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dc.contributor.advisorMayersohn, Michael B.en_US
dc.contributor.authorSCHAAF, LARRY JOE.
dc.creatorSCHAAF, LARRY JOE.en_US
dc.date.accessioned2011-10-31T19:02:13Z
dc.date.available2011-10-31T19:02:13Z
dc.date.issued1985en_US
dc.identifier.urihttp://hdl.handle.net/10150/188129
dc.description.abstractPart I. The disposition kinetics of 5-fluorouracil (5-FU) and a 5-FU prodrug, 5'-deoxy-5-fluorouridine (5'dFUR), were investigated in twelve patients with colorectal carcinoma. Each patient randomly received either two single, intravenous (iv) doses of 5-FU (7.5 and 15 mg/kg) or 5'dFUR (2 and 4 g/m²) on separate days. In addition, the whole blood/plasma concentration ratio and stability of 5-FU and 5'dFUR at 37°C was determined in whole blood from normal volunteers and in five patients with colorectal carcinoma. A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of both 5-FU and 5'dFUR. The renal clearance of both compounds was independent of dose. Therefore, the mechanism for dose-dependence appears to be primarily due to nonlinear elimination associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose suggesting product-inhibition as a possible explanation for the observed nonlinearity in 5-FU elimination. The present studies demonstrate that both 5-FU and 5'dFUR degrade when incubated in whole blood. However, the estimated whole blood clearance does not contribute significantly to the observed total body clearance values. Part II. This investigation examined the influence of gender and cigarette smoking on the disposition of propranolol (P) and metoprolol (M) after both oral and iv administration to twenty healthy volunteers. The only significant differences between smokers and nonsmokers were a higher total body clearance of P and a larger volume of distribution of M in smokers. A comparison of oral clearance values demonstrated that smokers and nonsmokers had a similar capacity to metabolize P and M. Differences between males and females were not observed for any of the pharmacokinetic parameters examined. Nonlinearity in the absorption of P and M was observed and the data suggest marked intersubject differences in the ability of the liver to extract or metabolize these drugs on their first-pass through the liver.
dc.language.isoenen_US
dc.publisherThe University of Arizona.en_US
dc.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.en_US
dc.subjectFluoropyrimidines -- Metabolism.en_US
dc.subjectPharmacokinetics.en_US
dc.titlePHARMACOKINETIC STUDIES OF BETA-BLOCKERS AND FLUOROPYRIMIDINES.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.identifier.oclc697287447en_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.contributor.committeememberPerrier, Donald G.en_US
dc.contributor.committeememberBlanchard, Jamesen_US
dc.contributor.committeememberCarter, Dean E.en_US
dc.contributor.committeememberSipes, I. Glennen_US
dc.identifier.proquest8603349en_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.namePh.D.en_US
dc.description.noteThis item was digitized from a paper original and/or a microfilm copy. If you need higher-resolution images for any content in this item, please contact us at repository@u.library.arizona.edu.
dc.description.admin-noteOriginal file replaced with corrected file July 2023.
refterms.dateFOA2018-09-03T16:50:12Z
html.description.abstractPart I. The disposition kinetics of 5-fluorouracil (5-FU) and a 5-FU prodrug, 5'-deoxy-5-fluorouridine (5'dFUR), were investigated in twelve patients with colorectal carcinoma. Each patient randomly received either two single, intravenous (iv) doses of 5-FU (7.5 and 15 mg/kg) or 5'dFUR (2 and 4 g/m²) on separate days. In addition, the whole blood/plasma concentration ratio and stability of 5-FU and 5'dFUR at 37°C was determined in whole blood from normal volunteers and in five patients with colorectal carcinoma. A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of both 5-FU and 5'dFUR. The renal clearance of both compounds was independent of dose. Therefore, the mechanism for dose-dependence appears to be primarily due to nonlinear elimination associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose suggesting product-inhibition as a possible explanation for the observed nonlinearity in 5-FU elimination. The present studies demonstrate that both 5-FU and 5'dFUR degrade when incubated in whole blood. However, the estimated whole blood clearance does not contribute significantly to the observed total body clearance values. Part II. This investigation examined the influence of gender and cigarette smoking on the disposition of propranolol (P) and metoprolol (M) after both oral and iv administration to twenty healthy volunteers. The only significant differences between smokers and nonsmokers were a higher total body clearance of P and a larger volume of distribution of M in smokers. A comparison of oral clearance values demonstrated that smokers and nonsmokers had a similar capacity to metabolize P and M. Differences between males and females were not observed for any of the pharmacokinetic parameters examined. Nonlinearity in the absorption of P and M was observed and the data suggest marked intersubject differences in the ability of the liver to extract or metabolize these drugs on their first-pass through the liver.


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