EFFECT OF ENTEROHEPATIC CIRCULATION ON THE PHARMACOKINETICS OF CHLORAL HYDRATE AND ITS METABOLITES IN F344 RATS

Abstract

Chloral hydrate (CH) is a commonly found disinfection by-product in water purification, a metabolite of trichloroethylene, and a sedative/hypnotic drug. CH and two of its reported metabolites, trichloroacetic acid (TCA) and dichloroacetic acid (DCA), are hepatocarcinogenic in mice. Another metabolite of CH, trichloroethanol (TCE), is also metabolized into TCA, and the enterohepatic circulation (EHC) of TCE maintains a pool of metabolite for the eventual production of TCA. To gain insight on the effects of EHC on the kinetics of CH and on the formation of TCA and DCA, dual cannulated F344 rats were infused with 12, 48, or 192 mg/kg of CH and the blood, bile, urine, and feces were collected over a 48-h period. CH was cleared rapidly (>3000 ml/h/kg) and displayed biphasic elimination kinetics, with the first phase being elimination of the dose and the second phase exhibiting formation rate-limited kinetics relative to its TCE metabolite. The effects of EHC on metabolite kinetics were only significant at the highest dose, resulting in a 44% and 17% decease in the area under the curve (AUC) of TCA and TCE, respectively. The renal clearance of CH, free TCE (f-TCE), and TCA of 2, 2.7, and 38 ml/h/kg, respectively, indicates an efficient reabsorption mechanism for all of these small chlorinated compounds. DCA was detected at only trace levels (<2 muM) as a metabolite of CH, TCA, or TCE.