Effects of dose, age, inhibition of metabolism and elimination on the toxicokinetics of 2-butoxyethanol and its metabolites.
Acute exposure to 2-butoxyethanol (BE) causes dose- and age-dependent hemolytic anemia in rats. Recently, we have shown that butoxyacetic acid (BAA) is the proximate hemolytic agent and that inhibition of alcohol or aldehyde dehydrogenases protected rats against BE-induced hemolytic anemia. In the present investigations, the kinetics of 14C-BE metabolism and clearance were studied in control adult (3-4 months old) and old (12-13 months old) male F344 rats and in adult male F344 rats treated with pyrazole, cyanamide or probenecid. Our results showed that the area under the curve (AUC), maximum plasma concentration (Cmax) and systemic clearance (Cls) of BE were dose-dependent. In contrast, there was no effect of dose on half-life (T1/2) or volume of distribution (Vd) of BE. These results also showed that there was no age effect on T1/2, Vd or Cls of BE. However, Cmax and AUC of BE increased as a function of age. Also, analysis of variance indicated no significant interactions (P less than or equal to .05) between dose and age in relation to BE kinetics. As expected, inhibition of BE metabolism by pretreatment of rats with pyrazole or cyanamide resulted in a significant increase in the T1/2 and AUC of BE, whereas it caused a significant decrease in the Cls. Furthermore, pyrazole had no effect, whereas cyanamide had decreased Vd of BE. Analysis of the toxicokinetic parameters of BAA revealed that T1/2, AUC and Cmax of BAA were directly related to the age of the rats and the dose of BE administered.(ABSTRACT TRUNCATED AT 250 WORDS)
Ghanayem
B I
BI
National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Sanders
J M
JM
Clark
A M
AM
Bailer
J
J
Matthews
H B
HB
D000367:Age Factors; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000704:Analysis of Variance; D000818:Animals; D003484:Cyanamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005026:Ethylene Glycols / Q000493:pharmacokinetics* / Q000633:toxicity; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D011339:Probenecid / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D005026:Ethylene Glycols; D011720:Pyrazoles; C031280:pyrazole; D003484:Cyanamide; D000426:Alcohol Dehydrogenase; C017096:n-butoxyethanol; D011339:Probenecid