Cutaneous metabolism of nitroglycerin in vitro. I. Homogenized versus intact skin.
The metabolism of nitroglycerin (GTN) to 1,2- and 1,3-glyceryl dinitrate (GDN) by hairless mouse skin in vitro has been measured. In the first set of experiments, GTN was incubated with the 9000g supernatant of fresh, homogenized tissue in the presence and absence of glutathione (GSH), a cofactor for glutathione-S-transferase. After 2 hr of incubation with GSH, 30% of the initially present GTN had been converted to 1,2- and 1,3-GDN; without GSH, less than 5% of the GTN was metabolized. The ratio of 1,2-GDN to 1,3-GDN produced by the homogenate was 1.8-2.1. In the second series of studies, GTN was administered topically to freshly excised, intact hairless mouse skin in conventional in vitro diffusion cells. The concurrent transport and metabolism of GTN was then monitored by sequential analysis of the receptor phase perfusing the dermal side of the tissue. Three topical formulations were used: a low concentration (1 mg/ml) aqueous solution, a 2% ointment, and a transdermal delivery system. Delivery of total nitrates (GTN + 1,2-GDN + 1,3-GDN) into the receptor phase was similar for ointment and patch formulations and much greater than that from the solution. The percentage metabolites formed, however, was greatest for the solution (61% and 2 hr, compared to 49% for the patch and 35% for the ointment). As has been noted before, therefore, the relative level of skin metabolism is likely to be greatest when the transepidermal flux is small. Distinct from the homogenate experiments, the 1,2/1,3-GDN ratios in the penetration studies were in the range 0.7-0.9.(ABSTRACT TRUNCATED AT 250 WORDS)
Higo
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Department of Pharmacy, University of California, San Francisco 94143-0446.
Hinz
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Lau
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Benet
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LZ
Guy
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RH
D000287:Administration, Topical; D000818:Animals; D001711:Biotransformation; D005982:Glutathione Transferase / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008812:Mice, Hairless; D005996:Nitroglycerin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption
C014509:dinitroglycerol; D005982:Glutathione Transferase; D005996:Nitroglycerin