Intranasal Coadministration of a Diazepam Prodrug with a Converting Enzyme Results in Rapid Absorption of Diazepam in Rats.

Autor:	Rautiola D; 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.)., Maglalang PD; 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.)., Cheryala N; 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.)., Nelson KM; 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.)., Georg GI; 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.)., Fine JM; 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.)., Svitak AL; 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.)., Faltesek KA; 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.)., Hanson LR; 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.)., Mishra U; 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.)., Coles LD; 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.)., Cloyd JC; 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.)., Siegel RA; 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.) siege017@umn.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2019 Sep; Vol. 370 (3), pp. 796-805. Date of Electronic Publication: 2019 Mar 05.
DOI:	10.1124/jpet.118.255943
Abstrakt:	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 human aminopeptidase B 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 -1 for diazepam and 0.122 ± 0.022 minutes -1 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. (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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