Bioavailability and pharmacokinetic profile of glyceryl trinitrate and of glyceryl dinitrates during application of a new glyceryl trinitrate transdermal patch
A. Santoro et al., Bioavailability and pharmacokinetic profile of glyceryl trinitrate and of glyceryl dinitrates during application of a new glyceryl trinitrate transdermal patch, ARZNEI-FOR, 50(9), 2000, pp. 779-785
The pharmacokinetics and bioavailability of glyceryl trinitrate (GTN, CAS 5
5-63-0) and of its main metabolites, i.e. 1,2-glyceryl dinitrate (1,2-GDN,
CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87-0), were comp
ared during a single 24-h application of a new GTN transdermal patch (Epini
tril (R) 10, hereinafter called EPI-10) or a reference patch (hereinafter c
alled ND-10) releasing 10 mg GTN in 24 h. The study was an open, randomized
balanced cross-over study on 24 healthy male volunteers to whom the patche
s were applied to the antero-lateral part of the thorax in two periods sepa
rated by a 3-day wash-out. Blood samples were collected before administrati
on, during the 24-h patch application and at 0.5, 2 and 3 h after patch rem
oval. Assayed in plasma were GTN, 1,2-GDN and 1,3-GDN using validated GC/MS
methods with stable isotope-labeled internal standards (N-15(3)-GTN, N-15(
2)- 1,2-GDN, and N-15(2)-1,3-GDN).
The ratios of the AUCs of GTN, 1,2-GDN and 1,3-GDN measured during applicat
ion of EPI-10 or of ND-10 were within the 0.85-1.25 limits required to asse
ss equivalence of the extent of bioavailability. The ratios of the C-max we
re within said limits for the signal metabolite 1,2-GDN and only slightly b
elow (0.78-1.16) for the parent GTN. EPI-10 can therefore be considered equ
ivalent to ND-10 also with regard to the rate of bioavailability. Under bot
h patches GTN reached steady-state levels after 3-6 h of patch application
and remained on sustained levels during the whole 24-h application. The pla
sma levels of 1,2-GDN were about 6 times higher than those of GTN. The plas
ma levels of 1,3-GDN were similar to those of GTN. Upon removal of the patc
hes the concentrations of the three nitrates fell to negligible values with
in 3 h.
Both patches were well tolerated at the application site. For its small siz
e, thinness and transparency, EPI-10 is very patient friendly, a quality th
at improves compliance with the therapeutic regimen.