Modulating nasal mucosal permeation using metabolic saturation and enzyme inhibition techniques

Abstract

Metabolic loss of melatonin during nasal permeation demonstrates CYP450 activity in the nasal epithelium and submucosal tissues. The extent of biotransformation of melatonin during its transport across the nasal mucosal explants suggests that, although the nasal route bypasses hepatic first-pass metabolism, nasal bioavailability can be significantly influenced by mucosal enzymatic activity.

Evaluation of Recent Intranasal Drug Delivery Systems to the Central Nervous System

“…This protective feature can greatly limit the intranasal pathway for drugs which are metabolized by these enzymes. Several studies have shown that inhibition of proteases or cytochrome P-450 enzyme in the nasal mucosa increases the amount of drug transported from the nasal cavity to the brain [ 81 , 94 , 95 ]. This same principle applies to the brain as well.…”

Nucleic acid-based therapeutics for the treatment of central nervous system disorders

“…Other additives that have been shown to improve intranasal delivery in vivo include vasoconstrictors which reduce the likelihood of the drug being absorbed into circulation, enzyme modulators which can reduce the function of enzymes that may degrade the drug, and nasal permeability enhancers which increase absorption through the nasal epithelium ( Dhamankar and Donovan, 2017 ; Rabinowicz et al, 2021 ; Moradi and Dashti, 2022 ).…”

Nose-to-Brain Drug Delivery: An Update to the Alternative Path to Successful Targeted Anti-Migraine Drugs

“…Inhibition of these enzymes can improve in situ stability and avoid biotransformation, and thus increase the amount of active drug that can be ingested into the brain to create an Effect [36,40,41]. After fluvoxamine, a competitive CYP450 inhibitor, Dhamankar and Donovan have recently demonstrated an improvement in melatonin permeation through the respiratory nasal olfactory mucosa [42]. In addition, the saturation of the enzyme at a high melatonin concentration also increased the permeation of melatonin without metabolic activity [42].…”

“…After fluvoxamine, a competitive CYP450 inhibitor, Dhamankar and Donovan have recently demonstrated an improvement in melatonin permeation through the respiratory nasal olfactory mucosa [42]. In addition, the saturation of the enzyme at a high melatonin concentration also increased the permeation of melatonin without metabolic activity [42]. Hussain et al also showed that α-aminoboronic acid derivatives inhibit protease degradation in the nasal mucosa, even though no research on enhanced nasal absorption and nose-to-brain transmission was conducted to understand the effect on [43].…”