Absorption and Elimination Phases

The two exponential terms model drug absorption and elimination. The rate of absorption depends on the properties of the drug and is described by kah, the absorption rate constant. The variable F is the bioavailability of the drug and a measure of observed drug exposure relative to an experimental maximum. Bioavailability is more thoroughly described in the next subsection. 

Valid values of F fall between 0 and 1. The term FD0/ Vd is related to the concentration of drug (same units as Cp) theoretically available to the bloodstream in the absence of elimination. Equation 7.21 assumes first-order elimination and a single compartment 

FIGURE 7.14 Single-dose oral Cp-time plot 

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Computation of oral absorption (kj and elimination (E) rates is often complicated by the flip-flop of the absorption and elimination phases when they differ by less than a factor of 3. Because of these analysis problems, computation of absorption and elimination rates should not be attempted on the basis of oral dosing results alone. 

A particularly significant Cp-time point for an oral drug is Cpmax and tmax. Cpmax occurs during a transition between the absorption and elimination phases. At Cpmax, dCp/dt is 0, and the rate of absorption is balanced by the rate of elimination (Equation 7.29). Through analysis and rearrangement of the first derivative of Equation 7.21 with respect to time, Equation 7.30 can be obtained and used for simple calculation of tmax. Substitution of tmax into Equation 7.21 then provides Cpmax. 

To illustrate how these algorithms may differ in their estimates, a simple simulation was conducted. A total of 100 subjects were simulated under a Phase 2 clinical study design where 1/3 of the subjects had two samples collected, 1/3 had four samples collected, and 1/3 had six samples collected. If subjects were assigned to have two samples collected, samples were collected randomly from the time intervals (0 6 h) and (6 24 h). If subjects were assigned to have four samples collected, samples were collected randomly from the time intervals (0-2 h), (2-4 h), (4—10 h), and (10-24 h). If subjects were assigned to have six samples collected, samples were collected randomly from the time intervals (0-2 h), (2-4 h), (4-6 h), (6-10 h), (10-16 h), and (16-24 h). The sample time windows were arbitrarily chosen to cover the entire concentration time profile and to capture the absorption and elimination phases. 

Figure 8.1 Drug dose response profile for a hypothetical drug, showing the absorption and elimination phases following administration.

Competing against drug absorption into the body is its removal from the body. Dmgs are viewed as toxins and the body has evolved mechanisms for their removal metabolism and excretion. Figure 8.1 shows the absorption and elimination phases for a dmg. The shape of this curve is influenced by the properties of a dmg and thus is an important consideration in dmg design. 

If after single dose administration, the blood samples are not collected at time intervals, which allow for a description of the whole plasma concentration time course, including the absorption, distribution, and elimination phase, the information obtained is limited. In particular, data should be available in the hrst hours after administration to cover the absorption phase. If measurements of the parent compound and its metabolite(s) are made in this period, this will allow assessment of an extensive first pass effect, i.e., when a substance after oral administration is transported via the portal vein to the liver where metabolism takes place before the substance enters the systemic circulation. 

Drug metabolism and pharmacokinetic (DMPK) studies are used to show how the concentrations of the drug and its metabolites vary with the administered dose of the drug and the time from administration. They are normally carried out using suitable animal species and in humans in Phase I trials. The information obtained from animal studies is used to determine safe dose levels for use in the Phase I clinical trials in humans. However, the accuracy of the data obtained from animal tests is limited, since it is obtained by extrapolation. In addition, it is necessary to determine the dose that just saturates the absorption and elimination processes so that the toxicological and pharmacological events may be correctly interpreted. 

Figure 6.21 Phase plane plot for a drug obeying one-compartment model disposition with first-order absorption and elimination. Time indexes each point along the curve. The time flow is indicated by the arrows, while the. x-axis intercept corresponds to cmax-...

Note The inhalation results were fitted with a discontinuous function [(—)-sarin] = A + Be for the absorption phase, and [(—)-sarin] = Ce ° + De for the distribution and elimination phase. The i.v. results were fitted according to [(—)-sarin] = Ce ° + De. ... 

Figure 10.43 Graphical representation of the absorption phase (rising concentration) and elimination phase (falling concentration) for a one-compartment first-order absorption model.

