Blood drug concentration-time curve

The Drug Delivery Index (DDI) ahows a quantification of the reduction in the drug dose and the systemic exposure observed after drug release specificahy to the colon [37]. It may be calculated using AUC (Area l/nder the plasma drug concentration-time Curve) data or drug concentrations in blood and colonic tissues under steady-state conditions ... 

An increase in bioavailability of orally administered cyclosporine A was observed after healthy male volunteers were administered a single dose of 3 mg cyclosporine A followed by a single oral dose of 300 mg of the compound berberine. The increase in area under the time-concentration curve of cyclosporine A was 19.2% no changes in elimination half-life, maximum blood drug concentration, time to maximum concentration, or apparent oral clearance were observed (Xin et al. 2006). Conversely, no changes in bioavailability of orally administered cyclosporine A were observed after healthy male volunteers were administered 300 mg of the compound berberine twice daily for 10 days followed by a single dose of 6 mg cyclosporine A (Xin et al. 2006). 

Fig. 1. Blood—drug concentration curve used to determine bioavailabiLitv and bioequivalence. C is the maximum dmg concentration in the blood and corresponds to some The AUC (shaded) represents the total amount of orally adininistered dmg the time from points A to B represents dmg onset, from points B to D, the duration MEC = minimum effective concentration MTC = minimum toxic concentration and TI = therapeutic index.

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. 

Thus, %F is defined as the area under the curve normalized for administered dose. Blood drug concentration is affected by the dynamics of dissolution, solubility, absorption, metabolism, distribution, and elimination. In addition to %F, other pharmacokinetic parameters are derived from the drug concentration versus time plots. These include the terms to describe the compound s absorption, distribution, metabolism and excretion, but they are dependent to some degree on the route of administration of the drug. For instance, if the drug is administered by the intravenous route it will undergo rapid distribution into the tissues, including those tissues that are responsible for its elimination. 

The answer is e. (Hardman, p 21J The fraction of a drug dose absorbed after oral administration is affected by a wide variety of factors that can strongly influence the peak blood levels and the time to peak blood concentration. The Vd and the total body clearance (Vd x first-order fte) also are important in determining the amount of drug that reaches the target tissue. Only the area under the blood concentration-time curve, however, reflects absorption, distribution, metabolism, and excretion factors it is the most reliable and popular method of evaluating bioavailability... 

Blood concentration-time curves, illustrating how changes in the rate of absorption and extent of bioavailability can influence both the duration of action and the effectiveness of the same total dose of a drug administered in three different formulations. The dashed line indicates the target concentration (TC) of the drug in the blood. 

MPA usually reaches maximal concentrations within an hour of the time of oral administration of MME Distribution of the drug is rapid and essentially complete in most patients within 2 to 3 hours of administration. In whole blood, >99.9% of the drug is in the plasma compartment. MPAs clearance is affected by (1) glucuronidation, (2) enterohepatic circulation (EHC), and (3) the quantity of its free fraction. EHC is considered to be a significant contributor to the dose interval kinetics of MPA, especially the post-distribution phase of the concentration-time curve. The contribution of EHC to the MPA AUC is about 37%, ranging from 10% to 61%, based on the effect of concomitant administration of cholestyramine. The appearance of a secondary MPA concentration peak anywhere from 4 to 12 hours following the morning dose of MMF is believed to result from EHC. 

When a drug is administered as an i.v. bolus, the entire dose of the drug is injected straight into the blood. Therefore, the absorption process is considered to be completed immediately, and the concentration-time profile of fhe drug in plasma will be determined by the rate of distribution and elimination. When the distribution of the drug is very fast, the plasma concentration-time curve is determined only by the elimination rate and shows a mono-exponential (first-order) decline (a theoretical example is shown in Figure 31.7a ... 

In Equation 17.22, the body is considered as a single homogeneous pool of body fluids as described above for digoxin. For most drugs, however, two or three distinct pools of distribution space appear to exist. This condition results in a time-dependent decrease in the measurable blood or plasma concentration, which reflects distribution into other bod pools independent of the body s ability to eliminate the drug. Figure 17.3 describes mean serum IFN-a concentrations after a 40-min intravenous infusion as well as after intramuscular and subcutaneous injections of the same dose. Note the logarithmic biphasic nature of the mean plasma concentration-time curve after the intravenous infusion. This biphasic nature represents both the distribution and elimination processes. 

Figure 1-3. Serum concentration-time curve after administration of chlordiazepoxide as an intravenous bolus. The experimental data are plotted on a semilogarithmic scale as filled circles. This drug follows first-order kinetics and appears to occupy two compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination half-life (f gj) can be extracted graphically as shown by measuring the time between any two plasma concentration points that differ by twofold. (See Chapter 3 for additional details.) (Modified and reproduced, with permission, from Greenblatt DJ, Koch-Weser J. Drug therapy Clinical pharmacokinetics. N Engl J Med 1975 293 702.)...

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