The overall objective of our research is to examine the relationship between the pharmacokinetics and the pharmacodynamics of nitroglycerin (NTG) and its dinitrate metabolites. We believe that much of the controversy in the literature concerning the efficacy of oral and long-acting nitrates might be explained in terms of the generation of sufficiently high concentrations of the dinitrate metabolites, particularly following oral NTG dosing. Although animal studies have shown these metabolites to be considerably less active than the parent NTG, no analytical methods have been available to quantitate the dinitrate metabolites. We have developed such a method and have shown in preliminary studies that the dinitrate metabolite concentrations observed are sufficiently high, relative to NTG concentrations so that pharmacodynamic responsses to the metabolites might be expected.
The specific aims of this proposal are: 1. Validate the analytical and sample handling procedures for the dinitrate metabolites; 2. Determine the pharmacokinetics of NTG and metabolites following intravenous, sublingual, topical and oral dosing of NTG in healthy volunteers; 3. Use a dog model to investigate individually the pharmacokinetics of the 1,2- and 1,3-dinitrate metabolites and to investigate the possibility of a pharmacokinetic interaction between these metabolites and the parent drug; 4. Measure Laser-Doppier Velocimentry response to various doses of nitroglycerin; 5. In patients with stable angina pectoris compare the efficacy of two different oral doses of NTG, a sublingual dose and a placebo solution employing graded treadmill exercise testing; and 6 in patients in the Cardiac Care Unit receiving NTG as an intravenous infusion measure NTG and metabolite levels in arterial and venous blood samples and compare these values with hemodynamic parameters.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032243-06
Application #
3343575
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1984-04-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Han, C; Jung, P; Sanders, S W et al. (1994) Pharmacokinetics of nitroglycerin and its four metabolites during nitroglycerin transdermal administration. Biopharm Drug Dispos 15:179-83
Lee, F W; Salmonson, T; Benet, L Z (1993) Pharmacokinetics and pharmacodynamics of nitroglycerin and its dinitrate metabolites in conscious dogs: intravenous infusion studies. J Pharmacokinet Biopharm 21:533-50
Gumbleton, M; Benet, L Z (1993) Simultaneous pharmacodynamic modeling of the non-steady-state effects of three oral doses of 1,3-glyceryl dinitrate upon blood pressure in healthy volunteers. J Pharmacokinet Biopharm 21:515-32
Lee, F W; Hu, J; Metzler, C H et al. (1993) Nitroglycerin dinitrate metabolites do not affect the pharmacokinetics and pharmacodynamics of nitroglycerin in the dog: a preliminary report. J Pharmacokinet Biopharm 21:163-73
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Lau, D T; Chan, E K; Benet, L Z (1992) Glutathione S-transferase-mediated metabolism of glyceryl trinitrate in subcellular fractions of bovine coronary arteries. Pharm Res 9:1460-4
Han, C; Gumbleton, M; Lau, D T et al. (1992) Improved gas chromatographic assay for the simultaneous determination of nitroglycerin and its mono- and dinitrate metabolites. J Chromatogr 579:237-45
Haefeli, W E; Gumbleton, M; Benet, L Z et al. (1992) Comparison of vasodilatory responses to nitroglycerin and its dinitrate metabolites in human veins. Clin Pharmacol Ther 52:590-6
Higo, N; Hinz, R S; Lau, D T et al. (1992) Cutaneous metabolism of nitroglycerin in vitro. I. Homogenized versus intact skin. Pharm Res 9:187-90
Higo, N; Hinz, R S; Lau, D T et al. (1992) Cutaneous metabolism of nitroglycerin in vitro. II. Effects of skin condition and penetration enhancement. Pharm Res 9:303-6

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