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Physicochemical and Structural Determinants of Pharmacokinetic Behaviour.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Physicochemical and Structural Determinants of Pharmacokinetic Behaviour./
作者:	Rodgers, Trudy A.
面頁冊數:	1 online resource (264 pages)
附註:	Source: Dissertations Abstracts International, Volume: 80-07, Section: C.
Contained By:	Dissertations Abstracts International80-07C.
標題:	Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13804411click for full text (PQDT)
ISBN:	9780438722170

Physicochemical and Structural Determinants of Pharmacokinetic Behaviour.
Rodgers, Trudy A.

Physicochemical and Structural Determinants of Pharmacokinetic Behaviour. - 1 online resource (264 pages)

Source: Dissertations Abstracts International, Volume: 80-07, Section: C.

Thesis (Ph.D.)--The University of Manchester (United Kingdom), 2003.

Includes bibliographical references

The aims of the current research were to improve the prediction of pharmacokinetic behaviour in vivo from in vitro and in silico data, focussing on the distribution of the enantiomers of eight β-blocking drugs within the body. This was achieved by investigating quantitative structure-pharmacokinetic relationships (QSPR) and whole body physiologically based pharmacokinetic (WBPBPK) models, which required the generation of vast amounts of in vivo pharmacokinetic data in rats. To immensely reduce the timeframes, cost and animal usage involved in generating this in vivo data cassette dosing was investigated and employed, with sample analysis being via chiral LC-MS methods developed in the current research. The resultant clearance values highlighted stereoselective differences for some of the compounds, arising from a combination of renal and hepatic routes. Tissue distribution was also enantioselective and largely influenced by the enantiomeric differences in plasma protein binding, although the data indicates that some compounds may also stereoselectively interact with tissue components. Regional and compound differences in tissue distribution were also apparent, which were found to be best accounted for by tissue levels of acidic phospholipids (phosphatidylserine, phosphatidylinositol and phosphatidylglycerol) and the affinity for blood cells, respectively. This tissue distribution information was used to develop a mechanistic equation for predicting tissue affinities (Kpu values), since existing equations were found to be inappropriate for β-blockers and other moderate to strong bases. The ability to predict tissue affinities could greatly assisit WBPBPK modelling where generation of such data is very time, cost and labour intensive thereby acting as a deterrent for industrial companies. In addition, tissue affinities are rarely determined in humans and large animals due to the requirement for invasive tissue biopsies or tissue excision, as such the ability to predict Kpu values would provide an insight into the regional tissue distribution in these species. A further use of the mechanistic equation was in the prediction of the Vuss, which provides a global measure of distribution and, through comparison with the Vuss value determined from plasma data, provides a means of assessing the overall accuracy of the tissue distribution predictions. Good predictions were obtained using this mechanistic equation for both the tissue affinities (8 rat tissues) and the Vuss values of the enantiomers of a series of β-blocking drugs, and this approach was successfully extened to a selection of other structurally unrelated moderate to strong bases in rats. An alternative approach to Vuss predictions was also uncovered in the current research, namely that the Kpu value in muscle (predicted using mechanistic equations) was almost identical to the Vuss. This approach was successfully applied to Vuss predictions for structurally unrelated acids, neutrals and bases (weak and moderate to strong) in both rats and humans. Finally, WBPBPK modelling was used to simulate 95% prediction intervals for concentration time profiles in rat plasma and 12 rat tissues, using Monte-Carlo simulations. These simulations can be used to assist the design of future bolus studies necessary to confirm the model structure and the ability of steady state data to predict dynamic events. Once refined, the WBPBPK model could then be used to predict the pharmacokinetic behaviour of β-blockers in humans.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9780438722170Subjects--Topical Terms:

634543
Pharmacology.
Subjects--Index Terms:

PharmacokineticsIndex Terms--Genre/Form:

542853
Electronic books.

Physicochemical and Structural Determinants of Pharmacokinetic Behaviour.
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