Drug accumulation defined

The clinical development stage comprises three distinct components or phases (I, II, and III), and culminates in the filing of the NDA/MAA. Each phase involves process scale-up, pharmacokinetics, drug delivery, and drug safety activities. During phase I clinical development, the compound s safety and pharmacokinetic profile is defined. The determination of maximum concentration at steady state (Cmax), area under the plasma concentration time curve (AUC), elimination half-life, volume of distribution, clearance and excretion, and potential for drug accumulation is made in addition to studies that provide estimates of efficacious doses. Dose levels typically... 

Experiments in this laboratory identified apoptosis as a consequence of the action of cisplatin and many other anticancer agents [50-52], Many authors have subsequently misquoted these results when suggesting that cisplatin kills by apoptosis, and that suppression of apoptosis is a mechanism of resistance. It should be evident by now that apoptosis is better defined as a consequence of the mechanism of action of cisplatin and a failure of the mechanisms of resistance. Apoptosis is certainly not an alternative to the formation of DNA cross-links, nor to the cell-cycle perturbations that result these are still essential events in the initiation phase of apoptosis. The mechanisms of resistance to cisplatin still include reduced drug accumulation, reduced DNA platination, and altered DNA repair. However, apoptosis provides a framework for understanding the complete pathway from initial insult to eventual death of a cell. It provides the realization that there are additional factors that influence cell survival and death. Expression of Bcl-2 family members or changes in signal transduction pathways impact... 

Sahin, S. and Benet, L. Z., The operational multiple dosing half-life A key to define drug accumulation in patients and to designing extended release dosage forms, Pharm. Res., 25(12), 2869, 2008. 

When pharmaceuticals are administered to feed animals there is a special concern about the possible accumulation of drug residues in the animals tissues. Thus, in these bioequivalency studies it may be appropriate to carefully monitor parameters that define possible tissue accumulation [45]. 

At the inner border of ONH, the ILM becomes continuous with the basement membrane of fibrous astrocytes lining the internal surface of the ONH [21]. However, the lateral borders between the ONH and the adjacent choroid and retina are not well defined. Furthermore, it was reported [49] that micro vessels in the prelaminar region of the ONH lack classical blood-brain barrier characteristics and display nonspecific permeability, possibly mediated by vesicular transport. Thus, there is a theoretical possibility that topically applied drugs can penetrate indirectly through the retrobulbar space and then, through the ONH, reach the posterior choroid and retina. It was reported that following retrobulbar administration of fluorescein, the dye rapidly accumulated in the ONH and penetrated later to the vitreous [50],... 

The distribution of drugs depends on both the physicochemical properties of the drug molecules and the composition of tissue membranes. These factors can either result in a uniform or uneven distribution of dmgs into the various body compartments and fluids. In the extreme, distribution may tend toward an accumulation of drugs in particular tissues or to an almost complete exclusion of the drag from a particular compartment in a defined length of time. One unique compartment that has to be considered in this respect is the brain, which is separated from the capillary system of the blood by the blood-brain barrier, whose membrane has a special structure. It consists of a cerebral capillary network formed by a capillary endothelium that consists of a cell layer with continuous compact intercellular junctions. It has no pores, but special cells, astrocytes, which support the stability of the tissues, are situated at the bases of the endothelial membrane separating the brain and CSF from the blood. The astrocytes form an envelope around the capillaries. 

The limit t —> oo defines the total drug amount, qs = csV, that could be eventually dissolved in the volume V assuming that the amount used qo is greater than qs. Thus, we can define the accumulated fraction of the drug... 

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