Modulating nasal mucosal permeation using metabolic saturation and enzyme inhibition techniques

Presystemic elimination resulting from local enzymatic degradation can play a key role in limiting the bioavailability of intranasally administered drugs. The aim of this study was to evaluate the transfer of a metabolically susceptible drug across the nasal mucosa to illustrate the relative contributions of drug diffusivity and metabolic susceptibility on overall nasal mucosal permeation and to understand the effects of changes in enzymatic activity on the transfer across nasal epithelial and submucosal tissues.

The concentration-dependent permeation of melatonin, a CYP450 substrate, across excised bovine nasal olfactory and respiratory explants was studied along with quantifying the extent of melatonin 6-hydroxylation. Microsomal preparations were also used to determine the kinetic parameters for melatonin to 6-hydroxymelatonin biotransformation.

Enzyme saturation at higher melatonin concentrations and inclusion of a CYP450 inhibitor both resulted in the significant increase in melatonin permeation across the nasal mucosa.

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.