Departments of Pharmaceutics (D.R., R.A.S.), Experimental and Clinical Pharmacology (J.C.C.), Medicinal Chemistry (N.C., K.M.N., G.I.G.), and Biomedical Engineering (R.A.S.), Center for Orphan Drug Research (P.D.M., U.M., L.D.C., J.C.C.), and Institute for Therapeutics Discovery and Development (N.C., K.M.N., G.I.G.), University of Minnesota, Minneapolis, Minnesota; and Neuroscience Research, HealthPartners Institute, St. Paul, Minnesota (J.M.F., A.L.S., K.A.F., L.R.H.).
Departments of Pharmaceutics (D.R., R.A.S.), Experimental and Clinical Pharmacology (J.C.C.), Medicinal Chemistry (N.C., K.M.N., G.I.G.), and Biomedical Engineering (R.A.S.), Center for Orphan Drug Research (P.D.M., U.M., L.D.C., J.C.C.), and Institute for Therapeutics Discovery and Development (N.C., K.M.N., G.I.G.), University of Minnesota, Minneapolis, Minnesota; and Neuroscience Research, HealthPartners Institute, St. Paul, Minnesota (J.M.F., A.L.S., K.A.F., L.R.H.)
J Pharmacol Exp Ther. 2019 Sep;370(3):796-805. doi: 10.1124/jpet.118.255943. Epub 2019 Mar 5.
Intranasal administration is an attractive route for systemic delivery of small, lipophilic drugs because they are rapidly absorbed through the nasal mucosa into systemic circulation. However, the low solubility of lipophilic drugs often precludes aqueous nasal spray formulations. A unique approach to circumvent solubility issues involves coadministration of a hydrophilic prodrug with an exogenous converting enzyme. This strategy not only addresses poor solubility but also leads to an increase in the chemical activity gradient driving drug absorption. Herein, we report plasma and brain concentrations in rats following coadministration of a hydrophilic diazepam prodrug, avizafone, with the converting enzyme Single doses of avizafone equivalent to diazepam at 0.500, 1.00, and 1.50 mg/kg were administered intranasally, resulting in 77.8% ± 6.0%, 112% ± 10%, and 114% ± 7% bioavailability; maximum plasma concentrations 71.5 ± 9.3, 388 ± 31, and 355 ± 187 ng/ml; and times to peak plasma concentration 5, 8, and 5 minutes for each dose level, respectively. Both diazepam and a transient intermediate were absorbed. Enzyme kinetics incorporated into a physiologically based pharmacokinetic model enabled estimation of the first-order absorption rate constants: 0.0689 ± 0.0080 minutes for diazepam and 0.122 ± 0.022 minutes for the intermediate. Our results demonstrate that diazepam, which is practically insoluble, can be delivered intranasally with rapid and complete absorption by coadministering avizafone with aminopeptidase B. Furthermore, even faster rates of absorption might be attained simply by increasing the enzyme concentration, potentially supplanting intravenous diazepam or lorazepam or intramuscular midazolam in the treatment of seizure emergencies.
鼻腔给药是一种有吸引力的全身给药途径，适用于小的亲脂性药物，因为它们可以通过鼻腔黏膜迅速吸收进入全身循环。然而，亲脂性药物的低溶解度通常会排除亲水性鼻喷雾剂制剂。一种独特的方法是将亲水性前药与外源性转化酶共同给药。这种策略不仅解决了溶解度问题，还导致了化学活性梯度增加，从而促进了药物吸收。在此，我们报告了大鼠同时给予亲水性地西泮前药阿维扎芬（avizafone）和转化酶后血浆和脑内浓度。阿维扎芬的单剂量相当于地西泮 0.500、1.00 和 1.50mg/kg，鼻腔内给予，生物利用度分别为 77.8%±6.0%、112%±10%和 114%±7%；最大血浆浓度分别为 71.5±9.3、388±31 和 355±187ng/ml；达峰时间分别为 5、8 和 5 分钟。每个剂量水平均吸收了地西泮和短暂的中间产物。将酶动力学纳入基于生理学的药代动力学模型中，能够估算出一级吸收速率常数：地西泮为 0.0689±0.0080 分钟，中间产物为 0.122±0.022 分钟。我们的结果表明，地西泮几乎不溶于水，但通过与氨基肽酶 B 共同给予阿维扎芬，可以经鼻腔快速、完全地给药。此外，通过简单地增加酶浓度，甚至可以达到更快的吸收速度，从而可能取代静脉内给予地西泮或劳拉西泮或肌肉内给予咪达唑仑治疗癫痫发作急症。
