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 tri nitrate (GTN, CAS 55-63-0) and of its main metabolities 1,2-glyceryl dinitr ate (1,2-GDN, CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87 -0) during a single 74-h application of three strengths of a newly develope d GTN transdermal patch (Epinitril (R)) were investigated. The three streng ths coded in this paper EPI-5, EPI-10 and EPI-15 have a nominal release rat e 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 m ale volunteers, to whom the patches were applied for 24 h to the antero-lat eral part of the thorax in three periods, separated by an at least 3-day wa sh-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 iso tope labeled internal standards (N-15(3)-GTN, N-15(2)-1,2-GDN, and N-15(2)- 1,3-GDN). GTN and its two metabolites reached the plateau already 3 h after applicati on of the patches and remained on extended and fairly constant levels durin g 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 w ere 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 p roperty when an intermittent GTN therapy is needed in order to avoid tolera nce to the drug. The patches were well tolerated at the application site. For their good tol erability, small size and transparency, the new GTN patches are very patien t friendly, a quality that improves compliance with the therapeutic regimen .