Elimination, drug plasma concentration

Most cases of poisoning are treated conservatively, i.e. the symptoms arc treated and the drug is eliminated by nonnal metabolism and renal excretion. When there is hepatic or renal insufficiency, active measures such as haemodialysis or charcoal haemoperfusion may be attempted.. Such measures are normally restricted to a small group of drugs and poisons including salicylate, phenobarbitone. theophylline, ethanol, methanol, ethylene glycol and lithium. Where active measures are used to eliminate drugs, plasma concentrations should be monitored. 

After Cmax and distribution equilibrium have been reached, the subsequent drug elimination phase can generally be described by first-order kinetics. The time-dependent decrease in drug-plasma concentration is paralleled by a corresponding decrease in elimination rate. Under these conditions, the plasma concentration of the drug at time t is given by Eq. (3.1). 

In calves and cows at high dose levels (100 SDM mg/kg), a biphasic elimination SDM plasma concentration-time curve was observed with a steady state plasma SCH2OH concentration resulting from the capacity limited hydroxylation of SDM into the latter. The drug concentrations in the milk reflected those in plasma. 

As with classic compartment pharmacokinetic models, PBPK models can be used to simulate drug plasma concentration versus time profiles. However, PBPK models differ from classic PK models in that they include separate compartments for tissues involved in absorption, distribution, metabolism and elimination connected by physiologically based descriptions of blood flow (Figure 10.1). 

Linear pharmacokinetics. For a simple linear pharmacokinetics case, the body can be modeled as a single drug compartment with first-order kinetic elimination—where the dose is administered and drug concentrations are drawn from the same compartment. For an intravenous bolus dose, the expected drug plasma concentration Cp versus time curves are shown in Fig. 1.10. The kinetics for this system are described by Eq. (1.6). The well-known solution to this equation is given by Eq. (1.7), and a linearized version of this solution is given in Eq. (1.8) and shown graphically in Fig. 1.13. 

FIGURE 2.5 Siimilation of plasma (solid line) and tissue (heavy dashed line) digoxin concentrations after intravenous administration of a 0.75-mg loading dose to a 70-kg patient with normal renal function. Cq is estimated by back extrapolation (dotted line) of elimination-phase plasma concentrations. is calculated by dividing the administered drug dose by this estimate of Cq, as shown. Tissue concentrations are referenced to the apparent distribution volume of a peripheral compartment that represents tissue distribution. (Reproduced with permission from Atkinson AJ Jr, Kushner W. Annu Rev Pharmacol Toxicol 1979 19 105-27.)... 

Figure 7.8 Logarithmic drug plasma concentration-time curve for an oral administration illustrating the elimination rate constant (Ke) and first-order absorption rate constant [Ka).

Drug efficacy is dependent on the concentration at the site of action, and therefore, monitoring of drug release from controlled release formulations is critical. Pharmacokinetic (PK) studies are performed to determine drug plasma concentrations versns time as well as drug concentrations at the local site of action. The properties of absorption, distribution, metabolism, and elimination of the drug can be... 

After dialysis, often a rebound is seen in concentrations since elimination from plasma is faster than drug flux from tissue to plasma (Crebound — Ctissue - C). The concentration in plasma follows a bi-exponential kinetics during hemodialysis whereas the concentration in tissue follows mono-exponential kinetics. 

These drugs are thought to prolong the effect of levodopa by blocking an enzyme, catechol-O-methyltransferase (COMT), which eliminates dopamine. When given with levodopa, the COMT inhibitors increase the plasma concentrations and duration of action of levodopa... 

Figure 39.4a represents schematically the intravenous administration of a dose D into a central compartment from which the amount of drug Xp is eliminated with a transfer constant kp. (The subscript p refers to plasma, which is most often used as the central compartment and which exchanges a substance with all other compartments.) We assume that mixing with blood of the dose D, which is rapidly injected into a vein, is almost instantaneous. By taking blood samples at regular time intervals one can determine the time course of the plasma concentration Cp in the central compartment. This is also illustrated in Fig. 39.4b. The initial concentration Cp(0) at the time of injection can be determined by extrapolation (as will be indicated below). The elimination pool is a hypothetical compartment in which the excreted drug is collected. At any time the amount excreted must be equal to the initial dose D minus the content of the plasma compartment Xp, hence ...

