Plasma/blood pharmacokinetics and metabolism after dermal exposure to para-aminophenol or para-phenylenediamine.
The pharmacokinetics and metabolism following dermal application of [(14)C]-para-aminophenol (PAP) or [(14)C]-para-phenylenediamine (PPD) were investigated. Groups of rats were treated under occlusion for 24 h with 12.5 mg/kg [(14)C]-PAP, or for 4h with 50 mg/kg [(14)C]-PPD on 10% or 20% of their body surface area, respectively. A female minipig was also treated dermally (24 h, occlusion) with 4.7 mg/kg [(14)C]-PAP on 10% of its body surface area. Blood and plasma samples were analysed for radioactivity and presence of metabolites. In PAP-treated rats, mean plasma levels at 0.5, 1, 2, 4, 8 or 24h were 0.16, 0.24, 0.38, 0.50, 0.36 or 0.14 microg [(14)C]-PAP equivalents/ml, respectively. The plasma half-life was 5.95 h, the C(max) was 0.5 microg/ml, the t(max) was 4 h, and the AUC(0-infinity) was 9.27 microg-equivalentsh/ml. No free PAP was detected in the plasma, but 3 metabolites (M1, M2 and M3) were found in 2-, 4- or 8-h samples at ranges from 0% to 17.7% (M1), 27.6% to 45.0% (M2) or 46.9% to 70% (M3) of the total plasma radioactivity. M2 was identified as acetylated PAP (paracetamol, acetaminophen, APAP), whereas M1 and M3 were identified as O-glucuronide or O-sulfate conjugates of APAP, respectively. In the pig, very low levels of radioactivity (C(max) of approximately 10 ng/ml) were found in the blood, and identified as APAP. Analysis of plasma of PPD-treated rats at 4 h after topical treatment revealed levels of 1.41 +/- 0.34 microg/ml [(14)C]-PPD-equivalents in males, and 7.40 +/- 1.83 microg/ml in females. Radioactivity, reflected a single metabolite, which was identified to be N,N'-diacetylated PPD. Comparison of the plasma APAP levels in rats or the pig following topical PAP with corresponding human plasma levels after a single oral therapeutic dose of APAP suggested a substantial margin of safety. Overall, the results suggest that topically applied PAP or PPD are metabolised in the skin, presumably by N-acetyltransferase-1 resulting in systemic exposure to acetylated metabolites, and not to their parent arylamines.
Dressler
William E
WE
williamedressler@aol.com
Appelqvist
Terence
T
D000042:Absorption; D000284:Administration, Oral; D000287:Administration, Topical; D000627:Aminophenols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D019540:Area Under Curve; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D002250:Carbon Radioisotopes; D004396:Coloring Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D006202:Hair Dyes / Q000493:pharmacokinetics / Q000633:toxicity; D006207:Half-Life; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009153:Mutagens / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D010655:Phenylenediamines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013552:Swine; D013556:Swine, Miniature
D000627:Aminophenols; D002250:Carbon Radioisotopes; D004396:Coloring Agents; D006202:Hair Dyes; D007527:Isoenzymes; D009153:Mutagens; D010655:Phenylenediamines; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C026729:4-aminophenol; C029728:4-phenylenediamine