Area under the plasma concentration

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. 

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... 

Area under the plasma concentration-time profile Chromium-51-labeled ethylenediamine-tetraacetic acid Cytochrome P450, 3A4 isozyme... 

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. 

AUC, area under the plasma concentration cuive BZ, benzodiazepine Cl, clearance t, elimination half-life Vd, volume of distribution. Data from Benzodiazepines. Fads and Comparisons 4.0 Online. Wolters Kluwer Health, Inc. 2005, http //online.factsandcomparisons.com and Madabushi R, Frank B, DrewelowB, etal. Hyperforinin St. John s wort drug interactions. Fur J Gin Pharmacol 2006 62 225-233. 

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. 

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.

The pharmacokinetic information that can be obtained from the first study in man is dependent on the route of administration. When a drug is given intravenously, its bioavailabihty is 100%, and clearance and volume of distribution can be obtained in addition to half-life. Over a range of doses it can be established whether the area under the plasma concentration-time curve (AUC) increases in proportion to the dose and hence whether the kinetic parameters are independent of dose (see Figure 4.1). When a drug is administered orally, the half-life can still be determined, but only the apparent volume of distribution and clearance can be calculated because bioavailability is unknown. However, if the maximum concentration (Cmax) and AUC increase proportionately with dose, and the half-life is constant, it can usually be assumed that clearance is independent of dose. If, on the other hand, the AUC does not increase in proportion to the dose, this could be the result of a change in bioavailability, clearance or both. 

Most physicians will be familiar with the basic shape of a plasma concentration-time curve following oral or intravenous administration, and they are likely to be familiar with, or at least readily imderstand, the simple terms that relate to this shape. Such terms - (1) maximum plasma concentration (Cmax). (2) time to maximum plasma concentration (fmax), (3) area under the plasma concentration-time curve (AUC) and (4) half-life (fi/2) - are illustrated in Figure 5.2. 

Pharmacokinetics Ticlopidine is rapidly absorbed (more than 80%), with peak plasma levels occurring at approximately 2 hours after dosing, and is extensively metabolized. Administration after meals results in a 20% increase in the area under the plasma concentration-time curve (AUC). Ticlopidine displays nonlinear pharmacokinetics and clearance decreases markedly on repeated dosing. Ticlopidine binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein at concentrations attained with the recommended dose, 15% or less in plasma is bound to this protein. 

Coadministration with food has no significant effect on the peak plasma concentration and the area under the plasma concentration time curve of oseltamivir carboxylate. 

In the past the results of toxicology studies were interpreted and extrapolated to the human situation on the basis of the dose/kg or dose/m. However, it has long been recognized that measuring the plasma concentration of the compound and its metabolites often provides a better indication of exposure, and therefore this has become mandatory. The area under the plasma concentration-time curve (AUC) and... 

Indinavir was rapidly absorbed in the fasted state, with a time to peak plasma concentration of 0.8 0.3 hours (mean S.D.) (n=l 1). A greater than dose-proportional increase in indinavir plasma concentrations was observed over the 200-1000 mg dose range. At a dosing regimen of 800 mg every 8 hours, the steady-state area under the plasma concentration time curve (AUC) was 30,691 11,407 nM-hour (n=16), peak plasma concentration was 12,617 4037 nM (n=16), and plasma concentration eight hours post dose (trough) was 251 178 nM... 

Sertraline pharmacokinetics were described in 61 children and adolescents (ages 6 to 17) with depression or OCD (Alderman et ah, 1998). Mean area under the plasma concentration-time curve, peak plasma concentration, and elimination half-life for sertraline and des-methylsertraline were similar to previously reported adult values. No differences between children and adolescents were apparent when values were normalized for body weight. 

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