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Agents for measuring pyrimidine metabolizability

A technology of metabolic ability and pyrimidine, which is applied in the field of preparations, can solve problems such as unexplained, decreased DPD activity, and difficulty in evaluating whether DPD activity exists or not.

Inactive Publication Date: 2004-05-19
OTSUKA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, there are many reports about DPD gene polymorphisms, and DPD gene polymorphisms can cause DPD activity to decrease
However, the relationship between DPD gene polymorphisms and DPD activity has not been elucidated
Thus, on the basis of genetic information, it is difficult to evaluate the presence or absence of DPD activity, especially the degree of DPD activity

Method used

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  • Agents for measuring pyrimidine metabolizability
  • Agents for measuring pyrimidine metabolizability
  • Agents for measuring pyrimidine metabolizability

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] in the 2nd place is 13 C-labeled carbon atom of uracil (2- 13 C-labeled uracil) was used as the isotope-labeled pyrimidine compound. Preparation of a preparation containing 2- 13 C-labeled uracil is used as the active ingredient in the form of an intravenous solution for determination of pyrimidine metabolizing capacity.

[0134] (1) Production of preparations for determination of pyrimidine metabolism capacity

[0135] Uracil-2- 13 C (Cambridge Isotope Laboratory) (300 mg) was dissolved in 24 ml of 0.1N NaOH / saline solution (measured from 200 ml of 0.1N NaOH / saline solution, which was diluted with normal saline to 2 ml of 10N NaOH / saline solution), the preparation for determination of pyrimidine metabolizing capacity was obtained in the form of intravenous injection, in (each 4 ml injection contains 50 mg uracil-2- 13 C).

[0136] (2) Preparation of (E)-5-(2-bromovinyl)-uracil preparation

[0137](E)-5-(2-Bromovinyl)-uracil is known to be an inhibitor of dihyd...

Embodiment 2

[0143] The preparation for determining pyrimidine metabolizing ability was prepared in oral form, using the same 2- 13 C-labeled uracil was used as the active ingredient and its detection was useful for determining pyrimidine metabolizing capacity.

[0144] (1) Preparation of preparations for determination of pyrimidine metabolism capacity

[0145] 2- 13 C-labeled uracil (Cambridge Isotope Laboratory) (300 mg) was dissolved in 24 ml of 0.1N NaOH / saline solution (measured from 200 ml of 0.1N NaOH / saline solution, which was diluted with normal saline 2 ml of 10N NaOH / brine solution). Water was then added to obtain in oral form 60 ml of a preparation of determined pyrimidine metabolizing capacity (per 10 ml of oral solution containing 50 mg of 2- 13 C-labeled uracil).

[0146] (2) experiment

[0147] Fasted beagle dogs were used as experimental animals. In group 1 (n=3), the preparation prepared above for determining pyrimidine metabolizing ability was orally administered (...

Embodiment 3

[0151] 56.5 mg, 113.1 mg, 226.2 mg and 452.3 mg of 2- 13 C-labeled uracil (Cambridge Isotope Laboratory) to prepare solutions with concentrations of 10 μmol / ml, 20 μmol / ml, 40 μmol / ml and 80 μmol / ml. These solutions were forcibly administered orally to fasting male Beagle dogs (n=3) using oral test tubes for dogs at a dose of 1 ml / kg body weight (doses: 10, 20, 40 and 80 μmol / kg), after which water was administered in 2 ml Amounts per kg body weight are administered orally to dogs compulsorily. Exhaled air was collected before administration and at 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 210, and 240 minutes after administration. 13 C labeled CO 2 concentration, and pharmacokinetic parameters (area under the curve (AUC) and maximum 13 C labeled CO 2 Concentration (Cmax)) obtained from exhaled 13 C labeled CO 2 Calculated from the concentration transition curve.

[0152] Figure 4 shown exhaling 13 C labeled CO 2 Concentration transition curve. Figure 5 and...

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Abstract

The present invention provide a method for assessing the sensitivity to a pyrimidine drug such as 5-FU which is degraded in the pyrimidine metabolic pathway, specifically in vivo pyrimidine metabolizing activity, of an individual subject; and a preparation useful for the assessment. The present invention can be carried out by: administering a preparation comprising as an active ingredient a pyrimidine compound or its metabolite which acts as a substrate for a pyrimidine metabolizing enzyme, in which compound or metabolite at least one of C, O and N is labeled with an isotope; and assessing in vivo pyrimidine metabolizing activity based on the amount of excreted metabolite.

Description

technical field [0001] The present invention relates to a preparation which can be effectively used to determine and evaluate the pyrimidine metabolizing ability of a single subject, that is, the presence, absence and degree of pyrimidine metabolic disorders, etc. More specifically, the present invention relates to a preparation that can easily determine the ability of a single subject to metabolize different fluorouracil drugs, such as 5-fluorouracil, etc., by using exhaled breath or the like. Furthermore, the invention relates to the use of such formulations. Background of the invention [0002] 5-Fluorouracil (hereinafter sometimes referred to as "5-FU") and its derivatives (such as tegafur, carmofur, and doxifluridine) are fluorouracil drugs that are currently It is widely used as an anticancer drug. [0003] In the liver, the degradation and inactivation of 5-FU is mainly through the action of a series of pyrimidine metabolizing enzymes in the pyrimidine metabolic pat...

Claims

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Application Information

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IPC IPC(8): A61K49/00A61K49/18
CPCA61K49/0004A61K49/1815Y10T436/24A61K49/00
Inventor 稲田睦池井畅浩野野村英二入江康夫
Owner OTSUKA PHARM CO LTD
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