whole_CossumPaulAdrian1985_thesis.pdf (12.54 MB)
Pharmacokinetics and pharmacodynamics of nitroglycerin and aspirin
thesisposted on 2023-05-27, 08:46 authored by Cossum, PA
The pharmacokinetics and pharmacodynamics of nitroglycerin and aspirin have been evaluated with emphasis being placed on the in vitro and in vivo metabolism of these drugs in various tissues of the body. Nitroglycerin (GTN) was metabolized by blood components to the dinitro- (GDN) and in turn mononitroglycerin (GMN) metabolites. The rate of GTN and GDN metabolism was concentration dependent. The rate of GTN metabolism was reduced in the presence of GDNs and prevented by iodoacetamide which was used to stabilize GTN in blood samples obtained for pharmacokinetic studies. Intravenous (IV) bolus doses of GTN administered to sheep evoked rapid and substantial changes in haemodynamic parameters in a dose-dependent manner. The magnitude of the responses was related to the peak GTN femoral arterial A or V plasma concentration. Large differences in peak GTN concentrations and area under the plasma-time curves (AUC) for A and V were observed. The extent of this femoral A-V gradient, and of gradients across the liver and lungs, was further examined at apparent steady state plasma GTN concentrations attained by continuous IV GTN infusions in sheep. These studies demonstrated substantial extra-hepatic metabolism of GTN; the availability of GTN was in the rank order leg < liver < lung. In vitro studies showed that GTN was metabolized to GDNs and GMNs by sheep liver, leg muscle, lung, venous and arterial tissue homogenates and that the presence of GDNs reduced the rate of GTN metabolism. Administration of bolus doses of GDNs to sheep receiving GTN infusion reversed the femoral A-V gradient and reduced the systemic clearance of GTN. GDN and GMN pharmacokinetics were monitored in some sheep receiving GTN infusions. Extra-hepatic metabolism of aspirin (ASA) was also investigated in the sheep. During continuous IV ASA infusions an A-V gradient in apparent steady state plasma ASA concentrations across the leg and liver was observed but not across the lungs. In vitrostudies of the metabolism of ASA by sheep leg muscle, liver and lung tissue homogenates showed that hydrolysis of ASA to salicylic acid (SA) occurred in all three tissues. The presence of SA had no effect on the rate of ASA hydrolysis by any of the tissues. Bolus doses of SA administered during ASA infusions failed to modify the pharmacokinetics or A-V gradients of plasma ASA concentrations except at the largest SA dose when the rate of elimination of ASA was increased. This was due to the displacement, by SA, of ASA from plasma protein binding sites. ASA metabolite pharmacokinetics were monitored in sheep receiving ASA infusions. Human platelet function was used to evaluate the pharmacodynamics of ASA administered as a single 300 mg dose of a soluble or a slow-release preparation. Despite marked differences in peak plasma ASA concentrations and AUCs, there was similar inhibition of platelet function elicited by the two doses of ASA. Dose ranging studies using the slow-release preparation once daily for 7 days indicated that maximal inhibition of platelet function occurred using doses of 100-200 mg ASA daily.
Rights statementCopyright 1985 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s). Thesis (Ph.D.)--University of Tasmania, 1986. Bibliography: leaves 178-209