Percutaneous Penetration Kinetics of Nitroglycerin and Its Dinitrate Metabolites Across Hairless Mouse Skin in Vitro

Publisher Website
Google Scholar
Abstract
The percutaneous penetration kinetics of the antianginal, nitroglycerin (GTN), and its primary metabolites, 1,2- and 1,3-glyceryl dinitrate (1,2- and 1,3-GDN), were evaluated in vitro, using full-thickness hairless mouse skin. GTN and the 1,2- and 1,3-GDNs were applied (a) in aqueous solution as pH 7.4 phosphate-buffered saline (PBS) and (b) incorporated into lipophilic ointment formulations. The cutaneous transformation of GTN to its dinitrate metabolites was detected, but no interconversion between 1,2-GDN and 1,3-GDN was observed. Following application of the nitrates in PBS solution, all three compounds exhibited steady-state transport kinetics. The steady-state flux of GTN (8.9 ± 1.5 nmol cm−2 hr−1) was significantly greater (P < 0.05) than those of 1,2-GDN (0.81 ± 0.54 nmol cm−2 hr−1) and 1,3-GDN (0.72 ± 0.20 nmol cm−2 hr−1). The corresponding permeability coefficient (ρ) for GTN (20 ± 3 × 10−3 cm hr−1) was significantly larger than the corresponding values for 1,2-GDN (1.4 ± 0.9 × 10−3 cm hr−1) and 1,3-GDN (1.2 ± 0.4 × 10−3 cm hr−1), which were statistically indistinguishable (P > 0.05). Further analysis of the transport data showed that the differences between GTN and the GDNs could be explained by the relative stratum corneum/water partition coefficient (Ks) values of the compounds. The apparent partition parameters, defined as κ = Ks · h [where h is the diffusion path length through stratum corneum (SC)] were 19.8 ± 2.5 × 10−2 cm for GTN and 1.91 ± 1.07 × 10−2 and 1.81 ± 0.91 × 10−2 cm for 1,2- and 1,3-GDN, respectively. However, when the nitrates were administered in an ointment base, the apparent partition parameter (κ') and permeability coefficient (ρ') of GTN markedly decreased, to 2.51 ± 0.75 × 10−2 cm and 1.6 ± 0.3 × 10−3 cm hr−1, respectively. In contrast, the κ' and ρ' results for 1,2- and 1,3-GDN were not significantly different (P > 0.05) from the corresponding κ and ρ values, which were measured following dosing as aqueous solutions. As a result, the steady-state fluxes of all three nitrates from the ointment formulation were comparable (GTN, 154 ± 28 nmol cm−2 hr−1; 1,2-GDN, 162 ± 22 nmol cm−2 hr−1; 1,3-GDN, 162 ± 34 nmol cm−2 hr−1). It follows that the dinitrates can be as efficiently delivered across the skin as GTN when a suitable formulation is employed. This finding may support transdermal therapy using 1,2- or 1,3-GDN if, indeed, they are found to be pharmacologically effective.