Plasma areas under the curve

Absolute systemic bioavailabUity (absorbed fraction of the dose or concentration administered) can only be calculated by comparing the so-called Area Under the Plasma Curve (AUC, the area under the curve in a plot of the concentration of a substance in the plasma against time) after oral, inhalation, or dermal administration with the AUC after direct administration into the systemic circulation, e.g., after intravenous administration. In order to obtain a rehable estimate for AUC after single administration, it is necessary to have blood samples for 3-5 half-hves. In case data are not available for a calculation of the AUC, the absorbed fraction can be indicated from data on the amount of the parent compound and its metabohte(s) excreted in the urine, feces, and exhaled air. It should be noted that the amount excreted in the feces stems from both the unabsorbed fraction as well as from the fraction of the substance following bUiary excretion. 

An important limitation of compartment analysis is that it cannot be applied universally to any drug. A simpler approach that is useful in the case of bioequivalency testing is the model independent method. It is based on statistical-moment theory. This approach uses the mean residence time (MRT) as a measure of a statistical half-life of the drug in the body. The MRT can be calculated by dividing the area under the first-moment curve (AUMC) by the area under the plasma curve (AUC). ... 

Plasma levels per se are difficult to compare in various species because of differences in time relationships with respect to peak levels and disappearance of the drug. However, the area under the plasma curve, represented by the product of drug concentration x time ((xg/ml x min), provides an arithmetical value which can be used for inter-species comparisons. Plasma levels of Cytoxan in various species after different doses have been determined by Mellett [96-98]. These data are summarized in Table 6. The relationship between Cytoxan dosage (mg/m body surface area basis) and the plasma C Xt ([xg/ml x... 

Similar data have been obtained by Henderson et al. [101] for dogs and monkeys. Mellett [102] has obtained data for the mouse using the method developed by Henderson et al. The correlation of the area under the plasma curve with the dose expressed in mg/m is similar to the Cytoxan correlation. The relationship of half-life to the km-factor and area under the serum curve is shown in Table 7. 

If the areas under the plasma curves for mouse and man are compared for equal doses expressed on a mg/kg basis, the average ratio can be shown to be about 12 1, which is the ratio of the km-value for man/mouse and the ratio of... 

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

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. 

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

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... 

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

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... 

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

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. 

FIGURE 3.3 Area under the plasma decay curve, AUC, after an IV dose of drug. 

Sampling Interval To be able to perform valid toxicokinetic analysis, it is not only necessary to properly collect samples of appropriate biological fluids, but also to collect a sufficient number of samples at the current intervals. Both of these variables are determined by the nature of the answers sought. Useful parameters in toxico-kinetic studies are Cmax, which is the peak plasma test compound concentration Tmax, which is the time at which the peak plasma test compound concentration occurs, Cmin, which is the plasma test compound concentration immediately before the next dose is administered AUC, which is the area under the plasma test compound concentration-time curve during a dosage interval, and t which is the half-life for the decline of test compound concentrations in plasma. The samples required to obtain these parameters are shown in Table 18.12. Cmin requires one blood sample immediately before a dose is given and provides information on accumulation. If there is no accumulation in plasma, the test compound may not be detected in this sample. 

An acute intravenous study can provide accurate rates of metabolism without interference from intestinal flora, plus rates of renal and biliary elimination, if urine and bile are collected. This route also avoids the variability in delivered dose associated with oral absorption and ensures that the maximum amount of radiolabel is excreted in the urine or bile for purposes of detection. Once IV data and parameters are available, they can be used with plasma concentrations from limited oral studies to compute intestinal absorption via the ratio of Areas Under the (plasma and/or urine) Curves or via simulations of absorption with gastrointestinal absorption models. 

Quantitative assessment of the extent of absorption (absolute bioavailability) is most rigorously obtained by comparison of the areas under the plasma concentration-time curves (after adjusting for dose) following IV and oral administration. However, even after oral administration alone some idea of absorption or bioavailability can be obtained in the following ways ... 

If the apparent plasma clearance (dose/area under the plasma concentration-time curve, equivalent to true clearance/fraction of dose absorbed) gives an implausibly high value of clearance (e.g., greater than hepatic and renal plasma flow), it is likely the bioavailability is low. However, this could be due to presystemic metabolism in addition to low absorption. 

The term clearance is used here in the sense of total body clearance and is analogous to the term renal clearance. The body as a whole is regarded as acting as a xenobiotic-eliminating system, where the rate of elimination divided by the average plasma concentration of the compound is the total body clearance. Here clearance is calculated (25) by dividing the administered dose of the substance by the area under the plasma concentrationtime curve produced by that dose. This pharmacokinetic parameter, as well as others presented in this publication, was calculated by the use of the MLAB on-line computer system established at the National Institutes of Health by Knott and Reece (26). Similar to t the total clearance is a composite of the individual clearances of the material by the various tissues of the body. 

Figure 2.4. In vivo measurement of blood-brain barrier (BBB) permeability, (a) Internal carotid artery perfusion technique (i) in the rat. Other branches of the carotid artery are ligated or electrically coagulated (o, occipital artery p, pterygopalatine artery). The external carotid artery (e) is cannulated and the common carotid artery (c) ligated. Perfusion time may range from 15 s to 10 min, depending on the test substance. It is necessary to subtract the intravascular volume, Vo, from (apparent volume of distribution), to obtain true uptake values and this may be achieved by inclusion of a vascular marker in the perfusate, for example labelled albumin. Time-dependent analysis of results in estimates of the unidirectional brain influx constant Ki (pi min which is equivalent within certain constraints to the PS product. BBB permeability surface area product PS can be calculated from the increase in the apparent volume of distribution Vd over time. Capillary depletion, i.e. separation of the vascular elements from the homogenate by density centrifugation, can discriminate capillary uptake from transcytosis. (b) i.v. bolus kinetics. The PS product is calculated from the brain concentration at the sampling time, T, and the area under the plasma concentration-time curve, AUC.

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