Plasma concentration determination

Elderly Plasma concentrations (determined as AUC) of dipyridamole in healthy elderly subjects older than 65 years of age were approximately 40% higher than in subjects younger than 55 years of age receiving treatment with the dipyridamole and aspirin combination. 

Following oral administration of 400 mg to 7 subjects, peak plasma concentrations of about 0.5 to 1 pg/ml were attained in about 7 hours. After administration of 200 mg 8-hourly to 6 subjects for one month, plasma concentrations determined immediately before the morning dose ranged from 0.75 to 2.8 pg/ml (mean 1.5) (F. Andreasen et al., Eur. J. din. Pharmac., 1981,19, 293-299). 

In 3 fatalities due to disopyramide overdose, postmortem blood concentrations of 8.5, 34, and 114pg/ml were reported the dose was estimated to be about 6 to 7 g in 2 of the cases. In a further 2 fatalities, antemortem plasma concentrations, determined 9 hours and 3 hours after ingestion, respectively, were 4.3 and 35 pg/ml (A. M. Hayler etal.. Lancet, 1978,7,968-969). 

Following chronic oral administration of 15 to 60 mg daily in divided doses to 15 subjects, plasma concentrations, determined 2 to 21 hours after the last daily dose, were in the range 0.010 to 0.023 pg/ml (mean... 

In a retrospective analysis of 210 randomly selected digoxin plasma concentration determinations in inpatients, the indications were considered to have been inappropriate in 67, appropriate in 81, and unevaluable in 4 (317). Timing of the blood sample was wrong in 17 cases (samples should be taken at least 6 hours and preferably about 11 hours after the dose). Of the measurements whose indications were considered to have been inappropriate, most (52) were performed as part of routine monitoring. 

Figure 12.2 Chromatogram of a sample taken from a patient, administered with AMP, RIT, and LOP. The plasma concentrations determined were 7.20, 10.1, and 1.28 pg/ml, respectively. Reprinted from [35] with permission. 2002, Elsevier Science BV.

Once the steady-state concentration is known, the rate of dmg clearance determines how frequendy the dmg must be adininistered. Because most dmg elimination systems do not achieve saturation under therapeutic dosing regimens, clearance is independent of plasma concentration of the dmg. This first-order elimination of many dmgs means that a constant fraction of dmg is eliminated per unit time. In the simplest case, clearance can be deterrnined by the dose and the area under the curve (AUC) describing dmg concentration as a function of total time ... 

These observations consummated in a growth model that confers on the millions of aligned zone 1 nanotubes the role of field emitters, a role they play so effectively that they are the dominant source of electron injection into the plasma. In response, the plasma structure, in which current flow becomes concentrated above zone 1, enhances and sustains the growth of the field emission source —that is, zone 1 nanotubes. A convection cell is set up in order to allow the inert helium gas, which is swept down by collisions with carbon ions toward zone 1, to return to the plasma. The helium flow carries unreacted carbon feedstock out of zone 1, where it can add to the growing zone 2 nanotubes. In the model, it is the size and spacing of these convection cells in the plasma that determine the spacing of the zone 1 columns in a hexagonal lattice. 

In addition to the elimination rate constant, the half-life (T/i) another important parameter that characterizes the time-course of chemical compounds in the body. The elimination half-life (t-1/2) is the time to reduce the concentration of a chemical in plasma to half of its original level. The relationship of half-life to the elimination rate constant is ti/2 = 0.693/ki,i and, therefore, the half-life of a chemical compound can be determined after the determination of k j from the slope of the line. The half-life can also be determined through visual inspection from the log C versus time plot (Fig. 5.40). For compounds that are eliminated through first-order kinetics, the time required for the plasma concentration to be decreased by one half is constant. It is impottant to understand that the half-life of chemicals that are eliminated by first-order kinetics is independent of dose. ... 

The latter approach is used in the enantioselective determination of a Phase I metabolite of the antihistaminic drug, terfenadine. Terfenadine is metabolized to several Phase I compounds (Fig. 7-13), among which the carboxylic acid MDL 16.455 is an active metabolite for which plasma concentrations must often be determined. Although terfenadine can be separated directly on Chiralpak AD - an amy-lose-based CSP - the adsorption of the metabolite MDL 16.455 is too high to permit adequate resolution. By derivatizing the plasma sample with diazomethane, the carboxylic acid is converted selectively to the methyl ester, which can be separated in the presence of all other plasma compounds on the above-mentioned CSP Chiralpak AD [24] (Fig. 7-14). Recently, MDL 16.455 has been introduced as a new antihistaminic drug, fexofenadine. 

