Regional pharmacokinetics of halogenated pyrimidines.
dc.contributor.author | Kuan, Han-Yi | |
dc.contributor.advisor | Smith, David E. | |
dc.date.accessioned | 2016-08-30T17:28:47Z | |
dc.date.available | 2016-08-30T17:28:47Z | |
dc.date.issued | 1997 | |
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:9732119 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/130517 | |
dc.description.abstract | The regional pharnacokinetics of halogenated pyrimidines were studied in the liver, GI tract, and lungs using dogs as an animal model. The first objective was to examine the effect of route of hepatic administration on the regional pharmacokinetics and systemic exposure of 5-fluorouracil (FUra) and 5-bromo-2$\sp\prime$-deoxyuridine (BrdUrd). BrdUrd was studied at 0.250 and 0.500 $\mu$mol/min/kg, and FUra was studied at 0.125 and 0.500 $\mu$mol/min/kg. Both drugs were highly extracted across the liver (E scH $\ge$ 0.65) at the dose rates studied, and no significant differences were observed in the regional kinetics (i.e., hepatic extraction, fraction escaping hepatic elimination, and hepatic clearance) and systemic exposure of BrdUrd and FUra following hepatic arterial versus portal venous infusions. Thus, it appears that regional chemotherapy may be applied to halogenated pyrimidines following hepatic arterial, portal venous, and alternating dosing routes with no additional risk of systemic toxicity. The second objective was to investigate the regional kinetics of FUra in the liver, GI tract, and lungs, and to characterize the relative importance of each organ to systemic kinetics. The initial dose-rate studies were performed with i.v. infusions of 0.125, 0.250, 0.500, 0.750, and 1.00 $\mu$mol/min/kg. In the dose range, hepatic extraction (E scH) remained above 0.70 while GI extraction (E scGI) decreased from 0.60 to 0.44 as the dose rate increased. This resulted in an unchanged splanchnic extraction (E scSpl) of 0.83. Extraction of FUra by the lung (E scLu) was evident and decreased from 0.11 to 0.03 with increasing doses. The extended dose-rate studies were performed with i.v. infusions of 0.0625, 0.250, 0.750, 1.50, and 2.00 $\mu$mol/min/kg. In the extended dose range, E scH decreased from about 0.70 to 0.60 while the dose-dependent decrease in E scGI was more significant, from 0.71 to 0.29. As a result, E scSpl decreased from 0.89 to 0.69 as the dose rate increased. Likewise, E scLu had a maximal value of 0.17 and decreased significantly to 0.005 and 0.05 at the higher dose rates. It appears that the splanchnic region becomes a more significant pathway while the lungs have a reduced role for overall drug elimination as the dose rate increases. | |
dc.format.extent | 229 p. | |
dc.language | English | |
dc.language.iso | EN | |
dc.subject | Gastrointestinal | |
dc.subject | Halogenated | |
dc.subject | Liver | |
dc.subject | Lung | |
dc.subject | Pharmacokinetics | |
dc.subject | Pyrimidines | |
dc.subject | Pyrinikines | |
dc.subject | Regional | |
dc.subject | Tract | |
dc.title | Regional pharmacokinetics of halogenated pyrimidines. | |
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/2027.42/130517/2/9732119.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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