Methods for Diagnosis and Intervention of Hepatic Disorders

• US 20100055734A1
• Filed: 09/11/2009
• Published: 03/04/2010
• Est. Priority Date: 01/26/2005
• Status: Active Grant

• Current Assignee: The Board of Regents of the University of Colorado (University of Colorado System), University of Colorado System
• Original Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Everson, Gregory Thomas
• Granted Patent: US 8,778,299 B2
• Time in Patent Office: Days
• US Class Current: 435/29
• CPC Class Codes: G01N 2800/08 Hepato-biliairy disorders other than hepatitis
• CPC Class Codes: G01N 2800/085 Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
• CPC Class Codes: G01N 33/49 Blood chemical methods for determining blood cell populations G01N33/5094; chemical analysis of blood groups or blood types G01N33/80
• CPC Class Codes: G01N 33/497 of gaseous biological material, e.g. breath
• CPC Class Codes: G01N 33/5308 for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743

Abstract

The disclosure provides a method for quantification of hepatic function in a subject comprising measuring the clearance of an orally administered isotopically labeled cholic acid in a subject with, or suspected of having or developing, a hepatic disorder, for example, chronic hepatitis C. The disclosure further provides methods and kits for assessment of hepatic function.

Claims

1. A method for assessment of hepatic function in a subject, the method comprising:

administering orally an isotopically labeled cholic acid to a subject with, or suspected of having or developing, a hepatic disorder, wherein no additional cholic acid compound is intravenously co-administered;

collecting samples from the subject over intervals for a period of less than 3 hours after administration of the agents to the subject; and

measuring the clearance of the orally administered isotopically labeled cholic acid as an indicator of hepatic function in the subject.

2. The method of claim 1 wherein the isotopically labeled cholate is selected from 24-¹³C cholic acid and 2,2,4,4-²H cholic acid.

3. The method of claim 1, wherein the samples collected over an interval period of time comprise blood or serum samples.

4. The method of claim 1, wherein collecting samples over an interval period of time comprises collecting samples over a period of about 90 minutes or less.

5. The method of claim 4, wherein the samples comprise blood samples collected from the subject at 5, 20, 45, 60 and 90 minutes post-administration.

6. The method of claim 1 wherein the measuring step comprises quantifying the isotopically labeled cholic acid in the samples by GC-MS or HPLC-MS.

7. The method of claim 1, further comprising at least one additional hepatic assessment test.

8. The method of claim 7, wherein the at least one additional hepatic assessment test is selected from the group consisting of clearance or metabolism of aminopyrine, clearance or metabolism of aminopyrine, clearance or metabolism of antipyrine, clearance or metabolism of bile acids other than cholate, clearance or metabolism of caffeine, clearance of or metabolism erythromycin, clearance or metabolism of nitroglycerin, clearance of or metabolism galactose, clearance or metabolism of indocyanine green, clearance or metabolism of lidocaine, clearance or metabolism of midazolam, clearance or metabolism of omeprazole, clearance or metabolism of dextromethorphan, clearance or metabolism of phenacetin, clearance or metabolism of methacetin, liver-spleen scan, serum bilirubin analysis, alanine aminotransferase analysis, aspartate aminotransferase analysis, and alkaline phosphatase analysis.

9. The method of claim 8 wherein the at least one additional hepatic assessment test is a multi-isotope test.

10. The method of claim 7, wherein the additional hepatic assessment test is a quantitative liver function test (QLFT).

11. The method of claim 10, wherein the quantitative liver function test (QLFT) is selected from a hepatic metabolic function test, a hepatic blood flow test or combination thereof.

12. The method of claim 11, wherein the hepatic metabolic function test is a multi-isotope caffeine test.

13. The method of claim 12, wherein the multi-isotope caffeine test comprises administering distinguishable caffeine solutions orally, intravenously or in combination thereof.

14. The method of claim 13, wherein the administering step comprises administering three distinguishable caffeine solutions to a subject at different time intervals.

15. The method of claim 14, wherein a single sample is obtained sometime after administration of the distinguishable caffeine solutions to assess the hepatic condition of the subject.

16. The method of claim 1 wherein the clearance of the isotopically labeled cholic acid is used as an indication of a need for at least one therapeutic treatment of the subject with a hepatic disorder.

