PROPIONIC ACID IS A KEY INTERMEDIATE IN A VARIETY OF HUMAN METABOLIC PATHWAYS INCLUDING CATABOLISM OF THE AMINO ACIDS ISOLEUCINE, VALINE, METHIONINE AND THREONINE DERIVED FROM A PROTEIN.

PROPIONIC ACID IS A KEY INTERMEDIATE IN A VARIETY OF HUMAN METABOLIC PATHWAYS INCLUDING CATABOLISM OF THE AMINO ACIDS ISOLEUCINE, VALINE, METHIONINE AND THREONINE DERIVED FROM A PROTEIN. A NUMBER OF INHERITED METABOLIC DISORDERS (ORPHAN DISEASES), AS WELL AS NUTRITIONAL DEFICIENCIES OF VITAMINS IN A BROAD SPECTRUM OF DISEASE STATES, AFFECT PROPIONATE METABOLISM. THUS A SIMPLE DIAGNOSTIC TEST FOR DEFICIENCY OXIDATION OF 1-(13)C-PROPIONIC ACID, ADMINISTERED ORALLY, WOULD HAVE CONSIDERABLE UTILITY IN THE NON-INVASIVE DIAGNOSIS AND MANAGEMENT OF A SIGNIFICANT NUMBER OF PATIENTSWITH ORGANIC ACIDEMIAS, BIOTIN DEFICIENCIES (SECONDARY TO TOTAL PARENTERAL NUTRITION), B(12) DEFICIENCIES AND ANEMIA. THE PROPOSED PHASE I PROGRAM (UNDER TOPIC 4, NIADDK SOLICITATION) WILL BE DIRECTED TOWARDS ESTABLISHING A MASTERDRUG FILE FOR 1-(13)C-PROPIONATE AND PREPARING A STUDY PROTOCOL FOR SUBMISSION TO THE FDA AS PART OF A NOTICE FOR AN INVESTIGATONAL NEW DRUG. EMPHASIS WILL BE PLACED ON THE METHODS FOR BREATH ANALYSIS AND ON DATA REDUCTION PROCEDURES(TEST SCORING) IN THE INTERPRETATION OF INTERINDIVIDUAL DIFFERENCES IN THE CONVERSION OF 1-(13)C-PROPIONATE INTO (13)CO(2). THE OVERALL OBJECTIVE WILL BE TO COMPARE THE FRACTIONAL EXCRETION RATE CONSTANTS, PEAK EXCRETION RATE ANDCUMULATIVE EXCRETION AT VARIOUS TIME INTERVALS AFTER TRACER ADMINISTRATION AS A FUNCTION OF DIFFERENT ORAL DOSES IN NORMAL CONTROLS AND IN PATIENTS WITH DISEASES AFFECTING PROPIONATE METABOLISM BOTH BEFORE AND AFTER NUTRITIONAL THERAPY. THE CLINICAL STUDIES IN WHICH THE BREATH TESTS METHOD IS TO BE VALIDATED ARE ALREADY UNDERWAY AS PART OF ANIRB APPROVED STUDY AT THE PEDIATRICS DEPARTMENT AT THE UNIVERSITY OF CALIFORNIA AT SAN DIEGO SO THAT BREATH TEST RESULTS OBTAINED IN THIS STUDY CAN BE PLACED INTO PERSPECTIVE WITH REGARD TO THE TOTAL CLINICAL PICTURE, INCLUDING THE RESULTS OF IN-VITRO CLINICAL CHEMISTRY TESTS FOR PROPIONATE METABOLISM. THUS, THE PHASE I PROGRAM CAN BESUMMARIZED AS AN EFFORT TO DEVELOP A UTILIZATION PROTOCOL AND A TEST SCORING ALGORITHM FOR (13)C-PROPIONATE METABOLISMIN ORDER TO DIFFERENTIATE WITH HIGH SENSITIVITY AND SPECIFICITY BETWEEN NORMALS AND PATIENTS WITH DISORDERS OF PROPIONATE METABOLISM.