Percutaneous penetration kinetics of nitroglycerin and its dinitrate metabolites across hairless mouse skin in vitro.
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 less than 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 (rho) for GTN (20 +/- 3 x 10(-3) cm hr-1) was significantly larger than the corresponding values for 1,2-GDN (1.4 +/- 0.9 x 10(-3) cm hr-1) and 1,3-GDN (1.2 +/- 0.4 x 10(-3) cm hr-1), which were statistically indistinguishable (P greater than 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 kappa = Ks.h [where h is the diffusion path length through stratum corneum (SC)] were 19.8 +/- 2.5 x 10(-2) cm for GTN and 1.91 +/- 1.07 x 10(-2) and 1.81 +/- 0.91 x 10(-2) cm for 1,2- and 1,3-GDN, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Kikkoji
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Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0446.
Gumbleton
M
M
Higo
N
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Guy
R H
RH
Benet
L Z
LZ
D000279:Administration, Cutaneous; D000818:Animals; D001711:Biotransformation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D066298:In Vitro Techniques; D051379:Mice; D008812:Mice, Hairless; D005996:Nitroglycerin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D009824:Ointments; D012869:Skin Absorption / Q000502:physiology*; D012995:Solubility; D014665:Vasodilator Agents / Q000494:pharmacology
D009824:Ointments; D014665:Vasodilator Agents; C014509:dinitroglycerol; D005996:Nitroglycerin