Significant effects of application site and occlusion on the pharmacokinetics of cutaneous penetration and biotransformation of parathion in vivo in swine.

Increasing attention has been paid to the variables of application site and dosing method in quantitation of chemical percutaneous absorption. Following topical and intravenous application of [ring-U-14C]parathion (PA) in weanling pigs, we have determined, in a previous publication, the profiles of 14C and HPLC-separated paraoxon (PO), p-nitrophenol (PNP), and p-nitrophenyl beta-D-glucuronide (PNP-G) in plasma, urine, tissues, and dosing device. The purpose of the present paper was to analyze these data further, focusing on a quantitation of the effects of application site (back versus abdomen) and dosing method (occluded versus nonoccluded) on in vivo disposition of both the parent PA and its sequential metabolites PO, PNP, and PNP-G. Cutaneous and systemic disposition parameters were determined using a numerical simulation modeling approach and moments analysis. Mean systemic bioavailability values of 8.9-9.2% for abdomen and 14.7-19.7% for back were determined. Under different dosing conditions, 1-35% of the topical dose was metabolized dermally, and 9-19% systemically. Radioactivity in plasma and urine was predominantly contributed by PNP-G and PNP. Site differences in 14C percutaneous absorption were governed by the differences in transport of PA, PO, and PNP from epidermis into blood, by local tissue distribution, and by the cutaneous metabolism to PNP. Systemic bioavailability of PA was higher from the back than from the abdomen. Occlusion not only increased the amount of 14C absorption and shortened the mean residence time in most compartments but also altered the systemic versus cutaneous biotransformation pattern.(ABSTRACT TRUNCATED AT 250 WORDS)