| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | January 30, 2001 |
| PATENT TITLE |
Breath test for detection of drug metabolism |
| PATENT ABSTRACT |
A breath test for determining the rate of metabolism of a drug is described. First, a safe and effective amount of the drug, preferably appropriately labelled and most preferably isotopically-labelled, is administered to a subject. After a suitable time period, the exhaled breath of the subject is analyzed to determine the concentration of a metabolite. The concentration of the metabolite is then used to determine the rate of metabolism of the drug. A breath test kit is also described. Such a breath test kit would include an item or items necessary for performing at least one of the methods of determining the rate of metabolism of a drug in a subject. For example, such a breath test kit could include an isotopically-labelled drug to be administered to the subject. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | June 28, 1999 |
| PATENT REFERENCES CITED | Peura, David., et al., The American Journal of Gastroenterology, "Microdose 14C-Urea Breath Test Offers Dianosis of Helicobacter pylori 10 Minutes", vol. 91, No. 2, pp. 233-238, Feb. 1996 |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method for measuring a characteristic of metabolism of a drug of therapeutic value to a subject and determining a therapeutically effective dosage of said drug for said subject, the characteristic of metabolism being selected from a group consisting of a rate of metabolism and an extent of metabolism, the method comprising the steps of: (a) administering said drug labeled with an isotope to said subject, such that said drug is an administered drug; (b) analyzing exhaled breath of the subject for a concentration of said isotope, said concentration of said isotope directly indicating the characteristic of metabolism of said administered drug in the subject and (C) employing said characteristic of metabolism to determine a therapeutically effective dosage of said drug for said subject. 2. The method of claim 1, wherein said exhaled breath of the subject is analyzed by a measuring instrument selected from the group consisting of an infrared spectrometer and a mass spectrometer. 3. The method of claim 1, wherein said exhaled breath contains carbon dioxide. 4. The method of claim 3, wherein said carbon dioxide is isotopically-labeled with an isotope selected from the group consisting of carbon-13, carbon-14 and oxygen-18. 5. The method of claim 1, wherein said exhaled breath contains ammonia. 6. The method of claim 5, wherein said ammonia is nitrogen-15 isotopically-labeled. 7. The method of claim 1, wherein said exhaled breath contains a substantially unchanged form of the drug. 8. The method of claim 7, wherein said exhaled breath is isotopically labeled with an isotope selected from the group consisting of carbon-13, carbon-14, nitrogen-15 and oxygen-18. 9. The method of claim 1, further comprising the step of analyzing a reference sample of said exhaled breath of the subject, said reference sample being obtained substantially before the drug is administered to the subject. 10. The method according to claim 7 wherein said isotope is nitrogen-15. 11. The method according to claim 10 wherein the analyzing step comprises using a measuring instrument selected from the group consisting of an infrared spectrometer and a mass spectrometer. 12. The method according to claim 10 wherein the metabolism characteristic is related to the amount of carbon dioxide labeled with said isotope. 13. The method according to claim 10 wherein said isotope is selected from the group consisting of carbon-13, carbon-14 and oxygen-18. 14. The method according to claim 10 wherein the metabolism characteristic is related to the amount of ammonia labeled with said isotope. 15. The method according to claim 14 wherein said isotope is nitrogen-15. 16. The method according to claim 10 wherein the metabolism characteristic is related to the amount of a substantially unchanged form of the drug labeled with said isotope. 17. The method according to claim 14 wherein said isotope is nitrogen-15. 18. The method according to claim 10 wherein the step of analyzing also comprises analysis of a reference sample of the exhaled breath of the subject, said reference sample being taken prior to the step of administration of the drug. 19. A method for measuring a rate of metabolism of a drug of therapeutic value to a subject and determining a therapeutically effective dosages of said drug for said subject, comprising: (a) administering said drug labeled with an isotope to said subject, such that said drug is an administered drug; (b) analyzing exhaled breath of the subject for a concentration of said isotope, said concentration of said isotope directly indicating the rate of metabolism of the administered drug in said subject and (c) employing said rate of metabolism to determine a therapeutically effective dosage of said drug for said subject. 20. The method according to claim 19 wherein the analyzing step comprises using a measuring instrument selected from the group consisting of an infrared spectrometer and a mass spectrometer. 21. The method according to claim 19 wherein the rate of metabolism is related to the amount of carbon dioxide labeled with said isotope. 22. The method according to claim 19 wherein said isotope is selected from the group consisting of carbon-13, carbon-14 and oxygen-18. 23. The method according to claim 19 wherein the rate of metabolism is related to the amount of ammonia labeled with said isotope. 24. The method according to claim 23 wherein said isotope is nitrogen-15. 