Transport mechanism pharmacokinetics

Xenobiotic Transport Mechanisms and Pharmacokinetics in the Dogfish Shark... 

In the present compilation of the distribution and pharmacokinetic data of a dozen xenobiotics studied in the dogfish shark, this species yielded excellent data consistent with what we know from similar studies on terrestrial mammals. The data from the shark occasionaly provided information not available in other animals. Major transport parameters in this fish were shown to be similar to those found in mammals. This aquatic organism handles lipid-soluble pollutants by sequestering them in its fatty liver. Together with a previous summary (23) we have now studied about three dozen xenobiotics in this species. Because of its ease of handling, low cost, abundance, predictive value of transport mechanisms, and well-developed pharmacokinetics, the dogfish shark is an ideal fish species to use as a model to study aquatic pollutants. 

The permeability, P (P = Pc x D), of a nonpolar substance through a cell membrane is dependent on two physicochemical factors (1) solubility in the membrane (Pc), which can be expressed as a partition coefficient of the drug between the aqueous phase and membrane phase, and (2) diffusivity or diffusion coefficient (D), which is a measure of mobility of the drug molecules within the lipid. The latter may vary only slightly among toxicants, but the former is more important. Lipid solubility is therefore one of the most important determinants of the pharmacokinetic characteristics of a chemical, and it is important to determine whether a toxicants is readily ionized or not influenced by pH of the environment. If the toxicant is readily ionized, then one needs to understand its chemicals behavior in various environmental matrices in order to adequately assess its transport mechanism across membranes. 

Figure 33-10 Dose-response curves. L/ne A illustrates the linear relationship between serum drug concentration and total daily dose of a drug that displays first-order kinetics typical of most drugs. Line B illustrates the dose-response relationship for a drug that displays capacity-limited kinetics because of a saturable enzyme or transport mechanism in this situation, serum concentration becomes independent of total daily dose, and the relationship of drug concentration to dose becomes nonlinear. (Modified from Pippenger CE. Practical pharmacokinetic appiications. Syvo Monitor, Son Jose Syva Co, January, i 979 1-4.)...

As a response to diverse pressures to find alternatives to animal studies in pharmacokinetic studies, a number of cell culture-based methods have been developed, extensively validated, and applied. Considerable attention has been paid to the use of epithelial cell cultures for studying transport mechanisms, but culturing enterocytes has proved difficult because of their limited viability and the loss of important in vivo... 

In an oligonucleotide having n backbone linkages, this gives rise to 2 isomers that vary in their mechanism of action, cellular transport, as well as pharmacokinetics (53). Some of the most frequently encountered backbone modifications are Hsted in Table 1. 

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