Intranasal coadministration of a diazepam prodrug with a converting enzyme results in rapid absorption of diazepam in rats

Davin Rautiola, Patricia D. Maglalang, Narsihmulu Cheryala, Kathryn M. Nelson, Gunda I. Georg, Jared M. Fine, Aleta L. Svitak, Katherine A. Faltesek, Leah R. Hanson, Usha Mishra, Lisa D. Coles, James C. Cloyd, Ronald A. Siegel

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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 6.0%, 112% 6 10%, and 114% 6 7% bioavailability; maximum plasma concentrations 71.5 6 9.3, 388 6 31, and 355 6 187 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 6 0.0080 minutes21 for diazepam and 0.122 6 0.022 minutes21 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.

Original languageEnglish (US)
Pages (from-to)796-805
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 2019

Bibliographical note

Funding Information:
This study was supported by a grant [Grant U01HL127479] from the University of Minnesota’s NIH Research Evaluation and Commercialization Hub (MN-REACH). Financial support was also provided by the 3M Science and Technology Fellowship in Drug Delivery, American Foundation for Pharmaceutical Education (AFPE), and the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation. s This article has supplemental material available at

Publisher Copyright:
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics

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