Abstract
We recently compared plasma concentrations of nitroglycerin and its two dinitrate metabolites in 16 healthy male subjects after application of two controlled-release transdermal formulations of the drug. Analysis of the resulting plasma concentration–time curves indicated that the two formulations did not produce equivalent concentrations of parent drug or either of the dinitrate metabolites during the initial period of dosing. In addition, both formulations produced concentrations of the two dinitrate metabolites that exceeded the concentration of the parent drug by severalfold. Even if the pharmacologic effect of the dinitrate metabolites is low compared to that of nitroglycerin, these higher concentrations may contribute to the effect of nitroglycerin. Scrutiny of the ratio of 1,2-glyceryl dinitrate to 1,3-glyceryl dinitrate in the 16 subjects confirmed previous observations that preferential formation of the 1,2-glycerol dinitrate metabolite may occur depending on the route of administration. This ratio may thus be indicative of the bioavailability of nitroglycerin following transdermal application. Additional data suggesting racial differences in nitroglycerin absorption after transdermal application are presented.
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REFERENCES
W. Aronow. Medical treatment of angina pectoris. IV. Nitroglycerin as an antianginal drug. Am. Heart J. 84:415 (1972).
S. H. Taylor. Scientific and clinical experience with transdermal nitroglycerin. Am. Heart J. 112:197–207 (1986).
F. W. Lee, N. Watari, J. Rigod, and L. Z. Benet. Simultaneous determination of nitroglycerin and its dinitrate metabolites by capillary gas chromatography with electron-capture detection. J. Chromatogr. 426:259–266 (1988).
W. Murrell. Nitroglycerine as a remedy for angina pectoris. Lancet 1:80–81, 113–115, 151–152, 225–227 (1879).
R. K. Mahapatra, D. Mahapatra, and S. Vadan. Clinical experience with a transdermal nitroglycerin system. Angiology 4:277–286 (1987).
R. Greco, D. D'Alterio, M. Schiattarella, A. Boccia, L. Greco, and F. Marsico. Efficacy of a new transdermal nitroglycerin patch (Deponit 10) for stable angina pectoris. Am. J. Cardiol. 61:44E–51E (1988).
H. Dogar, D. Guzelsoy, N. Guitekin, N. Gurses, and C. Demiroglu. Acute and sustained antianginal effects of nitroglycerin patches: Objective evaluation with training-effect-eliminated exercise performance index. Am. J. Cardiol. 61:39E–43E (1988).
D. E. Rezokovic, L. Pavicic, and M. Majacic. A randomized placebo controlled, double-blind crossover trial of transdermal nitroglycerin in stable angina pectoris. Eur. Heart J. 9(Suppl A):73–81 (1988).
K. Lindvall, S. V. Eriksson, A. Lagerstrand, and A. Sjogren. Efficacy and tolerability of transdermal nitroglycerin in heart failure—a noninvasive placebo controlled double-blind crossover study. Eur. Heart J. 4:373–379 (1988).
L. Bolognese, G. Sarasso, G. Rognoni, J. Makmur, G. Fornaro, A. Perucca, and P. Rossi. Sustained beneficial hemodynamic effects of low-transdermal nitroglycerin doses compared with placebo in patients with congestive heart failure. Clin. Cardiol. 11:79–82 (1988).
H. R. Ochs, V. Verburg-Ochs, and N. J. Greenblatt. Kinetics of 1,2-dinitroglycerin following sustained release nitroglycerin: Influence of propranolol and metoprolol. Klin. Wochenschr. 63:1170–1173(1985).
P. K. Noonan and L. Z. Benet. Variable glyceryl dinitrate formation as a function of route of nitroglycerin administration. Clin. Pharmacol. Ther. 42:273–277 (1987).
P. K. Noonan, R. L. Williams, and L. Z. Benet. Dose dependent pharmacokinetics of nitroglycerin after multiple intravenous infusions in healthy volunteers. J. Pharmacokin. Biopharm. 13:143–157 (1985).
W. R. Good. TransdermR-Nitro controlled delivery of nitroglycerin via the transdermal route. Drug Dev. Ind. Pharm. 9:647–670 (1983).
A. McAllister, H. Mosberg, J. A. Settlage, and J. A. Steiner. Plasma levels of nitroglycerin generated by three nitroglycerin patch preparations, Nitradisc, Transderm-Nitro and Nitro-Dur and one ointment formulation, Nitrobid. Br. J. Clin. Pharmacol 21:365–369 (1986).
P. K. Noonan, M. A. Gonzalez, D. Ruggirello, J. Tomlinson, E. Babcock-Atkinson, M. Ray, A. Golub, and A. Cohen. Relative bioavailability of a new transdermal nitroglycerin delivery system. J. Pharm. Sci. 7:688–691 (1986).
B. Berner and G. C. Mazzenga. Ciba-Geigy Report BPR 86149.
P. Needleman, D. J. Blehm, and K. S. Rotskoff. Relationship between glutathione-dependent denitration and the vasodilator effectiveness of organic nitrates. J. Pharmacol. Exp. Ther. 165:286–288 (1969).
M. G. Bogaert, M. T. Rosseel, and A. F. DeSchaepdryver. Cardiovascular effects of glyceryl dinitrates as compared to glyceryl trinitrates. Arch. Int. Pharmacodyn. 176:458–460 (1968).
T. Winsor and J. H. J. Berger. Oral nitroglycerin as a prophylactic antianginal drug: Clinical physiologic, and statistical evidence of efficacy based on a three phase experimental design. Am. Heart J. 90:611–626 (1975).
P. J. Noonan and L. Z. Benet. The bioavailability of oral nitroglycerin. J. Pharm. Sci. 75:241–243 (1986).
D. K. Yu, R. L. Williams, L. Z. Benet, E. T. Lin, and D. H. Giesing: Pharmacokinetics of nitroglycerin and metabolites in humans following oral dosing. Biopharm. Drug Dispos. 9:557–565 (1988).
E. Nakashima, P. K. Noonan, and L. Z. Benet. Transdermal bioavailability and first-pass skin metabolism: A preliminary evaluation with nitroglycerin. J. Pharmacokin. Biopharm. 15:423–438 (1987).
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Williams, R.L., Thakker, K.M., John, V. et al. Nitroglycerin Absorption from Transdermal Systems: Formulation Effects and Metabolite Concentrations. Pharm Res 8, 744–749 (1991). https://doi.org/10.1023/A:1015802101272
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DOI: https://doi.org/10.1023/A:1015802101272