Terumichi Nakagawa

Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations

According to linear pharmacokinetics, the time course of plasma concentration of a drug, Cp,is expressed by a sum of exponential functions, Cp=εi=1nai

High-performance frontal analysis for drug–protein binding study ☆

C_p = \sum\nolimits_{i = 1}^n {a_i e^{ - b_i t} }

Liquid chromatography with crown ether-containing mobile phases : II. Retention behaviour of β-lactam antibiotics in reversed-phase high-performance liquid chromatography

.This article describes a statistical technique to estimate the number of exponential terms, n,for the time course of drug by the application of Akaikes information criterion (AIC). Plasma concentrations of ethoxybenzamide, sulfisoxazole, bishydroxycoumarin, and diazepam measured following bolus intravenous injection were used as clinical examples for this method. Selection of models is compared between the AIC method and an Ftest method at significance levels of 5% and 1%.

High-performance frontal analysis for the study of protein binding of troglitazone (CS-045) in albumin solution and in human plasma

Statistical moments are parameters that describe the characteristics of the time courses of plasma concentration (area, mean residence time, and variance of residence time) and of the urinary excretion rate that follow administration of a single dose of a drug. The relationship between the moments of a time-course curve and pharmacokinetic profiles of drug disposition, i.e., absorption, distribution, metabolism, and excretion, is described. The moments are related to the extent and rate of bioavailability, and it is shown that they can be effectively applied to the deconvolution operation.

Enantioselective binding analysis of verapamil to plasma lipoproteins by capillary electrophoresis–frontal analysis

High-performance frontal analysis (HPFA) is a novel analytical method which enables simultaneous determination of total and unbound drug concentrations under drug-plasma protein binding condition. HPFA can be achieved using separation systems such as HPLC and CE. This paper deals with the principle and feature of HPFA method and its application to the stereoselective protein binding study. HPFA allows a simple analysis following direct sample injection, and does not suffer from undesirable drug adsorption on membrane nor leakage of bound drug through the membrane which are often encountered in conventional ultrafiltration and dialysis methods. HPFA can be easily incorporated into on-line HPLC system. By coupling HPFA with a chiral HPLC column, the unbound concentration of a racemic drug can be determined enantioselectively. The detection limit can be improved by coupling of HPFA with a preconcentration column. High-performance capillary electrophoresis/frontal analysis (HPCE/FA) enables to determine unbound concentrations enantioselectively with ultramicro injection volume, and is hence useful especially for the binding study of proteins which are scarce and difficult to obtain.

Theoretical study of high-performance frontal analysis: a chromatographic method for determination of drug-protein interaction.

Sodium dodecyl sulphate (SDS) capillary electrophoresis using pullulan solution as a separation matrix was developed for the separation and molecular mass determination of proteins. The silanol functions on the inner surface of a fused-silica capillary were deactivated by coating with linear polyacrylamide through Si-C linkages, into which the pullulan solution was filled. The stability of the coating was examined by exposure to an alkaline buffer solution (pH 9.2) for up to 30 days. Compared with conventional coatings with linear polyacrylamide through siloxane linkages, the present capillary was more stable even under alkaline conditions and markedly reduced electroosmotic flow. Thus, polymer solutions of low viscosity such as pullulan solution could be stabilized in the capillary, resulting in a prolonged life-span of the capillary and improved reproducibility of separations. An excellent linear relationship was obtained between the mobility and the logarithm of the molecular mass of SDS-proteins. The relative standard deviation of migration times was below 0.5% when the pullulan solution was refilled in each analysis (n = 10). The calibration plots of the integrated peak areas at 214 nm vs. concentration of standard proteins were linear in the range 5 micrograms/ml-0.1 mg/ml.

Evaluation of Intestinal Absorption into the Portal System in Enterohepatic Circulation by Measuring the Difference in Portal–Venous Blood Concentrations of Diclofenac

Abstract The retention behaviour of several β-lactam antibiotics in reversed-phase liquid chromatography with mobile phases containing crown ether(18-crown-6 or dicyclohexyl-18-crown-6) has been investigated. The capacity factors were determined with various concentrations of crown ether and methanol in the aqueous mobile phase at different pH values. The observed profiles of capacity factor, k, vs. crown ether concentration and k vs. pH are discussed with reference to an equation derived from a chromatographic model involving association of β-lactam antibiotics with crown ethers and bindings of free and associated species to the hydrophobic stationary phase. The effect of ionic salts on the capacity factor is also discussed. The applicability of the method is demonstrated by specific separations of ampicillin in urine and cephalexin in plasma.

Retention properties of internal-surface reversed-phase silica parking and recovery of drugs from human plasma

An on-line frontal analysis HPLC system was developed for the determination of the unbound concentration of troglitazone (CS-045), a new oral antidiabetic agent, in human serum albumin (HSA) solution and in human plasma. This system consists of a high-performance frontal analysis (HPFA) column, an extraction column, and an analytical column, which are connected via two switching valves. After the direct injection of the sample solution into the HPFA column, the drug was eluted as a zonal peak with a plateau region. The unbound drug concentration was determined as the drug concentration in the plateau. As low as 0.3 nM unbound CS-045 was determined with good reproducibility. It was found that CS-045 strongly binds with HSA, and the bound fraction in the 550 microM HSA solution was 99.93%, which was very close to that in human plasma (99.89%). The bound fractions were constant within the total drug concentration range of 1-10 microM in the HSA solution and 250 nM-10 microM in human plasma.