Percutaneous penetration kinetics of nitroglycerin and its dinitrate metabolites across hairless mouse skin in vitro.
Percutaneous penetration kinetics of nitroglycerin and its dinitrate metabolites across hairless mouse skin in vitro.
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硝化甘油及其二硝酸盐代谢物在体外无毛小鼠皮肤上的经皮渗透动力学。
DOI：
10.1023/a:1015887309391
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发表时间：
1991
影响因子：
3.7
通讯作者：
Benet,LZ
中科院分区：
文献类型：
--
作者：
Kikkoji,T;Gumbleton,M;Higo,N;Guy,RH;Benet,LZ
使用全层无毛小鼠皮肤，在体外评估抗心绞痛药物硝酸甘油 (GTN) 及其主要代谢物 1,2- 和 1,3-二硝酸甘油酯（1,2- 和 1,3-GDN）的经皮渗透动力学。 GTN 以及 1,2- 和 1,3-GDN (a) 以 pH 7.4 磷酸盐缓冲盐水 (PBS) 的水溶液形式应用，(b) 掺入亲脂性软膏制剂中。检测到 GTN 经皮肤转化为其二硝酸盐代谢物，但未观察到 1,2-GDN 和 1,3-GDN 之间的相互转化。在 PBS 溶液中应用硝酸盐后，所有三种化合物均表现出稳态运输动力学。 GTN 的稳态通量 (8.9 ± 1.5 nmol cm−2hr−1) 显着大于 (P < 0.05) 1,2-GDN (0.81 ± 0.54 nmol cm−2hr−1) 和 1,3-GDN (0.72 ± 0.20 nmol cm−2hr−1)。 GTN (20 ± 3 × 10−3cm hr−1) 相应的渗透系数 (ρ) 显着大于 1,2-GDN (1.4 ± 0.9 × 10−3cm hr−1) 和 1,3-GDN (1.2 ± 0.4 × 10−3cm hr−1) 的相应值，两者在统计上无法区分 (P> 0.05)。对传输数据的进一步分析表明，GTN 和 GDN 之间的差异可以通过化合物的相对角质层/水分配系数 (Ks) 值来解释。表观分配参数定义为 κ =Ks·h[其中通过角质层 (SC) 的扩散路径长度] 对于 GTN 为 19.8 ± 2.5 × 10−2cm，对于 1,2- 和 1,3-GDN 分别为 1.91 ± 1.07 × 10−2 和 1.81 ± 0.91 × 10−2cm。然而，当硝酸盐以软膏基质形式给药时，GTN 的表观分配参数 (κ') 和渗透系数 (ρ') 显着下降，分别降至 2.51 ± 0.75 × 10−2cm 和 1.6 ± 0.3 × 10−3cm hr−1。相比之下，1,2-和1,3-GDN的κ'和ρ'结果与相应的κ和ρ值没有显着差异（P>0.05），这些值是在作为水溶液给药后测量的。因此，软膏配方中所有三种硝酸盐的稳态通量具有可比性（GTN，154 ± 28 nmol cm−2hr−1；1,2-GDN，162 ± 22 nmol cm−2hr−1；1,3-GDN，162 ± 34 nmol cm−2hr−1）。因此，当采用合适的配方时，二硝酸盐可以像 GTN 一样有效地穿过皮肤。如果确实发现 1,2- 或 1,3-GDN 具有药理学效果，这一发现可能支持使用 1,2- 或 1,3-GDN 进行透皮治疗。
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 evaluatedin 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−2hr−1) was significantly greater (P< 0.05) than those of 1,2-GDN (0.81 ± 0.54 nmol cm−2hr−1) and 1,3-GDN (0.72 ± 0.20 nmol cm−2hr−1). The corresponding permeability coefficient (ρ) for GTN (20 ± 3 × 10−3cm hr−1) was significantly larger than the corresponding values for 1,2-GDN (1.4 ± 0.9 × 10−3cm hr−1) and 1,3-GDN (1.2 ± 0.4 × 10−3cm 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[wherehis the diffusion path length through stratum corneum (SC)] were 19.8 ± 2.5 × 10−2cm for GTN and 1.91 ± 1.07 × 10−2and 1.81 ± 0.91 × 10−2cm 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 × 10−2cm and 1.6 ± 0.3 × 10−3cm 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−2hr−1; 1,2-GDN, 162 ± 22 nmol cm−2hr−1; 1,3-GDN, 162 ± 34 nmol cm−2hr−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.