Date of Graduation

1997

Document Type

Dissertation/Thesis

Abstract

Propranolol is a {dollar}\\beta{dollar}-adrenergic receptor blocking agent that has traditionally been administered for a number of clinical conditions. Although not as commonplace today, it still has significant clinical relevance. More importantly, however, is the large body of knowledge that has been generated which addresses the pharmacokinetic and pharmacodynamic characteristics of this {dollar}\\beta{dollar}-blocker. Indeed, propranolol has often been considered a model compound representative of other basic, lipophilic drugs which include narcotic analgesics, calcium-channel blockers, phenothiazines, and tricyclic antidepressants. For these reasons, we used propranolol in the studies reported in this disseration. One of our goals was to examine the capacity of constant-rate delivery systems to sustain stable plasma concentrations of drugs in "free-living" humans during precisely controlled physical activities which are known to significantly alter hepatic blood flow rate. This phenomenon could cause substantial fluctuations in drug levels due to both alterations in hepatic clearance (approximates total body clearance for these compounds) and, perhaps more importantly, transient drug disequilibrium between plasma and tissue compartments. Propranolol was used as a model "high-clearance" compound to assess the effects of postural manipulation and food consumption on concentrations of this drug during a constant-rate intravenous infusion in two clinical studies. Selected aspects of hepatic clearance and pharmacokinetics of propranolol and four other cardiovascular drugs (verapamil, propafenone, lidocaine, and nitroglycerin) are also reviewed. The first-pass metabolism of these agents is inconsistent with traditional models which assume that the hepatic extraction ratio of a drug is constant in each individual. The unusual accumulation kinetics of these compounds are discussed from a biochemical point of view with the primary focus being interactions at the level of the hepatic cytochrome P450 enzymes. Evidence exists for an interaction between propranolol and chlorpromazine in animals (rats and dogs) and humans in vivo and in vitro. This interaction was studied by investigating the recovery of propranolol, 4-hydroxypropranolol, and their glucuronide conjugates in rat urine after pretreatment of these species with chlorpromazine. In conclusion, the objective of this dissertation was to improve the understanding of the pharmacokinetics of propranolol and its interactions with other basic, lipophilic compounds.

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