Pharmacokinetics distributed

Although there has been little data generated on the topic, this altered method of delivery to the systemic circulation may have profound effects on the subsequent distribution, pharmacokinetics, and pharmacodynamics of the drug molecule and have an impact on the wider area of drug binding to plasma lipoproteins and the potential effects of lipids on this process. 

Mordenti J, Cuthbertson RA, Ferrara N, et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 1251-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol 1999 27 536. 

Distributed pharmacokinetics is characterized not only by spatially dependent concentration profiles but also by dose-response relationships that become spatially dependent. For example, biological responses such as cell kill are often quantified as functions of area under the concentration-vs.-time curve (ALIC). In compartment models, response is frequently correlated with the area under the plasma-concentration-vs.-time curve, where... 

In distributed pharmacokinetics, threshold models, in which a biological response is associated with the increase of concentration above a threshold value, are likewise dependent on spatial location. 

The use of distributed pharmacokinetic models to estimate expected concentration profiles associated with different modes of drug delivery requires that various input parameters be available. The most commonly required parameters, as seen in Equation 9.1, are diffusion coefficients, reaction rate constants, and capillary permeabilities. As will be encountered later, hydraulic conductivities are also needed when pressure-driven rather than diffusion-driven flows are involved. Diffusion coefficients (i.e., the De parameter described previously) can be measured experimentally or can be estimated by extrapolation from known values for reference substances. Diffusion constants in tissue are known to be proportional to their aqueous value, which in turn is approximately proportional to a power of the molecular weight. Hence,... 

Reaction rate parameters required for the distributed pharmacokinetic model generally come from independent experimental data. One source is the analysis of rates of metabolism of cells grown in culture. However, the parameters from this source are potentially subject to considerable artifact, since cofactors and cellular interactions may be absent in vitro that are present in vivo. Published enzyme activities are a second source, but these are even more subject to artifact. A third source is previous compartmental analysis of a tissue dosed uniformly by intravenous infusion. If a compartment in such a study can be closely identified with the organ or tissue later considered in distributed pharmacokinetic analysis, then its compartmental clearance constant can often be used to derive the required metabolic rate constant. 

Another example of a situation in which distributed pharmacokinetics plays an important role is in the infusion of drug solutions into the lateral ventricles or cisternal space of the brain. Drugs that have been delivered this way include chemotherapeutic agents for the treatment of tumors antibacterial antifungal and antiviral agents for the treatment of infection and neurotrophic factors for the treatment of neurodegenera tive disease. 

BtOchim. Biophys. Acta 218,463 (1970). Review B. Nilsson, Clin. Pharmacol. Drug Epidemiol 2, 273-277 (1979). Series of articles on pharmacology, toxicity, distribution, pharmacokinetics and clinical studies Arzncimittcl-Forsch. 33,... 

Btlhrer H Mappes A, Lauber R, Stanski DR, Maitre PO Dexmedetomidine decreases thiopental dose requirement and alters distribution pharmacokinetics Ams iesiology (1994) 80, 1216-27. 

Quantitative aspects of distribution. Pharmacokinetics. Sustained release. 109... 

---