Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
2001-08-14
2004-09-28
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S009200, C424S009300, C424S001810, C436S173000
Reexamination Certificate
active
06797256
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a preparation useful for assessing and determining the sensitivity of an individual subject to pyrimidine drugs, such as 5-fluorouracil, which serve as an anticancer drug. More specifically, the present invention relates to a preparation for measuring in vivo activity of pyrimidine metabolizing enzymes that participate pyrimidine drug metabolism, with ease by utilizing the expired air or urine.
The present invention further relates to a method for measuring in vivo pyrimidine metabolizing activity with ease using the preparation, and a method for assessing pyrimidine metabolizing activity (pyrimidine drug sensitivity) in an individual subject.
The present invention also relates to a method for establishing a dosage regimen (formula, dose, dosing frequency, etc.) of a pyrimidine drug for an individual subject, wherein pyrimidine metabolizing activity in the subject is assessed using the preparation before administration of the drug.
BACKGROUND OF THE INVENTION
Among pyrimidine drugs, 5-fluorouracil (hereinafter sometimes referred to as “5-FU”) and its derivatives (such as tegafur, carmofur and doxifluridine) are anticancer drugs most widely used at present. 5-FU is degraded and inactivated mainly in the liver, by the actions of pyrimidine metabolizing enzymes. Specifically stated, 5-FU is metabolized first into 5-fluoro dihydrouracil (hereinafter sometimes referred to as “FDHU”) by the action of dihydropyrimidine dehydrogenase (hereinafter sometimes referred to as “DPD”), and then into fluoro-&bgr;-alanine by the action of dihydropyrimidinase (hereinafter sometimes referred to as “DHPase”), and thereafter excreted in the urine (see FIG.
1
).
It is reported that about 80% of 5-FU administered is degraded by this metabolic system (Cancer (Phila), 68, 499-501, 1991), and that DPD is the ratelimiting enzyme in this metabolic system (Cancer Res., 47: 2203-2206, 1987). Accordingly, 5-FU administration to subjects with pyrimidine metabolic abnormalities such as DPD deficiency or DPD activity reduction is likely to result in abnormally high 5-FU concentration in blood, thus causing severe side effects (e.g., myelosuppression and digestive symptoms) (Cancer Inves. 11 (2): 239-240, 1993). DPD activity greatly varies from individual to individual, and is also different between the sexes (J. Clin. Oncol., 12:2248-2253, 1994; Adv. Exp. Med. Biol., 431:811-816, 1998). Thus, in Europe and America, there arises the necessity of diagnosing DPD deficiency and DPD activity reduction in individual subjects to prevent 5-FU side effects.
There is an established DPD deficiency diagnosis method, wherein DPD activity of peripheral blood mononuclear cells is measured (Cancer Res., 53:5433-5438, 1993; Phermacogenetics. 4:301-306. 1994; J. Inherited. Metab. Dis., 16:574-576, 1993). However, the method is not suitable for selecting subjects to be given 5-FU, since the method involves use of radioactive substances and complicated pretreatment.
Recent progresses in genetic analysis techniques have facilitated diagnosis of DPD gene deficiency. Further, a number of reports have been made on polymorphism of DPD gene, which may cause DPD activity reduction. However, the correlation between the DPD gene polymorphism and DPD activity has not been elucidated yet. Thus, it is extremely difficult to assess DPD activity, in particular the degree of DPD activity, at the genetic level.
In the present situation where 5-FU therapy has proved effective and is often enhanced by drugs that inhibit DPD activity, there is a demand for the development of a simple method for screening a subject for metabolic abnormalities before 5-FU therapy, to predict and prevent side effects of 5-FU therapy in subjects with pyrimidine metabolic abnormalities.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a preparation useful for determining the sensitivity, specifically in vivo metabolizing activity, of an individual subject to 5-FU or like pyrimidine drugs to be degraded in the pyrimidine metabolic pathway. Another object of the invention is to provide a preparation for measuring in vivo pyrimidine metabolizing activity in an individual subject with ease, using the expired air or urine. A further object of the invention is to provide a method for measuring in vivo pyrimidine metabolizing activity in an individual subject with ease, using the preparation.
A further object of the invention is to provide a method for assessing in vivo pyrimidine metabolizing activity in an individual subject with ease using the preparation. A still further object of the invention is to provide a method for establishing a dosage regimen of a pyrimidine drug for an individual subject, wherein the sensitivity of the subject to the drug is assessed by the above assessing method before administration of the drug to determine the dosage regimen based on the sensitivity.
The present inventors conducted intense research, focusing their attention to metabolic kinetics wherein pyrimidine compounds, which act as substrates for pyrimidine metabolizing enzymes, are degraded in vivo by the action of these enzymes and partially excreted as CO
2
in the expired air, the remainder being excreted predominantly in the urine. As a result, they found that excretion behavior of the metabolites can be precisely measured by labeling the substrate with an isotope, and that the pyrimidine metabolizing activity of an individual subject can be easily assessed from the excretion behavior. The inventors further found that the method for assessing pyrimidine metabolizing activity is useful for assessing the sensitivity of an individual subject to 5-FU or other pyrimidine drugs (pyrimidine drug metabolic capacity) to predict side effects of pyrimidine drugs in subjects with pyrimidine metabolic abnormalities. The present invention has been accomplished based on these findings.
The present invention provides the preparations for determining pyrimidine metabolizing activity, described in the following items 1 to 6:
1. A preparation for determining pyrimidine metabolizing activity, comprising as an active ingredient a pyrimidine compound or its metabolite in which at least one of C, O and N is labeled with an isotope.
2. A preparation according to item 1, wherein the pyrimidine compound or its metabolite is a substrate for a pyrimidine metabolizing enzyme or a precursor of the substrate.
3. A preparation according to item 2, wherein the pyrimidine metabolizing enzyme is at least one member selected from the group consisting of dihydropyrimidine dehydrogenase, dihydropyrimidinase and &bgr;-ureidopropionase.
4. A preparation according to any one of items 1 to 3, wherein the pyrimidine compound or its metabolite is at least one member selected from the group consisting of 5-fluorouracil, uracil, thymine, 5-fluorodihydrouracil, dihydrouracil, dihydrothymine, fluoro-&bgr;-ureidopropionic acid, &bgr;-ureidopropionic acid, &bgr;-ureidoisobutyric acid, doxifluridine, tegafur and carmofur.
5. A preparation according to any one of items 1 to 4, wherein the pyrimidine compound or its metabolite is a compound at least one of C and O is labeled with an isotope, and wherein the pyrimidine compound or its metabolite is capable of producing isotope-labeled CO
2
in vivo after administration.
6. A preparation according to any one of items 1 to 5, wherein the isotope is at least one member selected from the group consisting of
13
C
14
C
18
O and
15
N.
The present invention further provides the methods for determining pyrimidine metabolizing activity, described in the following items 7 to 10:
7. A method for determining pyrimidine metabolizing activity in an individual subject, comprising administering a preparation according to any one of items 1 to 6 to the subject, and measuring behavior of an isotope-labeled metabolite.
8. A method for determining pyrimidine metabolizing activity in an individual subject, comprising administering a preparation according to any one of items 1 to 6 to the subject, and measuring excretion behavi
Ikei Nobuhiro
Inada Makoto
Irie Yasuo
Nonomura Hideji
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Hartley Michael G.
Otsuka Pharmaceutical Co. Ltd.
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