Plasma levels of glyceryl trinitrate and dinitrates during application of three strengths of a new glyceryl trinitrate transdermal patch.
The pharmacokinetic characteristics and the bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) and of its main metabolities 1,2-glyceryl dinitrate (1,2-GDN, CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87-0) during a single 24-h application of three strengths of a newly developed GTN transdermal patch (Epinitril) were investigated. The three strengths coded in this paper EPI-5, EPI-10 and EPI-15 have a nominal release rate of GTN of 5, 10 and 15 mg, respectively, in 24 h. The study was an open, randomized balanced cross-over study on 18 healthy male volunteers, to whom the patches were applied for 24 h to the antero-lateral part of the thorax in three periods, separated by an at least 3-day wash-out. Blood samples were collected before administration, during the 24-h patch application and 1, 3 and 6 h after patch removal. Assayed in plasma were GTN, 1,2-GDN and 1,3-GDN using validated GC/MS methods with stable isotope labeled internal standards (15N3-GTN, 15N2-1,2-GDN, and 15N2-1,3-GDN). GTN and its two metabolites reached the plateau already 3 h after application of the patches and remained on extended and fairly constant levels during the whole 24-h application. The plasma levels of the three nitrates were proportional to the strengths of the patches. The plasma levels of 1,2-GDN were about 6 times higher than those of GTN. The plasma levels of 1,3-GDN were similar to those of GTN. Upon removal of the patches the concentrations of the three nitrates fell to negligible values within 3 h, an important property when an intermittent GTN therapy is needed in order to avoid tolerance to the drug. The patches were well tolerated at the application site. For their good tolerability, small size and transparency, the new GTN patches are very patient friendly, a quality that improves compliance with the therapeutic regimen.
Santoro
A
A
Department of Regulatory Affairs, Rotta Research Laboratories, Monza, Italy.
Rovati
L C
LC
Follet
M
M
Setnikar
I
I
Caplain
H
H
Gualano
V
V
D000268:Adhesiveness; D000279:Administration, Cutaneous; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D009325:Nausea / Q000139:chemically induced; D005996:Nitroglycerin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
D014665:Vasodilator Agents; C014509:dinitroglycerol; D005996:Nitroglycerin