Absorption pharmacokinetic parameters

Hellriegel et al. (1996) observed a signiLcant inverse linear relationship between the bioavailability of a drug and its coefLcient of variation. An insoluble drug with very low oral bioavailability usually has a very large intersubject variability in its absorption pharmacokinetic parameters, which may result in a worrisome safety proLle or unfavorable efLcacy. 

For all routes of administration, the absorption, distribution, and elimination kinetics are important for obtaining the desired therapeutic effect. For drugs expected to act in the eye after ocular absorption, pharmacokinetic parameters are difficult to obtain in both animals and humans. Accordingly, it has been proposed to rely essentially on pharmacodynamic measurements by use of a specific biological response after topical administration (258,259). For example, the apparent absorp-... 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

In Sec. VII we dealt with methods of determining the rate (and mechanism) of absorption. In this section we will deal with methods of determining the extent of absorption. In every example, the calculation will involve a comparison between two studies carried out in the same group of volunteers on different occasions. Usually it will be necessary to assume that the volunteers behaved identically on both occasions, especially with regard to their pharmacokinetic parameters. 

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... 

The most useful pharmacokinetic variable for describing the quantitative aspects of all processes influencing the absorption (fa) and first-pass metabolism and excretion (Eg and Eh) in the gut and liver is the absolute bioavailability (F) [40]. This pharmacokinetic parameter is used to illustrate the fraction of the dose that reaches the systemic circulation, and relate it to pharmacological and safety effects for oral pharmaceutical products in various clinical situations. The bioavailability is dependent on three major factors the fraction dose absorbed (fa) and the first-pass extraction of the drug in the gut wall (EG) and/or the liver (EH) (Eq. (1)) [2-4, 15, 35] ... 

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. 

C(t) modeled according to two-compartment model with zero-order and first-order absorption Pharmacokinetic/pharmacodynamic relationship modeled using Hill model with first-order absorption. Modeled parameters matched experimental parameters when bicompartmental model with zero-order input was used. Linear PKs, anticlockwise hysteresis loop established for all doses studied. Apomorphine and growth hormone concentration predicted with good accuracy... 

Pharmacokinetic parameters Absorption Distribution Metabolism Excretion Other studies... 

Fig. 2.6 Effect of variation in absorption rate on plasma drug concentration. The graph shows simulated plasma concentration-time curves for theophyUine after oral administration, illustrating a 20% difference in Cpmax values resulting from variation in the absorption rate constant. Absorption rate constants top curve 2.2 per h (Cpmax 20 pg/mL) middle curve 1.0 per h (Cptnax 18 M-g/mL) bottom curve 0.7 per h. Note that tmax also changes. The established therapeutic concentration of theophyUin is 10-20 pg/mL. The most rapidly absorbed formulation produces the highest concentration and greatest chance of side effects. Also, the duration for which the plasma concentration is within the therapeutic range also varies. Pharmacokinetic parameters dose, 400 mg bioavaUabiUty, 0.8 volume of distribution, 29 L half-Ufe, 5.5 h.

Absorption - The mean pharmacokinetic parameters of daptomycin on day 7 following the IV administration of 4, 6, and 8 mg/kg once daily to healthy young adults (mean age, 35.8 years) are summarized in the following table. 

In this project, compound A from a potential lead series was a neutral compound of MW 314 with low aqueous solubility (Systemic clearance, volume and AUC following a 0.5mg/kg intravenous dose to rats were well predicted (within twofold) from scaled microsomal clearance and in silica prediction of pKa, logP and unbound fraction in plasma. Figure 10.3a shows the predicted oral profile compared to the observed data from two rats dosed orally at 2mg/kg. The additional inputs for the oral prediction were the Caco-2 permeability and measured human fed-state simulated intestinal fluid (FeSSIF, 92(tg/mL). The oral pharmacokinetic parameters Tmax. Cmax. AUC and bioavailability were well predicted. Simulation of higher doses of compound A predicted absorption-limited... 

The basic principles outlined above can be applied to the interpretation of clinical drug concentration measurements on the basis of three major pharmacokinetic variables absorption, clearance, and volume of distribution (and the derived variable, half-life) and two pharmacodynamic variables maximum effect attainable in the target tissue and the sensitivity of the tissue to the drug. Diseases may modify all of these parameters, and the ability to predict the effect of disease states on pharmacokinetic parameters is important in properly adjusting dosage in such cases. (See The Target Concentration Strategy.)... 

Therefore, the pharmacokinetic parameters, which can be derived from blood level measurements, are important aids to the interpretation of data from toxicological dose-response studies. The plasma level profile for a drug or other foreign compound is therefore a composite picture of the disposition of the compound, being the result of various dynamic processes. The processes of disposition can be considered in terms of "compartments." Thus, absorption of the foreign compound into the central compartment will be followed by distribution, possibly into one or more peripheral compartments, and removal from the central compartment by excretion and possibly metabolism (Fig. 3.23). A very simple situation might only consist of one, central compartment. Alternatively, there may be many compartments. For such multicompartmental analysis and more details of pharmacokinetics and toxicokinetics, see references in the section "Bibliography." The central compartment may be, but is not necessarily, identical with the blood. It is really the compartment with which the compound is in rapid equilibrium. The distribution to peripheral compartments is reversible, whereas the removal from the central compartment by metabolism and excretion is irreversible. 

Pharmacokinetics attd Pharmacology. Older macrolides such as erythromycin exhibit relatively low serum concentrations, short in vivo half-hves, highly variable oral absorption, and low oral bioavailability. Improvements in these pharmacokinetic parameters have been accomplished for newer derivatives. The principal side effects of macrolides aie gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. 

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