Unacceptable pharmacokinetics (PK) relating to aldehyde oxidase (AO) metabolism have resulted in clinical failure of several promising drug candidates, yet reliable and standardized methods to predict the human PK and drug-drug interaction (DDI) liability of AO-metabolized drugs remains to be established. Investigations into the DDI liability associated with AO substrates also metabolized by cytochrome P450 and the potential utility of allometric scaling methods to predict human clearance (CL) of AO substrates were conducted. These investigations indicate a susceptibility of mixed AO/P450-metabolized drugs to DDI with P450 inhibitors, resulting in elevated AO metabolite exposure. In addition, data indicate allometric scaling with multiple or single species may be useful to predict human CL when appropriate species are utilized. Evaluations of biotransformation, fraction metabolized by AO (Fm,AO), hepatic extraction ratio (E), and allometric scaling of in vivo and in vitro CL indicate guinea pig and monkey may be most useful for single-species scaling, while minipig, rat, and mouse may also be of use in multispecies allometry.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11192016-142144 |
| Date | 28 November 2016 |
| Creators | Crouch, Rachel Denise |
| Contributors | Joey Barnett, Neil Osheroff, Wendell S. Akers, David Weaver, Colleen Niswender, J. Scott Daniels |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11192016-142144/ |
| Rights | restrictsix, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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