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    PHARMACOKINETIC STUDIES OF BETA-BLOCKERS AND FLUOROPYRIMIDINES.

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    Author
    SCHAAF, LARRY JOE.
    Issue Date
    1985
    Keywords
    Fluoropyrimidines -- Metabolism.
    Pharmacokinetics.
    Advisor
    Mayersohn, Michael B.
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © 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.
    Abstract
    Part 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.
    Type
    text
    Dissertation-Reproduction (electronic)
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Pharmaceutical Sciences
    Graduate College
    Degree Grantor
    University of Arizona
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