25. The method according to claim 19 wherein the rate of metabolism is related to the amount of a substantially unchanged form of the drug labeled with said isotope. 26. The method according to claim 25 wherein said isotope is selected from the group consisting of carbon-13, carbon-14, nitrogen-15 and oxygen-18. 27. The method according to claim 19 wherein the step of analyzing also comprises analysis of a reference sample of the exhaled breath of the subject. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD AND BACKGROUND OF THE INVENTION The present invention relates to a breath test for the detection of a drug metabolite and, more particularly, to a breath test which can be used to analyze the rate of metabolism of a drug. Drugs can be broadly defined to include any chemical agent which affects living processes. Generally, however, the term "drug" is used to refer to any chemical agent with therapeutic effects. By "therapeutic effects", it is meant that the chemical agent is useful in the prevention, diagnosis and/or treatment of disease. Hereinafter, unless otherwise stated, the term "drug" will be taken to be any chemical agent with therapeutic effects. Increasing knowledge about human physiology and disease has brought an exponentially increasing number of new drugs onto the market. These new drugs provide more effective treatments for many diseases, such as cancer, AIDS and bacterial infections which are resistant to formerly effective medications. However, these new drugs themselves can cause mild to severe side effects and even idiopathic disease, which is a disease state caused by the drug itself. These undesirable and even dangerous reactions are directly related to the concentration of the drug in the body. The concentration of the drug in the body, in turn, is regulated both by the amount of drug ingested by the subject over a given time period, or the dosing regimen, and the rate at which the drug is eliminated from the body. Hereinafter, the term "subject" refers to a human or lower animal to whom the drug is administered. The drug can be eliminated in two different ways, depending upon the molecular structure of the individual drug. First, the drug can be chemically modified into an inactive component or components which are then excreted. Second, the drug can be excreted from the body in a substantially unaltered form. Hereinafter, the term "elimination" of the drug is defined as the excretion or the chemical modification of the drug. Chemical modification of the drug is a common pathway for elimination of the drug. Such modification most frequently occurs in the liver, although it can also take place in the blood, the kidney and other tissues. Modification can be classified as either synthetic or nonsynthetic [L. S. Goodman and A. Gilman, eds, The Pharmaceutical Basis of Therapeutics, The Macmillan Company, 1970, p.11]. Nonsynthetic modification involves such chemical reactions as oxidation or hydrolysis, often resulting in the cleavage of the drug molecule into two or more inactive molecules. Synthetic modification results in the formation of a chemical bond between the drug and an endogenous substrate such as a carbohydrate or amino acid. In either case, the modified drug can be referred to as a "metabolite" and the process of modification as "metabolism". Identifying the type of metabolism which a particular drug will undergo in the body is further complicated by a number of factors. First, many drugs will be subject to a number of metabolic pathways within the body; that is, they will be able to undergo several different types of chemical modification. Second, although the choice of pathway or pathways is at least partly dependent upon the structure of the drug, predicting which pathway or pathways will be used is very difficult, and must usually be done through experimentation. Third, the particular metabolic pathway used will also depend upon the physiology of the individual subject. For example, a subject with hepatic dysfunction may eliminate a drug very differently from a subject with normal liver function. Fourth, the presence of other chemicals within the body can also change the metabolic pathway used by a particular drug. This can result in particularly dangerous side effects in those subjects taking multiple drugs simultaneously, or even in subjects ingesting non-therapeutic substances such as nicotine, since one drug can in effect overwhelm the capacity of a particular pathway, preventing other drugs from being properly modified. Of course, all of these factors also affect the rate at which at a particular drug is eliminated or "cleared" from the body. Thus, the particular type of chemical modification, and the rate at which this modification occurs, depends upon both the structure of the drug itself, and upon factors within the individual subject to whom the drug is administered. When a new drug is undergoing clinical trials, both the rate at which the drug is eliminated from the subject and the type of metabolite(s) formed are determined. The rate of elimination will of course vary from subject to subject, so the drug must be tested in many individuals to produce an average elimination rate. Preferably, of course, many different groups of individuals will be tested, since children eliminate drugs more slowly than adults, for example, even when the dosage is given by body weight. The type of metabolite(s) formed must also be determined to indicate which pathway or pathways will be used. For example, if the drug is largely eliminated by the liver, a lower dosing regimen may be required for subjects with hepatic dysfunction. Thus, dosing regimens, or the rate and amount of drug which should be administered to a subject, can be determined from this information. These