Area under the Curve (AUC) refers to the area under the curve in a plasma concentration-time curve. It is directly proportional to the amount of drug which has appeared in the blood ( central compartment ), irrespective of the route of administration and the rate at which the drug enters. The bioavailability of an orally administered drug can be determined by comparing the AUCs following oral and intravenous administration. 

In the total plasma response approach, the bioavailability of a compound is determined by measuring its plasma concentration at different times (up to weeks) after single or long-term ingestion of the compound from supplements or food sources. Generally, a plasma concentration-versus-time plot is generated, from which is determined the area-under-curve (AUC) value used as an indicator of the absorption of the componnd. Here, the term relative bioavailability is more appropriate since AUC valnes of two or more treatments are usually compared. This is in contrast to absolnte bioavailability for which the AUC value of the orally administered componnd is compared to that obtained with intravenous administration taken as a reference (100% absorption). 

Figure 39.4a represents schematically the intravenous administration of a dose D into a central compartment from which the amount of drug Xp is eliminated with a transfer constant kp. (The subscript p refers to plasma, which is most often used as the central compartment and which exchanges a substance with all other compartments.) We assume that mixing with blood of the dose D, which is rapidly injected into a vein, is almost instantaneous. By taking blood samples at regular time intervals one can determine the time course of the plasma concentration Cp in the central compartment. This is also illustrated in Fig. 39.4b. The initial concentration Cp(0) at the time of injection can be determined by extrapolation (as will be indicated below). The elimination pool is a hypothetical compartment in which the excreted drug is collected. At any time the amount excreted must be equal to the initial dose D minus the content of the plasma compartment Xp, hence ...

In practice, one will seek to obtain an estimate of the elimination constant kp and the plasma volume of distribution Vp by means of a single intravenous injection. These pharmacokinetic parameters are then used in the determination of the required dose D in the reservoir and the input rate constant k (i.e. the drip rate or the pump flow) in order to obtain an optimal steady state plasma concentration... 

Usually, the buffer compartment is not accessible and, consequently, the absolute amount of X cannot be determined experimentally. For this reason, we will only focus our discussion on the plasma concentration Cp. It is important to know, however, that the time course of the contents in the two compartments is the sum of two exponentials, which have the same positive hybrid transfer constants a and p. The coefficients A and B, however, depend on the particular compartment. This statement can be generalized to mammillary systems with a large number of compartments that exchange with a central compartment. The solutions for each of n compartments in a mammillary model are sums of n exponential functions, having the same n positive hybrid transfer constants, but with n different coefficients for each particular compartment. (We will return to this property of linear compartmental systems during the discussion of multi-compartment models in Section 39.1.7.)... 

The next step requires the determination of the residual concentrations C by subtracting from the observed Cp. The resulting a-phase function is again obtained by means of linear regression on the earlier part of the time course of the logarithmic plasma concentration (Fig. 39.13b) ... 

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. 

An important parameter of the one-compartment model is the apparent volume of the body compartment, because it directly determines the relationship between the plasma concentration and the amount of... 

Thus after 6 hours the semilog plot of Cp versus time shown in Fig. 10 becomes a straight line and kei can be determined from the slope. Therefore, the overall elimination rate constant for a drug may be accurately determined from the tail of a semilog plot of plasma concentration versus time following extravascular administration if ka is at least five times larger than kei. 

A great deal can be learned about the absorption process by applying Eqs. (40) and (41) to plasma concentration versus time data. Since there is no model assumption with regard to the absorption process, the calculated values of At/Vd can often be manipulated to determine the kinetic mechanism that controls absorption. This is best illustrated by an example. 

In these cases it is not necessary to determine the absolute bioavailability or the absorption rate constant for the product under study. It is only necessary to prove that the plasma concentration versus time curve is not significantly different from the reference product s curve. This is done by comparing the means and standard deviations of the plasma concentrations for the two products at each sampling time using an appropriate statistical test. 

For IV administration, the easiest way to determine the loading dose is in terms of Cp and Cmax. For example, if the desired Cmax is 20 pg/mL and a dose of 100 mg gives a Cp of 10 pg/mL, a loading dose of 200 mg should give a Cp of 20 pg/mL, which is the desired Cmax. If this loading dose is followed by maintenance doses of 100 mg every half-life, the plasma concentrations can be maintained at the... 

Age does not significantly affect plasma concentrations or disposition of ibuprofen however, investigators have determined that the onset of antipyresis and maximum antipyretic effect is greater in children less than one year old as compared to children older than 6 years [43]. The authors hypothesized that this accelerated response was related to the greater relative body surface area of the young child. It should be noted that cystic fibrosis patients do have a higher clearance of ibuprofen [43a]. 

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