Pharmacokinetics of Trichloroethanol and Metabolites and Interconversions Among Variously Referenced Pharmacokinetic Parameters

Abstract

The pharmacokinetics of intravenously administered trichloroethanol, chloral hydrate, sodium trichloroacetate, and trichloroethanol glucuronide were studied in the dog with developed GC analyses of blood, urine, and feces, and analyzed with aid of analog and digital computation. Trichloroethanol pharmacokinetics were evaluated at multiple-dosage levels and showed distribution from a central compartment assignable to extracellular body water into readily available and less available tissues assignable to total body water and lipoidal and other tissues. The major route of removal of trichloroethanol in the dog was by conjugation to the glucuronide, and the first-order rate constants of this metabolic route were dose dependent but did not appear to be a consequence of enzymic saturation or change in apparent volumes of distribution with dose. A possible explanation is that the hepatic lipid-water ratio may vary with the dose of trichloroethanol. The formed trichloroethanol glucuronide, after release from the liver, was rapidly distributed in the extracellular body water of the dog and rapidly eliminated in the urine by glomerular filtration and tubular secretion. Biliary elimination of the glucuronide accounted for about 5% of an intravenous dose of trichloroethanol. Saturation of the bile secretory mechanism was demonstrated at higher trichloroethanol doses, e.g., 100 mg./kg., but the absence of trichloroethanol and its glucuronide in the feces may be explained by hydrolysis of the biliary glucuronide in the GI tract with subsequent reabsorption of the formed trichloroethanol, i.e., an entero-hepatic shunt. No assayable trichloroacetic acid was observed in the blood or urine of dogs dosed with trichloroethanol. A long apparent disposition half-life of 75hr. was observed after intravenous administration of sodium trichloroacetate; this can be explained by the extensive tissue binding of trichloroacetate which gave high apparent volumes of distribution. Intravenously administered chloral hydrate was rapidly and quantitatively converted to trichloroethanol in the dog, with an apparent half-life of 3min. Protein binding of trichloroethanol and its glucuronide (about 35%) was determined. Although the glucuronide did not partition into the red blood cells, the trichloroethanol did so instantaneously, with a partition coefficient of 2.1 in favor of the red blood cells. Since apparent volumes of distribution and microscopic pharmacokinetic rate constants have quantitative values that vary widely, depending on whether they are referenced to total blood, total plasma, or unbound drug in plasma concentrations, a detailed analysis of the conversions among these variously referenced constants was made and applied to the data of these studies. Estimates of the microscopic rate constants and apparent volumes of distribution referenced to unbound drug in plasma have the most valid physiological significances. These are complex functions of the hematocrit, the degree of protein binding, the true volume of plasma or blood in the animal, and the red blood cell/plasma partition coefficient when the drug is assayed per millilitcr of whole blood or per milliliter of plasma. The awareness of these facts will necessitate extensive recalculation of many pharmacokinetic constants now given in the literature.