Absorption and disposition kinetics of 3,3',4,4'-tetrachloroazoxybenzene in the male Fischer 344 rat.
3,3',4,4'-Tetrachloroazoxybenzene (TCAOB) is a structural analog of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It is formed as a byproduct during the synthesis of industrial products such as herbicides. TCAOB is a ligand for the Ah receptor and, at much higher doses, exhibits toxicities similar to TCDD. Although the reduced in vivo toxicity of TCAOB probably reflects differences in disposition, this study characterized its absorption and disposition kinetics. Male Fischer 344 rats were administered [14C]TCAOB (3.4 or 34 mg/kg p.o., 3.4 mg/kg i.v.), and the excretion of the radiolabel was monitored over 96 hr. After the low and high dose, 35% and 30% of the [14C]TCAOB were eliminated in the urine, with 55% and 54% eliminated in the feces. At 96 hr, the adipose tissue:blood ratios of [14C]TCAOB equivalents were 8 and 26 for the low and high doses, respectively. After the intravenous dose of TCAOB, the adipose tissue:blood ratio was 21 at 96 hr. Other tissue:blood ratios were of little significance (0.06-3.2). Pharmacokinetic parameters indicate that the parent molecule is cleared from blood with an average half-life of 7 hr and an average clearance of 11 ml/min.kg. Absolute bioavailability was calculated to be approximately 9%. Urine contained a variety of dichlorolaniline conjugates, which support the importance of azo reduction in the disposition of TCAOB. When compared with TCDD, the absorption of TCAOB is greatly reduced and the elimination of metabolites greatly enhanced. Therefore, at equal molar oral doses, TCAOB would express lower levels of Ah receptor-mediated toxicity than those defined for TCDD.
Ziegler
T L
TL
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721-0207, USA.
Pillai
U A
UA
Smith
R L
RL
Kattnig
M J
MJ
Liebler
D C
DC
Mayersohn
M
M
Sipes
I G
IG
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001391:Azo Compounds / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D001682:Biological Availability; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D001391:Azo Compounds; D000072317:Polychlorinated Dibenzodioxins; C013280:3,4,3',4'-tetrachloroazoxybenzene