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Title: The effect of co-administered drugs on the pharmacokinetics and pharmacodynamics of propranolol
Author: Kitteringham, N. R.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1981
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Abstract:
The first pass elimination (FPE) of propranolol results in low oral bioavailability and larger inter-individual variation in blood concentrations. The aim of this study was to reduce the FPE of propranolol by co-administration of other drugs in an animal model. This thesis describes the use of the pithed rat to study the FPE of propranolol with respect to its pharmacokinetics and pharmacological effect. The extraction of the dose of propranolol (700 μg/kg) was shown to be approximately 90%; the major metabolites being unidentified, but having the chemical properties of conjugated metabolites. The FPE of propranolol was virtually abolished when chlorpromazine (CPZ, 4 mg/kg) was administered, via the hepatic portal vein, before injection of propranolol. This reduction was associated with a decrease in the formation of 'conjugated' metabolites and an increase in the pharmacological effect of propranolol. CPZ had only a small effect upon the disposition and pharmacological effect of propranolol administered via the jugular vein, suggesting inhibition of metabolism during the first pass by CPZ. The effect of CPZ was compared with the effects of imipramine, SKF 525-A and metyrapone, three drugs known to inhibit many cytochrome P450 mediated reactions. Imipramine and SKF 525-A, but not metyrapone, similarly reduced the FPE of propranolol. The ability of CPZ, imipramine and SK 525-A to inhibit the in vitro metabolism of propranolol was investigated in rat liver microsomes. All three drugs inhibited the formation of 4-hydroxy propranolol and another, unidentified, metabolite. A value for the intrinsic clearance of propranolol was calculated from in vitro data and was compared with values obtained in whole animal experiments. A close correlation was obtained between the predicted, in vitro, extraction ratio and the extraction ratio measured in the pithed rat. Finally, the pharmacological effect of propranolol was related to its blood and predicted tissue concentrations. A correlation was obtained between pharmacological effect and tissue, but not blood, concentrations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.592896  DOI: Not available
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