In vivo metabolism of nasally instilled dihydrosafrole [1-(3,4-methylenedioxyphenyl)propane] in dogs and monkeys.

Nasal metabolism of inhaled material may influence its biological fate and toxicity. The purpose of this study was to investigate, in a noninvasive and qualitative manner, the in vivo nasal metabolic activity towards 1-(3,4-methylenedioxyphenyl)propane (dihydrosafrole). Dihydrosafrole was the compound of choice as a representative of the methylenedioxyphenyl compounds. Methylenedioxyphenyl compounds, inhaled as essences or insecticide synergists, have complex interactions with cytochrome P-450-dependent monooxygenases, causing both inhibition and induction. Clearance of dihydrosafrole and its metabolites from both the ethmoid (olfactory) and maxillary (respiratory) turbinate regions of Beagle dogs and Cynomolgus monkeys was examined. Nasopharyngeal mucus was collected at frequent intervals during periodic instillation of dihydrosafrole (and, for the dogs, 24 h after instillation). Blood, urine and feces were collected to examine dihydrosafrole clearance from the nose during instillations and up to 48 h after completion of the nasal instillations of [3H]dihydrosafrole. Analysis of mucus for dihydrosafrole metabolites was by HPLC. Most of the recovered radioactivity was in urine and blood samples over the first 24 h. Radioactivity was recovered from the nasopharyngeal mucus in both organic extractable and water soluble forms. HPLC of the organic extracts demonstrated that [3H]dihydrosafrole instilled in either turbinate region was metabolized to 2-methoxy-4-propylphenol, 2-methoxy-4-propenylphenol and 1-(3,4-methylenedioxyphenyl)propan-1-ol. A number of minor metabolites were produced in both species. One mucus sample from an ethmoid-instilled dog contained 1-(3,4-methylenedioxyphenyl)propene (isosafrole) as a metabolite. Results from this study indicate that interspecies, inter-individual, and inter-regional differences occur in the metabolism of nasally deposited dihydrosafrole in monkeys and dogs.