Plasma-concentration curve

This shows that the initial steepness of the plasma curve depends, for a given dose D, on the volume of distribution and on the transfer constant of absorption k.. The various characteristics of the plasma concentration curve are also schematically displayed in Fig. 39.9 for different contingencies of k, k ... 

If an oral or parenteral plasma concentration curve is available together with an intravenous one from the same subject(s), then one can derive the absorption fraction from these. 

The area under the plasma concentration curve UAC results from integration of the sum of exponentials in eq. (39.60) between zero and infinity ... 

Fig. 39.15. Area under a plasma concentration curve AUC as the sum of a truncated and an extrapolated part. The former is obtained by numerical integration (e.g. trapezium rule) between times 0 and T, the latter is computed from the parameters of a least squares fit to the exponentially decaying part of the curve (P-phase).

Other non-compartmental parameters that are easily obtainable from a plasma concentration curve are the time of appearance of the maximum and the peak concentration value Cp(r ,). 

The variance of the residence times VRT is derived from the area under the second moment of the plasma concentration curve AUSC ... 

The quantities AUMC and AUSC can be regarded as the first and second statistical moments of the plasma concentration curve. These two moments have an equivalent in descriptive statistics, where they define the mean and variance, respectively, in the case of a stochastic distribution of frequencies (Section 3.2). From the above considerations it appears that the statistical moment method strongly depends on numerical integration of the plasma concentration curve Cp(r) and its product with t and (r-MRT). Multiplication by t and (r-MRT) tends to amplify the errors in the plasma concentration Cp(r) at larger values of t. As a consequence, the estimation of the statistical moments critically depends on the precision of the measurement process that is used in the determination of the plasma concentration values. This contrasts with compartmental analysis, where the parameters of the model are estimated by means of least squares regression. 

Compartmental analysis is the most widely used method of analysis for systems that can be modeled by means of linear differential equations with constant coefficients. The assumption of linearity can be tested in pharmaeokinetic studies, for example by comparing the plasma concentration curves obtained at different dose levels. If the curves are found to be reasonably parallel, then the assumption of linearity holds over the dose range that has been studied. The advantage of linear... 

AUC, area under the plasma concentration curve BZ, benzodiazepine Cl, clearance t1/2, elimination half-life. 

Ward et al. [130] studied the pharmacokinetics of (+)- and (—)-primaquine in the isolated perfused rat liver preparation. The perfusate plasma concentrations of primaquine in the isolated, perfused rat liver, declined biexponentially following the addition of either (+)- or (—)-primaquine at doses 0.5-2.5 mg in the perfusate reservoir. There were no differences between pharmacokinetic profiles of the two isomers at the 0.5 mg dose. By contrast, the elimination of (—)-primaquine was greater than (+)-primaquine when either was added in a dose of 2.5 mg also, the clearance of the (—)-isomer was greater, the half-life was shorter, and the area under the plasma concentration curve was shorter. The volume of distribution was similar for the two isomers. These results are relevant to both the therapeutic efficacy and toxicity of primaquine. 

Key points When both curves are drawn, mark a fixed concentration point on the y axis and label it C. Demonstrate that the plasma concentration curve crosses this value twice, at times tx and t2. At time f, the concentration in the plasma is rising and at t2 it is falling. The crucial point now that enables you to define hysteresis is to demonstrate that the effector site concentration is different at these two times depending on whether the plasma concentration is rising (giving concentration Ej) or falling (giving concentration E2). 

A few N-Mannich bases of the anti-inflammatory drug salicylamide are reported in Table 11.1. The pharmacokinetic behavior of one of these, N-(morpholinomethyl)salicylamide (11.54), was examined in the rabbit [90], Plasma concentration curves showed that the oral bioavailability of salicylamide was increased two- to sixfold by administration of the prodrug. 

Sundwall, A. Plasma concentration curves of N-methyl-pyridinium-2-aIdoxime methane sulphonate (P2S) after intravenous, intramuscular, and oral administration in man. 