dosing regimens have one major drawback, however: they are not tailored to the individual. At best, different regimens may be proposed for large groups of individuals, but even that is not always done. Thus, the geriatric patient with hepatic dysfunction, who is taking multiple drugs and who may have a low body weight, could potentially be given the same amount of a drug at the same rate as a young adult. Such a situation can be particularly dangerous for hospitalized patients, who frequently have both major organ dysfunctions and require multiple drug therapy. "Therapeutic drug monitoring" is already used in order to adjust dosing regiments for individual patients in certain cases. In therapeutic drug monitoring, the concentration of a drug is measured in the blood of a patient, generally either just after the administration of a dose or just before the administration of the next dose [A. Goodman Gilman et al., eds, Goodman and Gilman's The Pharmacological Basis of Therapeutics, Pergamon Press, 1991, p. 30-31]. Usually, the concentration of a drug is measured just before the administration of the next dose, in order to determine the rate at which the drug is being cleared from the body. The concentration of the drug is measured just after the administration of a dose if the drug is almost completely eliminated between doses. Of course, if the concentration of the drug is measured more than once, the rate of clearance from the body can be more accurately determined. Examples of drugs for which therapeutic drug monitoring is used include cyclosporine, which is an immunosuppressive agent [A. Lindholm and J. Sawe, Therapeutic Drug Monitoring, 17:570-3, 1995]. Indeed, A. Lindholm and J. Sawe specifically state that successful immunosuppression depends upon the tailoring of individual dosing regimens. In these cases, it would clearly be highly useful to have a test which is simple, rapid, reliable and non-invasive and which could allow medical professionals to easily tailor the dosing regimen for the particular patient. Unfortunately, currently available tests are invasive, difficult to administer or require an extended period of time for analysis. For example, therapeutic drug monitoring currently requires the analysis of a blood sample. Such a test is both invasive and complex, requires a laboratory to perform the analysis and requires an extended time period for analysis. Furthermore, such a test cannot be done in the home of a patient and, if performed in a doctor's office, often requires even more time for the sample to be sent away to a laboratory. Finally, such a test is difficult to perform many times on the same patient, due to the invasive nature of the sampling mechanism, and to the delay between the time the sample is obtained and the time it is analyzed. Another possible method to determine the proper dosing regimen for an individual is to analyze the rate of metabolism of the drug in that individual by measuring the concentration of a metabolite. Metabolites can be detected when excreted in urine, for example. The concentration of these metabolites in at least one, and preferably in repeated samples would allow the rate of metabolism to be measured. However, although urine is relatively easy to collect, a laboratory is still required for analysis. Furthermore, such an analysis may require an extended period of time. Finally, the increased accuracy obtained with repeated samples makes many of these tests impractical. Unless the patient is in a hospital, collecting repeated samples and bringing them to the doctor's office or clinic is time-consuming and unlikely to result in patient compliance. U.S. Pat. No. 5,100,779 to Watkins (hereinafter referred to as "Watkins") discloses a breath test in which a radiolabelled "reference drug", erythromycin, which is known to be metabolized by cytochrome p-450 is administered to a subject and the concentration of radiolabelled carbon dioxide in the exhaled breath of the patient is then measured in order to determine cytochrome p-450 activity. This activity is then correlated to the rate of metabolism of other drugs by using additional factors such as the age of the subject. However, such a test is necessarily restricted to those drugs whose metabolism can be directly correlated to the measured cytochrome p-450 activity on erythromycin. Furthermore, if multiple drugs are being administered to one patient, or even if the patient is ingesting non-therapeutic substances such as nicotine, the metabolic behavior of any one drug can be strongly affected, as noted above. In that case, the metabolism of a drug relative to the "reference drug" could be difficult to predict. It would be much more useful to have a breath test which can directly measure the rate of metabolism of each drug individually, rather than relying upon the predictive value of results obtained with a reference drug. There is thus a widely recognized need for, and it would be highly advantageous to have, a test for the rate of drug metabolism which is easy, reliable, rapid, substantially non-invasive and sensitive, and which could more easily be used for multiple measurements. SUMMARY OF THE INVENTION According to the present invention there is provided a method for measuring a characteristic of metabolism of a drug having a metabolite in a subject, including the steps of: (a) administering the drug to the subject; and (b) analyzing exhaled breath of the subject for a concentration of the metabolite after a suitable time period, the concentration indicating the characteristic of metabolism of the drug in the subject. Preferably, the exhaled breath of the subject is analyzed by a measuring instrument selected from the group consisting of an infrared