17. The method of claim 16, wherein the at least one therapeutic treatment comprises an antiviral therapy.

18. The method of claim 17, wherein the hepatic disorder comprises chronic hepatitis C.

19. The method of claim 1 wherein the clearance of the isotopically labeled cholic acid is used for assessment of the progression of at least one hepatic condition in a subject.

20. A method for assessment of the progression of at least one hepatic condition in a subject, the method comprising:

administering orally a first distinguishable isotopically labeled cholic acid to a subject having, or suspected of having or developing, a hepatic disorder;

co-administering intravenously a second distinguishable isotopically labeled cholic acid to the subject;

collecting blood or serum samples over intervals for a period of less than 3 hours after administration of the agents to the subject;

quantifying the first and the second isotopically labeled cholic acids in the samples by HPLC-MS; and

calculating the cholate shunt using the formula;

AUCoral/AUCiv×

Doseiv/Doseoral×

100%;

wherein AUCoral is the area under the curve of the serum concentrations of the first cholic acid and AUCiv is the area under the curve of the second cholic acid; and

wherein the cholate shunt is an indicator of the progression of at least one hepatic disorder of the subject.

21. The method of claim 20 wherein the orally administering of the first labeled cholic acid and the intravenously co-administering of the second labeled cholic acid are performed simultaneously.

22. The method of claim 21, wherein the collecting step comprises collecting samples over a period of about 90 minutes or less.

23. The method of claim 22, wherein the samples comprise blood or serum samples collected from the subject at 5, 20, 45, 60 and 90 minutes post-dose.

24. The method of claim 21 wherein the cholate shunt is an indicator of a need for at least one therapeutic treatment of the subject with a hepatic disorder.

25. The method of claim 24, wherein the at least one therapeutic treatment comprises an antiviral therapy.

26. The method of claim 25, wherein the hepatic disorder comprises chronic hepatitis C.

27. The method of claim 21, further comprising at least one additional hepatic assessment test.

28. The method of claim 27, wherein the at least one additional hepatic assessment test is selected from the group consisting of clearance or metabolism of aminopyrine, clearance or metabolism of aminopyrine, clearance or metabolism of antipyrine, clearance or metabolism of bile acids other than cholate, clearance or metabolism of caffeine, clearance of or metabolism erythromycin, clearance or metabolism of nitroglycerin, clearance of or metabolism galactose, clearance or metabolism of indocyanine green, clearance or metabolism of lidocaine, clearance or metabolism of midazolam, clearance or metabolism of omeprazole, clearance or metabolism of dextromethorphan, clearance or metabolism of phenacetin, clearance or metabolism of methacetin, liver-spleen scan, serum bilirubin analysis, alanine aminotransferase analysis, aspartate aminotransferase analysis, and alkaline phosphatase analysis.

29. The method of claim 25, wherein the additional hepatic assessment test is a quantitative liver function test (QLFT).

30. The method of claim 29, wherein the quantitative liver function test (QLFT) comprises a hepatic metabolic function test, a hepatic blood flow test or combination thereof.

31. A kit of components for determining one or both of cholate clearance and cholate shunt in a subject with, or suspected of having or developing, a hepatic disorder;

the kit comprising

a first component comprising one or more vials, each vial comprising a single oral dose of a first distinguishable cholate compound; and

a second component comprising one or more vials, each vial comprising a single intravenous dose of a second distinguishable cholate compound.

32. The kit of claim 31, further comprising

a third component comprising one or more vials, each vial comprising a quantity of human serum albumin for mixing with a single intravenous dose of the second distinguishable cholate compound prior to intravenous administration.

33. The kit of claim 32, further comprising

one or more sets of labeled sterile blood-serum sample collection tubes.

34. The kit of claim 33, further comprising

one or more sets of labeled transport vials, each transport vial containing an internal cholic acid standard.

35. The kit of claim 34, further comprising

a single box for both

shipping the vials to a health care practitioner and

shipping the samples from the health care practitioner to a reference lab for analysis.

36. The kit of claim 31, wherein the first distinguishable cholate compound is 2,2,4,4-²H cholic acid and the second distinguishable agent is 24-¹³C cholic acid.

37. The kit of claim 36, wherein the ²H-cholic acid is in a powder form or in a solution form.