The two-compartment first-order absorption plasma concentration versus time curve in Figure 10.79 displays a characteristic early rapid rise, which transitions into a rapidly declining period immediately after subsequently followed by a more slowly declining terminal line concentration period at later times. The early rise is due to absorption from the drug administration site, and hence this period is labeled the absorption phase. The rapid decline after t ax is caused by distribution to the tissue compartment, and hence is called the distribution phase. The slower decline at later times is due to drug elimination, and hence this later period becomes the elimination phase. The absorption, distribution, and elimination phases are graphically illustrated in Figure 10.80. 

During the postabsorption phase, the deciine in the plasma concentration with time follows first-order kinetics. A typicai piot of piasma concentration versus time is shown in Figure 9.31, where the intercept of the extrapoiated iine (i ) is a complex function of absorption and elimination rate constants (K and K, respectively) as well as the dose or amount absorbed, F(Xg)Q, and the apparent... 

Plasma and blood samples are preferred over urine and other tissue samples for evaluating drag/metabolite concentrations. An adequate number of samples should be taken to characterize the absorption, distribution, and elimination phases of the drug/metabolite accurately. 

The plasma concentration versus time profile presented in Fig. 1.10 represents a one-compartment model for a drug administered extravascularly. There are two phases in the profile absorption and elimination. However, the profile clearly indicates the presence of only one phase in the post-absorption period. Since distribution is the sole property that determines the chosen compartment model and, since the profile contains only one phase in the post-absorption period, these data can be described accurately and adequately by employing a one-compartment model. However, a biexponential equation would be needed to characterize the concentration versus time data accurately. The following equation can be employed to characterize the data ... 

The pharmacokinetic profile of hupA has been studied in healthy volunteers with oral as well as transdermal administration [66, 67]. In a recent study, hupA was administrated p.o. to 12 healthy, young volunteers as a single therapeutic dose of 0.4 mg and was found to be well tolerated with no adverse events reported. HupA was absorbed rapidly, and occurred in the plasma 5-10 min after administratimi and reached Cmax 2.59 ng ml at a 7]nax of 58.33 min. It was shown to distribute widely in the body at a moderate rate and to cross the blood-brain barrier (BBB) easily. The results conformed to a two-compartment model with the elimination half-life of oc-phase and (3-phase to be approximately 21 and 716 min, respectively [66]. Another study performed in China in 1995 which included six volunteers receiving a single 0.99 mg p.o. dose of hupA showed somewhat different results with shorter absorption and elimination half-lives, i.e., 13 and 288 min, respectively, compared to the previous study. However, both studies revealed rapid absorption and wide distribution, followed by a slower elimination rate [17, 66]. 

Pharmacokinetic constants for the absorption and elimination of pralid-oxime have been determined in man83. a pharmacokinetic model for flow, lipid solubility, protein binding and saturation-IImited metabolism of thiopental has permitted the a priori prediction of bodily distribution conslsten with experiment . Imipramine and its metabolites are rapidly distributed in the rat and renally and biliary excreted with enterohepatic circulation . Mathematical models have been established for the pharmacokinetics of neurohypophysial and related peptides . The oral administration of 2,3,5, triiodebenzoic acid in goats and a cow by whole-body radioactivity retention showed a rapid distributive and subsequent exponential elimination phase with the metabolites formed by deiodination . Bishydroxycoumarin shows dose-dependent first order elimination in man but not in other species and has been assigned to dose effects on el imi nation . ... 

The metabolic and pharmacokinetic profile of sucralose (this is a novel intense sweetener with a potency about 600 times that of sucrose) in human volunteers was studied by Roberts and coworkers [82]. Part of this study was realized using PLC in the following chromatographic system in which the stationary phase was silica gel and the mobile phase was ethyl acetate-methanol-water-concentrated ammonia (60 20 10 2, v/v). Separated substances were scraped off separately, suspended in methanol, and analyzed by filtration, scintillation counting, or enzymatic assay. It was shown that the characteristics of sucralose include poor absorption, rapid elimination, limited conjugative metabolism of the fraction absorbed, and lack of bio-accumulative potential. 

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