spectrometer and a mass spectrometer. Also preferably, the drug is isotopically-labelled. Most preferably, the metabolite is either carbon dioxide, most preferably carbon-13 isotopically-labelled, or ammonia, most preferably nitrogen-15 isotopically-labelled. Alternatively and preferably, the metabolite is a substantially unchanged form of the drug and is either nitrogen-15 isotopically-labelled or carbon-13 isotopically-labelled. The method also preferably includes the step of analyzing a reference sample of the exhaled breath of the subject, the reference sample being obtained substantially before the drug is administered to the subject. According to another embodiment, there is provided a breath test kit for determining the characteristic of metabolism of a drug in a subject, comprising an appropriately labelled drug having a metabolite for administering to the subject, the metabolite being present in exhaled breath of the subject. DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is of a breath test which can be used to determine the characteristic of metabolism of a drug in a subject. Specifically, the present invention can be used to determine this characteristic of metabolism by measuring the concentration of a metabolite in the exhaled breath of the subject after an appropriate amount of the drug has been administered to the subject. Hereinafter, the term "characteristic of metabolism" includes whether such metabolism occurs, the rate of metabolism and the extent of metabolism. However, for clarity the aforementioned and following descriptions specifically describe the measurement of the rate of metabolism. Breath tests as a non-invasive diagnostic tool are well known in the art. Generally, these tests involve the administration of a labelled substrate to the subject and the measurement of one or more cleavage products produced when the substrate is chemically cleaved. Such tests have been quite successfully used for the diagnosis of an infection by Helicobacter pylori and for the measurement of gastric emptying. For example, U.S. Pat. No. 4,830,010 to Marshall describes a method of detecting Helicobacter pylori by orally administering isotopically-labelled urea to a subject. Helicobacter pylori produces a large quantity of the enzyme urease, which hydrolyzes urea to form carbon dioxide and ammnonia. Either one or both of these hydrolysis products can have the isotopic label. At least one isotopically-labelled product is then exhaled by the subject and can be detected in the exhaled breath of the subject by an appropriate measuring instrument. Thus, the breath test for diagnosing Helicobacter pylori relies upon the use of a substrate specifically intended for diagnostic purposes and not for therapeutic effect. Other breath tests have been described to measure physiological processes such as the rate of gastric emptying. For example, gastric emptying rates were measured for solids and liquids by using [.sup.13 C]octanoate or [.sup.13 C]acetate, respectively, as the substrate [Duan, L.-P., Braden, B., Caspary, W. F. and B. Lembcke, Digestive Diseases and Sciences, 1995, 40:2200-2206]. The substrate was administered to the subject and the exhaled breath of the subject was measured with a mass spectrometer. Similarly to the breath test for diagnosing Helicobacter pylori, both substrates were specifically intended as diagnostic, rather than therapeutic, agents. As noted above, the present invention is of a breath test which can be used to determine the rate of metabolism of a drug in a subject. Thus, the breath test of the present invention is clearly different from these prior art tests, since the prior art tests use the isotopically-labelled substrate to measure the rate of a general physiological process, such as gastric emptying, while the breath test of the present invention uses an isotopically-labelled drug to measure the rate of metabolism of that drug. Furthermore, the breath test of the present invention is intended to be used with drugs of therapeutic value outside the breath test, while the substrates of prior art tests are not intended to have therapeutic value apart from their use in the tests themselves. Finally, the measurement of a physiological process is incidental to the breath test of the present invention, since as noted above, metabolism of a drug can incorporate many different physiological processes, all of which contribute to the measured rate of metabolism. Thus, the breath test of the present invention will not necessarily measure the rate of any one physiological process, and it is not necessary to identify a particular physiological process in order for the measurement of the rate of drug metabolism to be successful. The breath test of the present invention can be performed as follows. First, the drug is administered to the subject. Next, the exhaled breath of the subject is analyzed after a suitable time period for a concentration of a metabolite of the drug, the concentration indicating the rate of metabolism of the drug in the subject. To aid detection of the metabolite, the drug is preferably appropriately labelled, and most preferably isotopically-labelled. Hereinafter, the term "appropriately labelled" is defined as having a label which enables a metabolite of the drug to be detected in the exhaled breath of the subject. Such a breath test has a number of advantages over conventional methods for determining the concentration of a drug in the subject. Not only is a breath test non-invasive, it is also more rapid than analyzing blood samples and it can also be performed multiple times on the subject. |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
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