Plasma time curve

One can take this process a step further and extrapolate back from a plasma time curve to the y axis. This is theoretically the plasma concentration (C0) that would occur if, upon being administered, the material is instantly distributed throughout the body. The volume number obtained with the above equation becomes... 

Volume of distribution is a pharmacokinetic term, derived from analysing the plasma-time curve of a drug, and is the hypothetical volume in which a drug would have to distribute to give the observed plasma concentration. It modulates the half-life of the drug with a given clearance. 

Data from Yeh etal. [27]. Cmax refers to the maximum plasma concentration achieved, AUC is the calculated area under the plasma-time curve, and Irnax is the time at which Cmax occurs. The numbers in parentheses are the percentage variability on the means. The salt form has lower variability between subjects than the free base monohydrate. 

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. 

Bioavailability is the amount of drug in a formulation that is released and becomes available for absorption or the amount of the drug absorbed after oral administration compared to the amount absorbed after intravenous administration (bioavailability - 100%), judged from areas remaining under plasma drug concentration-time curves. 

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 ... 

Compound (1) suffered from an unfavorable pharmacokinetic profile when studied in rats. It is cleared very rapidly from rat plasma (half-life, t 2 — 0.4/z) and is poorly bioavailable F — 2%), as reflected by the low plasma concentration (area under the plasma concentration-time curve, AUCo oo = 0.2pMh) following a single oral dose of 25mg/kg in rats [42]. The main challenge was to further optimize this series to obtain NS3 protease inhibitors with low-nanomolar cell-based potency (EC5q< 10 nM) and with an adequate pharmacokinetic profile for oral absorption. 

In studies in rats and mink that used more than one dose, the area under the plasma-IMPA concentration time curves indicated that at high doses the principal pathway for the conversion of diisopropyl methylphosphonate to IMPA was saturated (Bucci et al. 1992). In rats, metabolism was saturated at an oral dose of 660 mg/kg, but not at 66 mg/kg in mink, an oral dose of 270 mg/kg caused metabolic saturation which did not occur at 27 mg/kg. 

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

In these instances, the time of the peak in the plasma concentration versus time curve provides a convenient measure of the absorption rate. For example, if three tablets of the same drug are found to be completely absorbed and all give plasma peaks at 1 hour, it can be safely concluded that all three tablets are absorbed at essentially the same rate. (In fact, if all tablets are completely absorbed and all peak at the same time, it would be expected that all three plasma concentration versus time curves would be identical, within experimental error.)... 

A. Area Under the Plasma Concentration Versus Time Curve... 

It is not necessary to apply the trapezoidal rule to the entire plasma concentration versus time curve in order to calculate the total AUC. After the semilog plot becomes a straight line, the remaining area out to t = can be calculated using the following equation ... 

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. 

Although the equations become considerably more complex than for the IV case, Cmax and Cm n can be calculated when the drug is administered by an extra-vascular route. The required equations may be developed as follows The equation describing the plasma concentration versus time curve following one extra-vascular administration was discussed previously. Equation (35) may be written as follows ... 

Table 2 Peak Plasma Levels and Areas Under Plasma Concentration Time Curves Following Oral and Intravenous Administration to Men...

AUMC = area under the first-moment curve for tissue i AUMCP = area under the first-moment curve for plasma AUCP = area under the plasma concentration-time curve... 

Area under the plasma concentration-time curve... 

Another method of predicting human pharmacokinetics is physiologically based pharmacokinetics (PB-PK). The normal pharmacokinetic approach is to try to fit the plasma concentration-time curve to a mathematical function with one, two or three compartments, which are really mathematical constructs necessary for curve fitting, and do not necessarily have any physiological correlates. In PB-PK, the model consists of a series of compartments that are taken to actually represent different tissues [75-77] (Fig. 6.3). In order to build the model it is necessary to know the size and perfusion rate of each tissue, the partition coefficient of the compound between each tissue and blood, and the rate of clearance of the compound in each tissue. Although different sources of errors in the models have been... 

Area under the (plasma concentration-time) curve... 

Piel et al. [109] studied the pharmacokinetics of miconazole after intravenous administration to six sheep (4 mg/kg) of three aqueous solutions - a marketed micellar solution containing polyoxyl-35 castor oil was compared with two solutions both containing 50 pM lactic acid and a cyclodextrin derivative (100 pM hydro-xylpropyl-/l-cyclodextrin or 50 pM sulfobutyl ether (SBE7)-/i-cyclodextrin. This work demonstrated that these cyclodextrin derivatives have no effect on the pharmacokinetics of miconazole by comparison with the micellar solution. The plasma concentration-time curves have shown that there is no significant difference between the three solutions. 

From such rat neuropharmacokinetic studies, in which animals (N = 2/ time point, >2 doses) are euthanized at specific time points postdose for plasma, CSF, and brain collection for compound concentration analysis, composite neuromatrix-specific compound concentration-time curves are generated (Figure 2). 

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