Area under plasma concentration time curve drug absorption

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... 

However, drug substances for which /a may be affected by active transport processes [e.g., the efflux transporter P-glycoprotein (P-gp)] may require further model characterization to prevent misclassification of their permeability class. For example, functional expression of efflux transporters must be determined in cultured human or animal epithelial monolayers. At this time, the FDA recommends limiting the use of non-human permeability test methods to drug substances whose absorption is controlled by passive mechanisms. When applying the BCS, an apparent passive mechanism may be inferred when one of the following conditions is satisfied (i) a linear pharmacokinetic relationship between dose and a measure of bioavailability (e.g., area under the plasma concentration-time curve, AUC) is demonstrated in humans ... 

Another important parameter is the area under the plasma concentration-time curve (AUC). It reflects the extent of drug absorption. From a product quality aspect, knowledge of the described pharmacokinetic parameters is important. Utilizing these parameters, one would establish drug release characteristics of a tablet in vivo. 

The relationship between bioavailability and area under the plasma concentration-time curve is nonlinear and absorption rate dependent when the plasma protein binding of a drug is concentration dependent. Two drug products from which a drug is equally well absorbed will produce different values for the area under the plasma concentration-time curve if a difference exists in the absorption rate. Generally, such a comparison will overestimate the extent of drug absorption of the more slowly absorbed product. 

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. 

This may be concentration and drug dependent. t = Increase = decrease — = no effect, k, = absorption rate constant = time AUC = area under the plasma drug concentration time curve. for peak drug concentration in plasma ... 

An indication of the rate of drug absorption can be obtained from the peak (maximum) plasma concentration (Cmax) and the time taken to reach the peak concentration (fmjx), based on the measured plasma concentration-time data. However, the blood sampling times determine how well the peak is defined and, in particular, fmax. Both Cmax and tm3LX may be influenced by the rate of drug elimination, while Cmax is also affected by the extent of absorption. The term Cmax/ AUC, where AUC is area under the curve from time zero to infinity or to the limit of quantification (LOQ) of the analytical method, provides additional information on the rate of absorption. This term, which is expressed in units of reciprocal time (h ), can easily be calculated. In spite of the imprecision of the estimation provided by Cmax, it generally suffices for clinical purposes. 

For many pharmaceutical compounds administered as transdermal drug delivery systems, absorption can be assessed by determining the area under the curve (AUC) of the plasma concentration-time profile, the peak plasma flux, and time of peak flux, much as it is for determining bioavailability from oral and other routes of administration. These are classical metrics of biophar-maceutical bioequivalence studies and are extensively covered in other texts... 

Bioavailability refers to the portion of a drug absorbed from the site of administration. The reference site of administration is intravenous, because this route produces 100% absorption. Figure 3-1 illustrates three sample drug concentration curves in plasma as a function of time. The area under the curve (AUC) is the total amount of drug in the systemic circulation available for distribution to the sites of action. The same dose completely absorbed from any of these routes would produce an identical area under the curve (i.e., 100% bioavailability), although the shape would differ. 

The useful estimate of relative absorption rates of a drug from different products, through different routes of administration or different conditions (i.e., with or without food or in the presence of other drugs, etc.) can be made by comparing the magnitude of time of occurrence of peak concentration, peak concentration, and area under the peak plasma concentration curve, (AUC)"q. The peak time and peak plasma concentration can be determined by employing Equations 9.74 and 9.76 or 9.79, respectively, and the extent of absorption can be determined as described below. 

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