Pharmacokinetics multicompartment model

PHYSICAL ORGANIC CHEMISTRY NOMENCLATURE Multicompartment modeling, PHARMACOKINETICS Multicyclic enzyme systems,... 

The mqor limitation to all pharmacokinetic approaches such as these relate to the large data requirements needed to solve model parameters. A full solution for a multicompartment model requires a series of repheated expmments using a single chranical applied at different doses and experiments tominated at various time points. As mmtioned, in vitro studies would be conducted to obtain specific biophysical parameter estimates. All data are simultaneously analyzed. For many compounds, specific components of the full model may not be required thus, in reality the actual model fitted is simpler. Statistical algorithms are presently und developmrait to select the optimum model for the specific compound studied and collapse the remainder of the model structure into a matrix from which individual rate parameters... 

On some occasions, the body does not behave as a single homogeneous compartment, and multicompartment pharmacokinetics are required to describe the time course of drug concentrations. In other instances certain pharmacokinetic processes may not obey first-order kinetics and saturable or nonlinear models may be required. Additionally, advanced pharmacokinetic analyses require the use of various computer programs, such as those listed on the website http //www.boomer.org/pkin/soft.html. 

Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992 76 334—41. 

It can be shown, of course, that Eq. (10) is identical to Eq. (5) in the n-compart-ment model, but the use of Eq. (10) requires fewer assumptions to be made in determining Vss. That is, Eq. (10) only requires that disposition rates are first order, while Eq. (5) requires additional assumptions related to the underlying multicompartment pharmacokinetic model. 

The observed empirical models should now be employed to simulate and predict kinetic behaviors obtained with administration protocols other than that used for observation. Moreover, we must develop pharmacokinetics in a multicompartment system by including the presence of a fractal organ. We have argued that the liver, where most of the enzymatic processes of drug elimination take place, has a fractal structure. Hence, we expect transport processes as well as chemical reactions taking place in the liver to carry a signature of its fractality. 

In the pharmacodynamic model, the drug concentration at the receptor site is proportional to the drug concentration in the plasma, regardless of the pharmacokinetic model (one compartment or multicompartment), and the interaction between the drug and receptor is directly and rapidly reversible after drug administration. 

Vancomycin is approximately 30 to 55% bound to plasma proteins. Its distribution after intravenous administration proceeds as a biphasic process and is consistent with a two or three compartment model. The half-life of the first distributive phase is approximately 0.4 hour in patients with normal renal function the second distributive phase is approximately 1.6 hours [172]. Consistent with its multicompartment pharmacokinetic modeling, vancomycin is widely distributed and penetrates into many different body fluids and... 

Dose-response models describe a cause-effect relationship. There are a wide range of mathematical models that have been used for this purpose. The complexity of a dose-response model can range from a simple one-parameter equation to complex multicompartment pharmacokinetic/pharmacodynamic models. Many dose-response models, including most cancer risk assessment models, are population models that predict the frequency of a disease in a population. Such dose-response models typically employ one or more frequency distributions as part of the equation. Dose-response may also operate at an individual level and predict the severity of a health outcome as a function of dose. Particularly complex dose-response models may model both severity of outcome and population variability, and perhaps even recognize the influence of multiple causal factors. 

Table 22.1 Pharmacokinetic considerations for gene therapy agents [Adapted from Ledley TS, Ledley FD. 1994. Multicompartment numerical model of cellular events in the pharmacokinetics of gene therapies. Hum. Gene Ther. 5 679-691]...

W. Krzyzanski and W. J. Jusko, Indirect pharmacodynamic models for response with multicompartment distribution or polyexponential disposition. J Pharmacokinet Bio-pharm 28 57-78 (2002). 

Compartmental models range from a simple well-mixed single compartment to more complicated muLticompart-ments that are used to describe the blood and/or plasma time course of a chemical or drug. These approaches have been utilized to model the pharmacokinetics of OP and CM insecticides and their major metabolites... 

Levy G etal. (1968). Multicompartment pharmacokinetic models and pharmacologic effects, f Pharm Sci 58 422-424. 

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