Population pharmacokinetics of nitroglycerin and of its two metabolites after a single 24-hour application of a nitroglycerin transdermal matrix delivery system.
The purpose of this study was to assess the ability of our previously constructed pharmacokinetic (PK) model to describe nitroglycerin (GTN), 1,2-dinitroglycerin (1,2-GDN), and 1,3-dinitroglycerin (1,3-GDN) plasma concentrations after a single-dose application of a GTN transdermal matrix delivery system. GTN, 1,2-GDN, and 1,3-GDN plasma concentrations were simultaneously fitted using a first-pass, mixed-order release, one-compartment PK model. Population PK parameter values were derived using an iterative two-stage methodology (IT2S). Some of the mean PK parameters estimates and their interindividual variability (CV%) were the percentage of the delivered GTN dose reaching the systemic circulation released by a first-order process A, 53% (44); the 1,2-GDN and 1,3-GDN formation rate constants, k(f1)9 h(-1) (67) and k(f2) 0.5 h(-1) (38), respectively; the metabolite elimination rate constant, k(m) 1 h(-1) (27); GTN, 1,2-GDN, and 1,3-GDN volumes of distribution (Vc/F 6 L [45]), V2/F 78 L [51]), and V3/F 29 L [40]), respectively). Mean calculated elimination half-lives (t1/2+/-standard deviation [SD]) for GTN and the GDN metabolites were 7+/-4 minutes and 33+/-7 minutes, respectively. The proposed PK model fitted the observed plasma concentrations of GTN, 1,2-GDN, and 1,3-GDN very well. This new transdermal matrix delivery system appears to behave pharmacokinetically in the same manner as a transdermal reservoir delivery system (Transderm-Nitro, Ciba-Geigy, Mississauga, Canada).
Auclair
B
B
Faculté de Pharmacie, Université de Montréal, QC, Canada.
Sirois
G
G
Ngoc
A H
AH
Ducharme
M P
MP
D000279:Administration, Cutaneous; D000293:Adolescent; D000328:Adult; D006801:Humans; D008954:Models, Biological; D005996:Nitroglycerin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood*; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000097:blood
D014665:Vasodilator Agents; C014509:dinitroglycerol; D005996:Nitroglycerin