial half-life of about 10 minutes. Elimination follows a first-order process and is characterized by a terminal half-life of about 1.3 hours in young healthy volunteers. As the IV dose is increased over the range of 0.1 to 0.4 mg/kg, the maximum plasma... 

It is important to note that the elimination half-life is a derived term, and any process that changes k will change the half-life of the drug. Factors that may affect pharmacokinetic parameters are discussed elsewhere, but in this example may include disease states, changes in urinary pH, changes in plasma protein binding, and coadministration of other drugs. 

The clinical development stage comprises three distinct components or phases (I, II, and III), and culminates in the filing of the NDA/MAA. Each phase involves process scale-up, pharmacokinetics, drug delivery, and drug safety activities. During phase I clinical development, the compound s safety and pharmacokinetic profile is defined. The determination of maximum concentration at steady state (Cmax), area under the plasma concentration time curve (AUC), elimination half-life, volume of distribution, clearance and excretion, and potential for drug accumulation is made in addition to studies that provide estimates of efficacious doses. Dose levels typically... 

Figure 11 Enzymatic activity profile of man rose-terminal ghicocerebraidase in plasma of a boy with Gaucher disease. Enzyme was infused over 4 hours at a constant rate of 1225 Uftg. A steady-stale value of 10.6 mUftnL was achieved during the first hour. When the infusion was terminated at 240 minutes, enzyme was cleared from the plasma by a firat-order process with an elimination half-life of 6.3 minutes. The dashed line represent the activity profile calculated from the observed kinetic constants.

To evaluate the pattern and the rate of excretion and to investigate the time course of radioactivity concentrations in blood and plasma with the aim of getting information about the absorption process, the AUC, Cmax and the elimination half-life of radioactivity in blood and plasma. Possibly, indices for enterohepatic... 

The half-life of a drug is the time required for plasma concentrations to decline by 50%, provided that elimination occurs by a first-order process (Fig. 3). It is related to the elimination rate constant (A ) by the equation... 

Following absorption, NMP is uniformly distributed throughout all major organs in the rat with a volume of distribution (about 0.71 kg ) that approximates total body water. In both the rat and man, NMP is eliminated primarily by metabolism to other compounds via a saturable process only about 2% of the absorbed NMP is excreted unchanged. The major metabolite is 5-hydroxy-NMP (50-70%) with lesser amounts of N-methylsuccinimde, 2-hy-droxy-N-methylsuccinimide, and possibly other unidentified metabolites. The half-life of NMP in plasma is 4h. Studies with radiolabeled NMP indicate the most of the radiolabel is excreted in the urine ( 95%), with lesser amounts in the feces ( 5%) and expired air ( 2%). Ongoing studies are investigating the use of 5-hydroxy-NMP as a urinary biomarker for human exposures to NMP. 

Vitamin A is readily absorbed from the intestine as retinyl esters. Peak serum levels are reached 4 h after ingestion of a therapeutic dose. The vitamin is distributed to the general circulation via the lymph and thoracic ducts. Ninety percent of vitamin A is stored in the liver, from which it is mobilized as the free alcohol, retinol. Ninety-five percent is carried bound to plasma proteins, the retinol-binding protein. Vitamin A undergoes hepatic metabolism as a first-order process. Vitamin A is excreted via the feces and urine. Beta carotene is converted to retinol in the wall of the small intestine. Retinol can be converted into retinoic acid and excreted into the bile and feces. The elimination half-life is 9 h. 

The advantages of using non-compartmental methods for calculating pharmacokinetic parameters, such as systemic clearance (CZg), volume of distribution (Vd(area))/ systemic availability (F) and mean residence time (MRT), are that they can be applied to any route of administration and do not entail the selection of a compartmental pharmacokinetic model. The important assumption made, however, is that the absorption and disposition processes for the drug being studied obey first-order (linear) pharmacokinetic behaviour. The first-order elimination rate constant (and half-life) of the drug can be calculated by regression analysis of the terminal four to six measured plasma... 

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