Dynamics, drug distribution

Figure 1. Drug distribution dynamics—i.e., many processes can act...

Drug therapy is a dynamic process. When a drug product is administered, absorption usually proceeds over a finite time interval, and distribution, metabolism, and excretion (ADME) of the drug and its metabolites proceed continuously at various rates. The relative rates of these ADME processes determine the time course of the drug in the body, most importantly at the receptor sites that are responsible for the pharmacological action of the drug. 

RK Jain, J Wei. Dynamics of drug transport in solid tumors Distributed parameter models. J Bioeng 1 313-330, 1977. 

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. 

Use of in vivo Tests. In vivo tests are more relevant indicators than are in vitro tests of immunotoxicity since the dynamic interactions between the various immuno-components, as well as the pertinent pharmacokinetic (absorption, distribution, plasma concentrations) and metabolic factors, are taken into consideration. However, it is important to select the appropriate animal model and to design the protocol such that it will accurately reflect drug (or relevant metabolite) exposure to humans. For example, one should consider species variability when selecting the animal model, since biological diversity may further obscure the ability to accurately predict human toxicity. 

Benet LZ, Kroetz DL, Sheiner LB. 1995. Pharmacokinetics The dynamics of drug absorption, distribution and elimination. In Hardman JG, Gilman, AG, Limbird LE, eds. Goodman Gilman s The pharmacological basis of therapeutics, 9th ed. New York, New York McGraw Hill. 

Benet LZ, Sheiner LB. 1985. Pharmacokinetics The dynamics of drugs absorption, distribution, and elimination. In 7th ed. Goodman s and Gilman s The pharmaceutical basis of therapeutics. New York, NY MacMillan Publishing Company. 

Pharmacokinetics and pharmacodynamics form the two major branches of pharmacoiogy. Pharmacokinetics is the study of drug disposition and deais with the processes of absorption, distribution, metaboiism and eiimination. Pharmacodynamics is concerned with the reiationship between the concentration of a drug and its effect. Put another way, pharmacodynamics is what a drug does to the body whiie pharmacokinetics is what the body does to a drug. This chapter wiii cover the generai principies reiating to these processes, and deveiop some of the principies that describe their kinetics and dynamics. 

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. 

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