Kinetics drug absorption

A measure of the actual amount of drug in the body can be obtained from the area under the curve of the temporal concentration curve (calculated by integration). Interestingly, the temporal behavior of a drug can be extremely important in therapeutics. For example, consider three preparations of a drug that present identical values for area under the curve (i.e., amount of drug absorbed) but have different kinetics of absorption (Figure 8.23). As shown, preparation B produces a useful profile whereby the concentration exceeds the minimal effective concentration... 

A special case for reduced bioavailabilty results from first-pass extraction that sometimes might be subjected to saturable Michaelis-Menten absorption kinetics. The lower the hepatic drug clearance is (Clhep) in relation to liver blood flow (Ql), or the faster the drug absorption rate constant (Ka), and the higher the dose (D) are, the more bioavailable is the drug (F). 

Equation (3) is in the form of a differential equation describing a first-order kinetic process, and, as a result, drug absorption generally adheres to first-order kinetics. The rate of absorption should increase directly with an increase in drug concentration in the GI fluids. 

It is far more difficult to establish the mechanism(s) of drug absorption in humans. Most investigators analyze drug absorption data in humans (from blood or urine data) by assuming first-order absorption kinetics. For the most part this assumption seems quite... 

While in vivo studies assess absorption rates as process-lumped time constants from blood level versus time data, these rate parameters encompass the kinetics of dosage-form release, GI transit, metabolism, and membrane permeation. The use of isolated tissue and cellular preparations to screen for drug absorption potential and to evaluate absorption rate limits at the tissue and cellular levels has been expanded by the pharmaceutical industry over the past several years. For more detail in this regard, the reader is referred to an article by Stewart et al. [68] for references on these preparations and for additional details on the various experimental techniques outlined below. 

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... 

The CAT model considers passive absorption, saturable absorption, degradation, and transit in the human small intestine. However, the absorption and degradation kinetics are the only model parameters that need to be determined to estimate the fraction of dose absorbed and to simulate intestinal absorption kinetics. Degradation kinetics may be determined in vitro and absorption parameters can also be determined using human intestinal perfusion techniques [85] therefore, it may be feasible to predict intestinal absorption kinetics based on in vitro degradation and in vivo perfusion data. Nevertheless, considering the complexity of oral drug absorption, such a prediction is only an approximation. 

Poelma, F. G. J., Tukker, J. J., Evaluation of the chronically isolated internal loop in the rat for the study of drug absorption kinetics, J. Pharm. 

The advantages of the in situ techniques include an intact blood supply multiple samples may be taken, thus enabling kinetic studies to be performed. A fundamental point regarding the in situ intestinal perfusion method is that the rat model has been demonstrated to correlate with in vivo human data [46 19], Amidon et al. [36] have demonstrated that it can be used to predict absorption for both passive and carrier-mediated substrates. However, the intestinal luminal concentrations used in rat experiments should reflect adequately scaled and clinically relevant concentrations to ensure appropriate permeability determinations [50], There are limitations of the in situ rat perfusion models. The assumption involved in derivation of these models that all drug passes into portal vein, that is drug disappearance reflects drug absorption, may not be valid in some circumstances as discussed below. 

Schurgers N, Bijdendijk J, Tukker JJ and Crommelin DJ (1986) Comparison of Four Experimental Techniques for Studying Drug Absorption Kinetics in the Anaesthetized Rat in Situ. J Pharm Sci 75 pp 117-119. 

Poelma FGJ and Tukker JJ (1987) Evaluation of a Chronically Isolated Internal Loop in the Rat for the Study of Drug Absorption Kinetics. J Pharm Sci 76 pp 433-436. 

Tucker IG (1988) A method to study the kinetics of oral mucosal drug absorption from solutions. J Pharm Pharmacol 40 679-683... 

For a drug to interact with a target, it has to be present in sufficient concentration in the fluid medium surrounding the cells with receptors. Pharmacokinetics (PK) is the study of the kinetics of absorption, distribution, metabolism, and excretion (ADME) of drugs. It analyzes the way the human body deals with a drug after it has been administered, and the transportation of the drug to the specihc site for drug-receptor interaction. For example, a person has a headache and takes an aspirin to abate the pain. How does the aspirin travel from our mouth to reach the site in the brain where the headache is and act to reduce the pain ... 

The present volume of the series Methods and Principles in Medicinal Chemistry focuses on the impact of pharmacokinetics and metabolism in Drug Design. Pharmacokinetics is the study of the kinetics of absorption, distribution, metabolism, and excretion of drugs and their pharmacologic, therapeutic, or toxic response in animals and man. 

Laplace transformation is particularly useful in pharmacokinetics where a number of series first-order reactions are used to model the kinetics of drug absorption, distribution, metabolism, and excretion. Likewise, the relaxation kinetics of certain multistep chemical and physical processes are well suited for the use of Laplace transforms. 

Fig. 11. Cumulative mean diuresis versus cumulative mean furosemide excretion following 60 mg doses given as two controlled release tablets (boxes), as plain tablets (closed triangles) and following an intravenous dosage of 0.5 mg/kg (open triangles). (From Paintaud G. Kinetics of drug absorption and infiuence of absorption rate on pharmacological effect. Diss. Karolinska Institutet, Stockholm 1993, reproduced by permission.)...

Paintaud G. Kinetics of drug absorption and influence of absorption rate on pharmacological effect. Diss. Karolinska Institutet, Stockholm 1993. 

Pharmacologic factors include (1) the kinetics of absorption, distribution, and elimination (2) the ability of the drug to be delivered to the site of infection (3) the potential toxicity of an agent and (4) pharmacokinetic or pharmacodynamic interactions with other drugs. 

The kinetics of absorption of the drug following administration of the formulation of thiotepa in gelatin particles to rabbits suggested that not only was the blood level elevated compared to a control but the area under the curve (AUC) was essentially more than doubled. Since this represents the amount of drug absorbed the authors suggested that administration of a simple gelatin particulate formulation... 

Doluisio, J.T., et al. 1970. Drug absorption III Effect of membrane storage on the kinetics of drug absorption. J Pharm Sci 59 72. 

Barr WH, Riegelman S. Intestinal drug absorption and metabolism. II. Kinetic aspects of intestinal glucuronide conjugation. J Pharm Sci 1970 59 164-168. 

Mizuma T. Kinetic impact of presystemic intestinal metabolism on drug absorption experiment and data analysis for the prediction of in vivo absorption from in vitro data. Drug Metab Pharmacokinet 2002 17(6) 496-506. 

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