Kiyoshi Yamaoka

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

Two-compartment dispersion model for analysis of organ perfusion system of drugs by fast inverse laplace transform (FILT)

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

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

.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%.

Improved anti‐cancer effect of interferon gene transfer by sustained expression using CpG‐reduced plasmid DNA

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.

Local Absorption Kinetics of Levofloxacin from Intestinal Tract into Portal Vein in Conscious Rat Using Portal-Venous Concentration Difference

A dispersion model developed in Chromatographic theory is applied to the analysis of the elution profile in the liver perfusion system of experimental animals. The equation for the dispersion model with the linear nonequilibrium partition between the perfusate and an organ tissue is derived in the Laplace-transformed form, and the fast inverse Laplace transform (FILT) is introduced to the pharmacokinetic field for the manipulation of the transformed equation. By the analysis of the nonlinear least squares method associated with FILT, this model (two-compartment dispersion model) is compared to the model with equilibrium partition between the perfusate and the liver tissue (one-compartment dispersion model) for the outflow curves of ampicillin and oxacillin from the rat liver. The model estimation by Akaikes information criterion (AIC) suggests that the two-compartment dispersion model is more proper than the one-compartment dispersion model to mathematically describe the local disposition of these drugs in the perfusion system. The blood space in the liver, VB, and the dispersion number DN are estimated at 1.30 ml (±0.23 SD) and 0.051 (±0.023 SD), respectively, both of which are independent of the drugs. The efficiency number, RN, of ampicillin is 0.044 (±0.049 SD) which is significantly smaller than 0.704 (±0.101 SD) of oxacillin. The parameters in the two-compartment dispersion model are correlated to the recovery ratio, FH, mean transit time, ¯tH, and the relative variance, σ2/¯tH2, of the elution profile of drugs from the rat liver.

Moment analysis for disposition kinetics of several cephalosporin antibiotics in rats

A new experimental system is used to determine exact information concerning local drug disposition. Rabbit hind leg is perfused in situusing a single-pass technique, and outflow curves of drugs are analyzed using statistical moment theory. By the introduction of Chromatographic concepts and the application of the well-stirred model to the local perfusion system, physiologically and/or physicochemically meaningful parameters are derived from the first three moments. Moreover, in the assessment, drug disposition is divided into elimination and distribution. The elimination process is also evaluated with respect to rate and extent. This system is used to elucidate the disposition characteristics of mitomycin C and its lipophilic derivative nonyloxycarbonyl mitomycin C.

Quantitative and temporal analysis of gene silencing in tumor cells induced by small interfering RNA or short hairpin RNA expressed from plasmid vectors

AbstractPurpose. We evaluated the first-pass effects in vivo by the intestine and liver during enterohepatic circulation (EHC) by simultaneously measuring the portal and venous plasma concentrations of the rat. Methods. The venous and upper portal blood vessels were cannulated through the jugular and the pyloric veins, respectively, to obtain simultaneously blood samples from both sites. After diclofenac was injected as a bolus through the jugular vein, the concentrations of diclofenac in the portal and jugular veins were measured at time intervals. The absorption rate from the intestinal tract into the portal system was determined using the portal–venous difference in plasma concentrations of diclofenac, considering 40% partitioning of diclofenac into erythrocytes. Results. After one hour, the plasma concentration in the portal vein was always higher than that in the jugular vein in awakening rats with intact EHC (portal–venous blood concentration difference). No portal–venous difference was observed in awakening rats with bile-duct cannulation. Therefore, it was concluded that this portal–venous concentration difference was not due to the hepatic clearance but to diclofenac reabsorption from the intestinal tract. Conclusions. Appropriately 40% of the dose of diclofenac was reabsorbed over 8 hours from the intestinal tract into the portal system. By comparing the reabsorbed amounts in the portal system and in the systemic circulation, the hepatic extraction ratio in vivo (FH) of diclofenac was estimated to be 63%.

Application of numerical Laplace transformation to chromatographic peak analysis

Plasmid DNA (pDNA) expressing mouse interferon (IFN)‐β or IFN‐γ (pCMV‐Muβ and pCMV‐Muγ, respectively) has been shown to be effective in inhibiting the growth of colon carcinoma CT‐26 cells in the liver (Kobayashi et al., Molecular Therapy 2002;6:737–44). The therapeutic effect of such IFN gene transfer could be significantly increased by the sustained expression of IFNs. In the present study, CpG‐reduced pDNA encoding IFN‐β or IFN‐γ (pGZB‐Muβ and pGZB‐Muγ, respectively) was constructed. pCMV‐Muβ and pCMV‐Muγ were used as conventional CpG‐replete pDNAs. Each pDNA was injected into the tail vein of mice by the hydrodynamics‐based procedure. An injection of pGZB‐Muβ resulted in very high IFN‐β activities in the serum for at least 24 hr after injection, whereas the IFN‐β activity after pCMV‐Muβ injection declined quickly. About a 14‐fold greater amount of IFN‐β was produced from pGZB‐Muβ than from pCMV‐Muβ. pGZB‐Muβ markedly inhibited the pulmonary metastasis of CT‐26 cells. Similar, but more marked results were obtained with pGZB‐Muγ: it increased the area under the concentration‐time curve by more than a 60‐fold and the mean residence time of IFN‐γ 4‐fold compared with pCMV‐Muγ. The survival time of the pGZB‐Muγ‐treated mice was significantly (p < 0.05) longer than that of the saline‐ or pCMV‐Muγ‐treated mice. These results indicate that long‐term expression of IFN can be achieved by CpG‐reduced pDNA and sustained IFN gene expression results in enhanced therapeutic effects of IFN gene transfer against tumor metastasis.