Distribution and metabolism of N'-nitrosonornicotine in the miniature pig

The distribution and metabolism of [5-3H]N'-nitrosonornicotine ([5-3H]NNN) was studied in three 18-day-old miniature pigs. [5-3H]NNN was administered by intracardiac administration into the right ventricle of the heart to mimic uptake by the lung. Whole body autoradiograms taken 15-220 min after treatment showed high levels of radioactivity in the mandibular and parotid salivary glands, Harder's gland, lacrimal glands, glands of the snout and respiratory part of the nasal cavity, and the melanin of the eyes and skin. Bound radioactivity was most abundant in the nasal mucosa and liver. Analysis of tissues by h.p.l.c. showed the presence of high levels of [5-3H]NNN in the mandibular glands and Harder's gland. Levels of [5-3H]NNN and its metabolites were determined in arterial and venous serum, 0.5-220 min after injection. The disappearance of [5-3H]NNN from serum was biphasic. 4-Oxo-4-(3-pyridyl) butyric acid, a metabolite of [5-3H]NNN resulting from 2'-hydroxylation, which is a suspected activation pathway, was detected 0.5 min after injection and appeared to reach a steady state 2-220 min after injection. 4-Hydroxy-4-(3-pyridyl)butyric acid, from 5'-hydroxylation of [5-3H]NNN, and norcotinine, from denitrosation, were also rapidly formed. These experiments are the first in which the appearance of NNN metabolites in blood has been measured. The ratio of 2'-hydroxylation to 5'-hydroxylation varied from 0.27 to 0.60 in arterial serum and from 0.33 to 0.49 in venous serum in the period from 2-220 min. [5-3H]NNN accumulated in the stomach contents such that its levels were greater than those in arterial or venous serum, 60 min after injection. The results of this study demonstrate that the miniature pig is a useful model for the investigation of nitrosamine metabolism and indicate some similarities and differences in metabolism and distribution compared with the rat.