Mechanistic modeling approaches to time -dependent oral drug absorption.
dc.contributor.author | Menon, Sujatha Sekara | |
dc.contributor.advisor | Amidon, Gordon L. | |
dc.date.accessioned | 2016-08-30T15:31:49Z | |
dc.date.available | 2016-08-30T15:31:49Z | |
dc.date.issued | 2004 | |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3121997 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/124132 | |
dc.description.abstract | Complex absorption characteristics of drugs which are often manifested as irregular plasma profiles, can result in delayed and variable therapy. Conventional models with a constant time-invariant absorption rate coefficient cannot adequately explain such irregularities. Several gastrointestinal factors are known to cause variable absorption including time-dependent and/or position-dependent factors such as gastric emptying, changes in lumenal volume, surface area of absorption, or permeability of the drug. Thus the overall objective of this project was to develop mechanistic modeling approaches to explain complex, time-dependent oral drug absorption. This objective was achieved by characterizing the complex absorption of two different drugs, cimetidine and valacyclovir. First, the complex absorption of cimetidine was evaluated using six different time-dependent models. These included four new multiphasic absorption models, all incorporating gastric motility, and some assuming multiple absorption processes. Two of these new models were integrated models which combined two important gastrointestinal time-dependent factors, gastric motility and fluid kinetics, in the same model. The proposed multiphase models were significantly better than the conventional model in describing the complex absorption kinetics of cimetidine. Based on these results, cimetidine's complex absorption may be attributed to multiple time-dependent gastrointestinal factors, the most important one being gastric emptying. Second, acyclovir plasma profiles after oral valacyclovir or acyclovir were examined using three time-dependent models as well as noncompartmental methods and deconvolution techniques. The proposed models, particularly a two phase model based on gastric emptying and two distinct absorption processes were significantly better than the conventional model. Deconvolution revealed a multiphasic absorption profile with two major peaks. The multiphasic absorption profile for valacyclovir is most likely a combined result of gastric emptying and the presence of multiple absorption processes, particularly carrier-mediated transport, with a major contribution probably from the oligopeptide transporter, HPT1. In conclusion, there is substantial value in the use of these mechanistic modeling approaches to describe complex and time-dependent oral drug absorption. This was clearly seen with both the example drugs studied in this thesis, the first drug, cimetidine whose absorption was largely affected by gastric motility, and the second drug, valacyclovir, whose absorption was mostly carrier-mediated. | |
dc.format.extent | 166 p. | |
dc.language | English | |
dc.language.iso | EN | |
dc.subject | Approaches | |
dc.subject | Mechanistic | |
dc.subject | Modeling | |
dc.subject | Oral Drug Absorption | |
dc.subject | Pharmacokinetic | |
dc.subject | Time-dependent Absorption | |
dc.title | Mechanistic modeling approaches to time -dependent oral drug absorption. | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Health and Environmental Sciences | |
dc.description.thesisdegreediscipline | Pharmaceutical sciences | |
dc.description.thesisdegreediscipline | Pharmacology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/124132/2/3121997.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.