Pharmacokinetics uptake process

Nishida, K., Takino, T., Eguchi, Y., Yamashita, F., Hashida, M. and Sezaki, H. (1992) Pharmacokinetic analysis of uptake process of lactosaminated albumin in rat liver constant infusion experiments. Int. J. Pharm., 80,101-108. 

As a general consideration of the pharmacokinetic profile of macrolides, Williams and Sefton [7] have described the following uptake process (Fig. 1). Briefly, after oral administration of macrolides, some of the dose is inactivated in the liver, but it is predominantly excreted into the bile and then enters the enterohepatic circulation. Only after biliary excretion is saturated does it flow into the hepatic vein. All macrolides flowing from the liver are carried through the right heart and... 

The first pharmacokinetic and pharmacodynamic experiments on mammalian uptake and mechanism were conducted on renal tubules (Jusko and Levy 1975). In vitro experiments on the uptake process were studied using isolated renal brush-border membrane vesicles (Yanagawa et al. 1997) and HK-2 cell line (Kumar et al. 1998). 

Apart from patient-specific parameters, external factors - most importantly the concomitant uptake of certain other chemicals present in diet, environment and especially other drugs - influence drug actions. Possible effects are manifold and can affect all stages of pharmacokinetic and pharmacodynamic processes in the body. Also direct interaction and inactivation of concomitantly administered substances are possible. Drug-drug interactions via modulation of metabolism present a very hot topic in pharmaceutical research and drug design. 

Many drugs have been recognized to cross the intestinal epithelial cells via passive diffusion, thus their lipophilicity has been considered important. However, as described above, recent studies have demonstrated that a number of drug transporters including uptake and efflux systems determine the membrane transport process. In this chapter, we provide an overview of the basic characteristics of major drug transporters responsible not only for absorption but also for disposition and excretion in order to delineate the impact of drug transport proteins on pharmacokinetics. 

The most important processes assessed in pharmacokinetic studies are absorption (uptake of a drug from the digestive tract), distribution (compart-mentalization in the body), metabolism (conversion or breakdown, especially in the liver) and elimination (excretion), summarized by the abbreviation ADME. 

Chemical clastogenesis and mutagenesis both involve a complex series of processes, including pharmacokinetic mechanisms (uptake, transport, diffusion, excretion), metabolic activation and inactivation, production of DNA lesions and their incomplete repair or misrepair, and steps leading to the subsequent expression of mutations in surviving cells or individuals (Thble 7.1). Each of the steps in these processes might conceivably involve first order kinetics at low doses (e.g., diffusion, MichaeUs-Menten enzyme kinetics) and hence be linear. In principle, therefore, the overall process edso might be linear and without threshold. 

In all three cases the contents of the intracellular vesicles will finally be released into the cytoplasm, or transported to the cell membrane to be released into the ex-travascular space. Receptor-mediated endocytosis is the predominant mechanism of cellular uptake for mAbs. As mentioned previously (see Sections 3.9.1 and 3.9.3), Fc-Rn is present in a large variety of cells and is very often involved in this process. In addition, the antigen-antibody complex via Fab can also undergo re-ceptor -mediated endocytosis. The impact of this internalization process on the pharmacokinetics of mAbs will be discussed later. 

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