Pharmacokinetics first-order elimination kinetics

Linear pharmacokinetics applies that is, the rate process obeys passive diffusion and first-order elimination kinetics (please review first-order process). 

Fig. 9. Semilogarithmic plots of plasma concentrations versus time for 3 doses of salicylate administered to the same subject, illustrating capacity-limited elimination. At low plasma concentrations, parallel straight lines are obtained from which the first-order elimination rate constant can be estimated. As long as concentrations remain sufficiently high to saturate the process, elimination follows zero-order kinetics (C. A. M. van Ginneken et al., J. Pharmacokinet. Biopharm., 1974,2, 395-415).

The concept of clearance is extremely useful in clinical pharmacokinetics because the systemic clearance of a drug is usually constant over the range of plasma concentrations of clinical interest. This is because the elimination of most drugs obeys first-order (linear) kinetics whereby a constant fraction is eliminated per unit of time. For drugs that exhibit dose-dependent elimination,... 

Answer E. In first-order kinetics, the elimination rate of a drug is directly proportional to its plasma concentration, which in turn is proportional to the dose. Drugs that follow first-order elimination have a constant elimination half-life. Likewise, clearance and volume of distribution are pharmacokinetic characteristics of a drug that do not routinely change with dose, although they may vary in terms of disease or dysfunction. 

Pharmacokinetics is the study of the movement of drug molecules in the body, requiring appropriate differential calculus equahons to study various rates and processes. The rate of elimination of a drug is described as being dependent on, or proporhonal to, the amount of drug remaining to be eliminated, a process that obeys first-order kinetics. The rate of eliminahon can, therefore, be described as... 

Pharmacokinetics In healthy adults treated with IV doses of iron sucrose, its iron component exhibits first order kinetics with an elimination half-life of 6 hours, total clearance of 1.2 L/h, non-steady-state apparent volume of distribution of 10 L, and steady-state apparent volume of distribution of 7.9 L. 

Pharmacokinetics Epoetin alfa IV is eliminated via first-order kinetics with a circulating half-life of 4 to 13 hours in patients with CRF. Within the therapeutic dosage range, detectable levels of plasma erythropoietin are maintained for at least 24 hours. After subcutaneous administration of epoetin alfa to patients with CRF,... 

For drugs that follow first-order kinetics, in addition to clearance, the half-life is a useful pharmacokinetic parameter to describe elimination. The elimination half-life (tj/j) is the time required for the concentration of drug to decrease by 50%. In clinical practice, this parameter is referred to as the plasma (or serum) half-life and is usually assessed by measuring the fall of... 

Valproic acid is eliminated by first-order kinetics and has an elimination half-life of 5-20 hours (average, 10.6 hours). Pediatric patients (3 months to 10 years) have a 50% higher clearance of the drug expressed by weight (i.e., mL/min/kg) over the age of 10 years, pharmacokinetic parameters of valproic acid approximate those in adults (Cloyd et al., 1993). Valproic acid is metabolized principally in the liver by (3 (over 40%) and CO oxidation (up to 15%-20%). Thirty through 50% of an administered dose is excreted as glucuron-ide conjugates (Cloyd et al., 1993). 

The concept of clearance is useful in pharmacokinetics because clearance is usually constant over a wide range of concentrations, provided that ehmination processes are not saturated. Saturation of biotransformation and excretory processes may occur in overdose and toxic okinetic effects should be considered. If a constant fraction of drug is eliminated per unit time, the elimination follows first-order kinetics. However, if a constant amount of drug is eliminated per unit time, the elimination is described by zero-order kinetics. Some drugs, for example, ethanol, exhibit zero-order kinetics at normal or non-intoxicating concentrations. However, for any drug that exhibits first-order kinetics at therapeutic or nontoxic concentrations, once the mechanisms for elimination become saturated, the kinetics become zero order and clearance becomes variable.3... 

Linear pharmacokinetics. For a simple linear pharmacokinetics case, the body can be modeled as a single drug compartment with first-order kinetic elimination—where the dose is administered and drug concentrations are drawn from the same compartment. For an intravenous bolus dose, the expected drug plasma concentration Cp versus time curves are shown in Fig. 1.10. The kinetics for this system are described by Eq. (1.6). The well-known solution to this equation is given by Eq. (1.7), and a linearized version of this solution is given in Eq. (1.8) and shown graphically in Fig. 1.13. 

If we let K = (D Sa Pc/d), then, since A is present in the equation, n must equal 1, so we have a first-order rate process. Fick s law of diffusion, which is important for quantitating rates of absorption, distribution, and elimination, is thus the basis for using first-order kinetics in most pharmacokinetic models. 

In conclusion, pharmacokinetics is a study of the time course of absorption, distribution, and elimination of a chemical. We use pharmacokinetics as a tool to analyze plasma concentration time profiles after chemical exposure, and it is the derived rates and other parameters that reflect the underlying physiological processes that determine the fate of the chemical. There are numerous software packages available today to accomplish these analyses. The user should, however, be aware of the experimental conditions, the time frame over which the data were collected, and many of the assumptions embedded in the analyses. For example, many of the transport processes described in this chapter may not obey first-order kinetics, and thus may be nonlinear especially at toxicological doses. The reader is advised to consult other texts for more detailed descriptions of these nonlinear interactions and data analyses. 

