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 sit e and dosing method in quantitation of chemical percutaneous absorptio n. Following topical and intravenous application of [ring-U-C-14]parat hion (PA) in weanling pigs, we have determined, in a previous publicat ion, the profiles of C-14 and HPLC-separated paraoxon (PO), p-nitrophe nol (PNP), and p-nitrophenyl beta-D-glucuronide (PNP-G) in plasma, uri ne, tissues, and dosing device. The purpose of the present paper was t o analyze these data further, focusing on a quantitation of the effect s of application site (back versus abdomen) and dosing method (occlude d 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 m odeling approach and moments analysis. Mean systemic bioavailability v alues 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 meta bolized dermally, and 9-19% systemically. Radioactivity in plasma and urine was predominantly contributed by PNP-G and PNP. Site differences in C-14 percutaneous absorption were governed by the differences in t ransport of PA, PO, and PNP from epidermis into blood, by local tissue distribution, and by the cutaneous metabolism to PNP. Systemic bioava ilability of PA was higher from the back than from the abdomen. Occlus ion not only increased the amount of C-14 absorption and shortened the mean residence time in most compartments but also altered the systemi c versus cutaneous biotransformation pattern. The occlusion effect of enhancing PA cutaneous metabolism appears to be the most important mec hanism for the previously observed increased C-14 absorption. Signific ant site-occlusion interactions were demonstrated, indicating that one cannot describe site differences without referring to the specific do sing method and vice versa. Moreover, novel and practical computationa l methods (bioavailability-excretion analysis, bioavailability-bioavai lability analysis) to clarify in vivo cutaneous metabolism from the sy stemic biotransformation of topically applied compounds were developed .