Theoretical and experimental considerations of drug distribution and hepatic uptake and metabolism
AuthorKhor, Soo Peang
Committee ChairMayersohn, Michael
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractSeveral pharmacokinetic parameters have been used to quantitatively describe distributional processes of drug in the body. These parameters include apparent volumes of distribution, tissue-to-blood distribution coefficients and extraction ratios. Several pharmacokinetic parameters have been determined based on statistical moment analysis of concentration-time data through the determination of areas. We apply this area-based method for the determination of the initial volume of distribution (V1) and extend it to determination of the elimination rate constant (K10). The area under the rate of change of concentration-time curve (AURC), whose value equals the sum of the coefficients of a multiexponential equation, is introduced. In addition, the normalized moment (AURC/AUC) is equal to K10. It has been shown here theoretically and mathematically that under certain conditions it is necessary to correct for the residual blood in the tissue when measuring tissue concentrations. The potential error in ignoring this residual blood is expressed mathematically in terms of several important factors which include the anatomical features of the tissue (volume fractions of the blood, interstitial fluid and cellular space) as well as the physicochemical properties of the drug (extent of binding in the blood and tissues). These theoretical considerations are evaluated using experimental data on the distribution of phencyclidine in the rat. We conclude that correction for the residual blood is necessary when the values of tissue distribution are very small or large (relative to one) and when the volume fraction of the blood in tissue is substantial. A model is formulated for the calculation of extraction ratio in an isolated perfused liver. This model takes into account the kinetics of binding between the drug and protein. This model differs from existing models in that binding equilibrium is not assumed. The model is able to predict several existing observations regarding the hepatic uptake of drug in the presence of albumin.
Degree ProgramPharmaceutical Sciences