Lauramide diethanolamine absorption, metabolism, and disposition in rats and mice after oral, intravenous, and dermal administration.
The disposition of carbon-14-labeled lauramide diethanolamine (LDEA) was determined in rats after iv, dermal, and oral administration, and in mice after iv and dermal administration. Intravenous doses of LDEA to rats and mice (25 and 50 mg/kg, respectively) were mostly excreted in the urine (ca. 80-90%), with only about 10% excreted in the feces 72 hr after dosing. No unchanged LDEA, diethanolamine, or diethanolamine-derived metabolites were detected in urine. LDEA concentrated to the highest levels in the adipose tissue, and was only very slowly cleared from that tissue. Residues were also observed in liver and kidney, but clearance from those tissues paralleled the decreases in blood concentrations. Incubations of LDEA with liver slices from rats and humans showed that the compound is well absorbed by hepatic tissue from both species. LDEA was readily converted to metabolites found in vivo in rats, as well as other metabolites that are potentially intermediate products formed after omega- and/or omega-1 to 4 hydroxylation. Treatment with diethylhexylphthalate, an inducer of cytochrome P4504A1, which catalyzes the omega-hydroxylation of lauric and other fatty acids, demonstrated the involvement of that isozyme in the hydroxylation of LDEA. Dermally applied LDEA, at doses of 25 and 400 mg/kg to rats, was moderately (25-30%) well absorbed. Repeat administration (25 mg/kg/day for 3 weeks) did not change the rate of LDEA absorption. The absorption of 100 mg/kg doses was studied in jugular vein-cannulated rats. Steady state levels of LDEA equivalents were reached 24 hr after dermal administration. LDEA comprised about 15% of the radioactivity in plasma, with the remainder present as polar metabolites. A range of 50-70% of the dermal doses to mice, applied at 50, 100, 200, and 800 mg/kg, was absorbed in 72 hr. Absorbed LDEA distributed into the tissues with the same relative profile as that for the iv dose, except that distribution into adipose tissue was considerably lower. High oral doses of LDEA (100 mg/kg) in rats were well absorbed and mostly excreted in the urine as two very polar metabolites. The metabolites were isolated and characterized as the half-acid amides of succinic and of adipic acid, presumably arising from omega-hydroxylation and eventual beta-oxidation to give the chain-shortened products.
Mathews
J M
JM
Center for Bioorganic Chemistry, Research Triangle Institute, RTP, NC 27709, USA.
deCosta
K
K
Thomas
B F
BF
D000042:Absorption; D000273:Adipose Tissue / Q000378:metabolism; D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000494:pharmacology; D004983:Ethanolamines / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D007850:Lauric Acids / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D004983:Ethanolamines; D007850:Lauric Acids; D003577:Cytochrome P-450 Enzyme System; D004051:Diethylhexyl Phthalate; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; C052237:lauric acid diethanolamide