When j,p > k, the time course of the plasma concentration Cp is dominated by the rate of elimination which is the slower of the two. This is desirable when a drug must be delivered as rapidly as possible to the plasma compartment, for example in the relief of acute pain. At sufficiently large times following administration, the... 

Equation (35) describes the line in Fig. 10, which is a semilog plot of Cp versus time for an orally administered drug absorbed by a first-order process. The plot begins as a rising curve and becomes a straight line with a negative slope after 6 hours. This behavior is the result of the biexponential nature of Eq. (35). Up to 6 hours, both the absorption process [exp(—kat) and the elimination process [exp( keil)] influence the plasma concentration. After 6 hours, only the elimination process influences the plasma concentration. 

Thus after 6 hours the semilog plot of Cp versus time shown in Fig. 10 becomes a straight line and kei can be determined from the slope. Therefore, the overall elimination rate constant for a drug may be accurately determined from the tail of a semilog plot of plasma concentration versus time following extravascular administration if ka is at least five times larger than kei. 

Example. A tablet containing 100 mg of a drug was administered to a healthy volunteer and the plasma concentration (Cp) versus time data shown in Table 6 were obtained. Figure 11 shows a semi-log plot of these Cp versus time data. The half-life for elimination of the drug can be estimated from the straight line tail of the plot to be 4.7 hours. The overall elimination rate constant is then... 

When drugs are administered on a multiple dosing regimen, each dose (after the first) is administered before the preceding doses are completely eliminated. This results in a phenomenon known as accumulation, during which the amount of drug in the body (represented by plasma concentration) builds up as successive doses are administered. The phenomenon of accumulation for a drug administered IV is shown in Fig. 14. 

Other applications of the previously described optimization techniques are beginning to appear regularly in the pharmaceutical literature. A literature search in Chemical Abstracts on process optimization in pharmaceuticals yielded 17 articles in the 1990-1993 time-frame. An additional 18 articles were found between 1985 and 1990 for the same narrow subject. This simple literature search indicates a resurgence in the use of optimization techniques in the pharmaceutical industry. In addition, these same techniques have been applied not only to the physical properties of a tablet formulation, but also to the biological properties and the in-vivo performance of the product [30,31]. In addition to the usual tablet properties the authors studied the following pharmacokinetic parameters (a) time of the peak plasma concentration, (b) lag time, (c) absorption rate constant, and (d) elimination rate constant. The graphs in Fig. 15 show that for the drug hydrochlorothiazide, the time of the plasma peak and the absorption rate constant could, indeed, be... 

To predict oral plasma concentration-time profiles, the rate of drug absorption (Eq. (53)) needs to be related to intravenous kinetics. For example, in the case of the one-compartment model with first-order elimination, the rate of plasma concentration change is estimated as... 

Yoshimura et al. [132] studied the pharmacokinetics of primaquine in calves of 180—300 kg live weight. The drug was injected at 0.29 mg/kg (0.51 mg/kg as primaquine diphosphate) intravenously or subcutaneously and the plasma concentrations of primaquine and its metabolite carboxyprimaquine were determined by high performance liquid chromatography. The extrapolated concentration of primaquine at zero time after the intravenous administration was 0.5 0.48 pg/mL which decreased with an elimination half-life of 0.16 0.07 h. Primaquine was rapidly converted to carboxyprimaquine after either route of administration. The peak concentration of carboxyprimaquine was 0.5 0.08 pg/mL at 1.67 0.15 h after intravenous administration. The corresponding value was 0.47 0.07 pg/mL at 5.05 1.2 h after subcutaneous administration. The elimination half-lives of carboxyprimaquine after intravenous and subcutaneous administration were 15.06 0.99 h and 12.26 3.6 h, respectively. 

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