Since there is a directly proportionate relationship between administered drug dose and steady-state plasma levels Equations 2.2 and 2.3 provide a straightforward guide to dose adjustment for drugs that are eliminated by first-order kinetics. Thus, to double the plasma levels the dose simply should be doubled. Con-versely to halve the plasma level, the dose should be halved. It is for this reason that Equations 2.2 and 2.3 are the most clinically important pharmacokinetic equations. Note that, as is apparent from Eigure 2.6, these equations also stipulate that the steady-state level is determined only by the maintenance dose and elimination clearance. The loading dose does not appear in the equations and does not influence the eventual steady-state level. 

Conceptual models of percutaneous absorption which are rigidly adherent to general solutions of Pick s equation are not always applicable to in vivo conditions, primarily because such models may not always be physiologically relevant. Linear kinetic models describing percutaneous absorption in terms of mathematical compartments that have approximate physical or anatomical correlates have been proposed. In these models, the various relevant events, including cutaneous metabolism, considered to be important in the overall process of skin absorption are characterized by first-order rate constants. The rate constants associated with diffusional events in the skin are assumed to be proportional to mass transfer parameters. Constants associated with the systemic distribution and elimination processes are estimated from pharmacokinetic parameters derived from plasma concentration-time profiles obtained following intravenous administration of the penetrant. 

We studied the in vivo pharmacokinetics of transscleral delivery of IgG. We used an osmotic pump, the tip of which was secured flush against bare sclera in rabbits to facilitate unidirectional movement, to deliver fluorescently labeled IgG (150kDa) at rates on the order of pL/hr. Biologically relevant concentrations in the choroid and retina were attained for periods of up to four weeks with negligible systemic absorption (6). Levels in the vitreous and aqueous humors, and orbit were negligible. Although there was a spatial concentration gradient, the IgG concentration in the choroidal hemisphere distal to the footprint of the osmotic pump tip was half of that in the proximal hemisphere. The elimination of IgG from the choroid and retina followed first-order kinetics with half-lives of approximately two to three days. 

Figure 1-3. Serum concentration-time curve after administration of chlordiazepoxide as an intravenous bolus. The experimental data are plotted on a semilogarithmic scale as filled circles. This drug follows first-order kinetics and appears to occupy two compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination half-life (f gj) can be extracted graphically as shown by measuring the time between any two plasma concentration points that differ by twofold. (See Chapter 3 for additional details.) (Modified and reproduced, with permission, from Greenblatt DJ, Koch-Weser J. Drug therapy Clinical pharmacokinetics. N Engl J Med 1975 293 702.)...

For the pharmacokinetics of rhG-CSF in humans, it has been reported that the absorption and clearance of rhG-CSF follow first-order kinetics without any apparent concentration dependence [114], When rhG-CSF was administered by 24-h constant i.v. infusion at a dose level of 20pg/kg, the mean serum concentration achieved 48ng/mL. Constant i.v. infusion for 11 to 20 days produced steady-state serum concentrations over the infusion period. Subcutaneous administration of rhG-CSF at doses of 3.45 and 11.5pg/kg resulted in peak serum concentrations of 4 and 49ng/mL, respectively. The mean value of volume of distribution was 150mL/kg. The elimination half-life was 3.5h after either i.v. routes or s.c. routes, with a clearance rate of 0.5-0.7 mL/min/kg. The administration of a daily dose for 14 consecutive days did not affect the half-life. 

Different tissues have been shown to display different DNA pharmacokinetics. Genes and gene products have been observed as long as 19 months after direct injection without indication of plasmid integration or replication (175). Direct injection of the chloramphenicol acetyltransferase gene into the thyroid resulted in elimination of DNA from the gland with a half-life of 10 hours. The enzyme activity was maximal for 24 hours and eliminated through first-order kinetics with an apparent half-life of 40 hours (176). Similar results were recorded for synovial fluid intra-articular administration of plasmid DNA (177). 

B. Pharmacokinetics. Chlorinated hydrocarbons are well absorbed from the gastrointestinal tract, across the skin, and by inhalation. They are highly lipid soluble and accumulate with repeated exposure. Elimination does not follow first-order kinetics compounds are slowly released from body stores over days to several months or years. 

Pharmacokinetic parameters, such as elimination half life (ti/2), the elimination rate constant (K), the apparent volume of distribution (V) and the systemic clearance (Cl) of most drugs are not expected to change when different doses are administered and/or when the drug is administered via different routes as a single or multiple doses. The kinetics of these drugs is described as linear, or dose-independent, pharmacokinetics and is characterized by the first-order process. The term linear simply means that plasma concentration at a given time at steady state and the area under the plasma concentration versus time curve (AUC) will both be directly proportional to the dose administered, as illustrated in Fig. 15.1. 

For drugs that exhibit non-linear or dose dependent kinetics, the fundamental pharmacokinetic parameters such as clearance, the apparent volume of distribution and the elimination half life may vary depending on the administered dose. This is because one or more of the kinetic processes (absorption, distribution and/or elimination) of the drug may be occurring via a mechanism other than simple first-order kinetics. For these drugs, therefore, the relationship between the AUC or the plasma concentration at a given time at steady state and the administered dose is not linear (Fig. 15.2). 

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