Figure 5.2 Plasma concentration curve of drug after single and repeated administration Csj. nax, maximal steady-state plasma concentration after repeated administration Css av, average steady-state concentration after repeated administration Css mm- minimal steady-state concentration after repeated administration n. maximal plasma concentration after single oral dose t Inax. time to maximal concentration after single oral dose t plasma half-life after single oral dose AUC, area under the concentration vs. time curve...

Distribution of etomidate is rapid, with a biphasic plasma concentration curve showing initial and intermediate distribution half-lives of 3 and 29 minutes, respectively. Redistribution of the drug from brain to highly perfused tissues appears to be responsible for the relatively short duration of its anesthetic effects. Etomidate is extensively metabolized in the liver and plasma to inactive metabolites, with only 2% of the drug excreted unchanged in the urine. 

Hundley et al. (1993a) exposed rats and mice to atmospheres of 10,250 and 500 ppm [30, 750 and 1500 mg/m ] dimethylformamide for single 1-, 3- and 6-h periods or for 6 h per day on 10 days over two weeks. Dimethylformamide was not detected in the plasma after the 10 ppm dose, while at the 250 ppm dose, steady-state plasma levels were approached after 6 h of exposure this was not the case at 500 ppm, where plasma levels increased two-fold in rats and three-fold in mice between 3 and 6 h of exposure. The area under the plasma concentration curve (AUC) values for dimethylformamide after a single 6-h exposure increased disproportionately (8-fold and 29-fold increases in rats and mice, respectively) compared with the increase in dimethylformamide exposure concentration (from 250 ppm to 500 ppm). Multiple 500 ppm dimethylformamide exposures resulted in... 

AUC, Area under the plasma concentration curve over all time A measure of total systemic exposure. AUC((M) denotes the area under the curve from zero to any time point t. 

It was noted in the previous section that both pharmacokinetics and pharmacodynamics are concerned with relationships over time. One illustration of the fundamental importance of the rates of these processes can be seen in the plasma concentration-time profile (also known as the plasma-concentration curve) for an administered drug. This was introduced in Section 4.2.1, along with several quantitative pharmacokinetic terms used to describe and quantify aspects of the plasma concentration-time profile ... 

Fig. 7.2 Plasma concentration curves of paclitaxel in rats after oral administration of paclitaxel (25 mg/kg) - - control, or in presence of 10 mg/kg - -KR30031. Figure adapted from Woo et al. (2003)...

Equivalence of area under the time-plasma concentration curve AUC to a an the prototype rapid release drug. 

Provide confidence that the pharmacological model will predict efficacy in humans. If a drag is effective in therapeutic models using different species and these animals receive equivalent exposures (as measured by the maximum plasma concentration, Cmax, or area under the plasma concentration curve, AUC), then the clinician can choose a dose for trials with confidence. 

When a plasma-concentration curve is constructed for different patients that have been given an identical dose of an identical drug, interindividual differences will be noted. In some cases, plasma concentrations in one patient may remain below the minimal effective concentration, whereas the plasma concentration in another patient reaches the minimum toxic concentration. Besides some very obvious causes, such as body weight and body composition, some other factors involved in the interindividual variability in pharmacokinetics are concisely described below. 

The most rigorous quantitative way to assess the extent of bioavailability for an orally administered drug is to compare the areas under the respective plasma-concentration curves after oral and intravenous administration of the same dose of drug. The AUC is then calculated for both, and a ratio calculated by dividing the AUC for the oral administration by that for the intravenous administration. If the area ratio for the... 

Stage 1 Pharmacokinetic (PK) data from the healthy subject studies (studies 1 and 2) were analyzed using the statistical moments analysis approach. From the results of the analysis, peak concentration (Cmax) and area under the plasma concentration curve (AUC) were selected for exploring the relationship between exposure and safety data (biomarker elevation). 

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