Junji Hirate

Disposition of warfarin in analbuminemic rats

The disposition characteristics of warfarin were studied in analbuminemic rats after intravenous bolus injection of 1 and 40 mg/kg of drug to investigate the effects of plasma protein binding on drug disposition. With both doses of warfarin, total body warfarin clearance (CL) was markedly faster and its apparent volume of distribution (Vdβ) significantly greater in the analbuminemic rats in comparison to controls. Further, the apparent elimination rate constant (β) was significantly greater and the corresponding elimination half-life (t12β) shorter in the rats with low plasma albumin. Whole body autoradiograms demonstrated that the distribution of warfarin to the liver, skeletal muscle and brain was greater in the analbuminemic rats which was in good agreement with the larger Vdβ observed in this group of rats. The results suggested that the disposition characteristics of warfarin were markedly altered in the rats with low plasma albumin concentrations due to reduced plasma warfarin protein binding.

Enhancement of phenytoin binding to tissues in rats by heat treatment.

Abstract— Phenytoin binding to heat‐treated tissue homogenates has been examined to characterize the phenytoin binding to tissues. The binding to the heat‐treated tissue homogenates was enhanced in all tissues studied compared with controls. The heating might produce the changes in conformation of proteins in tissues and then enhance phenytoin binding to tissue homogenates.

First-Pass Metabolism of Acetoaminophen in Thyroxine Treated Rats

The study on the first-pass metabolism of acetaminophen was carried out in normal and thyroxine-treated rats, administered 30 mg/kg by three routes of intravenous, intraperitoneal, and oral one. Unconjugated acetaminophen and two major metabolites, glucuronide and sulfate in the plasma and urine were then measured 5 and 24 h after the administration, respectively. It was found that there was no difference in total percentage of excreted amount, independent of the routes for administration, between normal and thyroxine-treated rats. This fact shows that acetaminophen is absorbed completely from the gastrointestinal tract. However, it was also found that the extraction ratio of gastrointestinal tract in thyroxine-treated rats became smaller, and that the volume of distribution and total body clearance became larger than those in normal rats. The first-pass metabolism of acetaminophen was found to be influenced by the continuous administration of thyroxine.

Determination of lower level of serum phenytoin by Emit method.

Determination of lower level of serum phenytoin (PHT) was made by homogeneous enzyme immunoassay (Emit) in the following methods:(A) Wide range calibration method, (B) Extrapolated calibration method, and (C) Mixed sample method. In the method A and B, calibration curves of serum PHT levels were generated using a nonlinear least-squares regression program (EMITFIT) with a microcomputer. It was concluded that method A was most reliable of the three. In method A, the PHT recoveries in spiked serum samples in the concentrations of 0.25, 0.5, 1.0 μg/ml were 104.6, 102.6, 100.1%, and coefficients of variation were 11.4, 6.8, 2.3%, respectively.