Labeled vitamin D compounds and the use thereof

Details Labeled vitamin D compounds and the use thereof Labeled vitamin D compounds and the use thereof

1998-06-10

1999-11-09

Dees, Jose' G.

Organic compounds -- part of the class 532-570 series

Organic compounds

9,10-seco-cyclopentanohydrophenanthrene ring system or...

514168, 544237, 5483037, 5483351, 549227, 549265, 549510, 549511, 552 653, 206569, 424 91, 424 92, 424 96, A61K 3159, C07D23354, C07D23356, C07C40100

Patent

active

059817798

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This application claims benefit of provisional application 60/009,432 filed Dec. 29, 1995.
1. Field of the Invention
The present invention relates to non-radioactive vitamin D compounds and methods to assay for the presence of vitamin D, vitamin D analogs and their metabolites which may be present in milk, blood or other biological fluids. The assay methods employed in this invention may be enzyme linked immunoassays (ELISAs) (with biotin containing compounds) and fluorimetric and chemiluminometric assays (with fluorescein or chemiluminiscence containing compounds).
2. Related Art
It is well-established that cutaneously synthesized vitamin D.sub.3, a seco-steroid, undergoes sequential metabolic conversions to 25-hydroxyvitamin D.sub.3 (25-OH-D.sub.3) in the liver and to 1,25(OH).sub.2 D.sub.3 in the kidney. 1,25(OH).sub.2 D.sub.3, the dihydroxylated metabolite of vitamin D.sub.3, is the most active form of vitamin D hormone which is intimately involved in calcium and phosphorous homeostasis (Holick, M. F. (1989), "Vitamin D: biosynthesis, metabolism and mode of action." In Endocrinology, vol. 2, Degroot et al. (eds.), Saunders, W. B., Philadelphia, pp. 902-926). In addition to vitamin D.sub.3 (synthesized in the skin), another chemical form of vitamin D.sub.3, called vitamin D.sub.2, exists in nature. Vitamin D.sub.2 is metabolized to 25-hydroxyvitamin D.sub.2 (25-(OH).sub.2 -D) and 1,25(OH).sub.2 D.sub.2 in a manner similar to vitamin D.sub.3. Vitamin D.sub.2 is obtained primarily from diet and vitamin D supplementation, and can be as little as 5-10%, or as high as 100% of the circulating concentration of 25-OH-D depending on the relative amounts of vitamin D.sub.2 present in the diet and cutaneously-produced vitamin D.sub.3 by exposure to sunlight (Holick, M. F. et aL (1986) "Calcium, phosphorus and bone metabolism: calcium regulating hormones," in Harrison's Principles of Internal Medicine, 13th Ed., Braunwald et al. (eds.), McGraw-Hill, N.Y., pp. 2137-2151). In the following discussion, it may be assumed that vitamin D, 25-OH-D and 1,25(OH).sub.2 D will represent the total pool of vitamin D and its metabolites, unless otherwise mentioned.
Biosynthesis of 25-OH-D and 1,25(OH).sub.2 D and their metabolism are regulated by the factors that control mineral and skeletal metabolism (Holick, M. F. (1989)). As a result, the serum 1,25(OH).sub.2 D level is an important pathophysiological indicator in several diseases. For example, production of 1,25(OH).sub.2 D is strongly influenced by a number of diseases such as acquired or inherited disorders of vitamin D-metabolism, including renal osteodystrophy, certain metabolic bone diseases, sarcoidosis, hypercalcemia associated with chronic granulotomous disorders, and vitamin D-dependent rickets types I and II (Holick, M. F. et al. (1986)).
On the other hand, the circulating concentration of 25-OH-D is considered to be an important indicator of vitamin D status in man (Holick, M. F. (1989); Holick, M. F. et al. (1986)). For example, hypovitaminosis, which results from the insufficient endogenous production of vitamin D in the skin, and insufficient dietary supplementation, and/or inability of the small intestine to absorb adequate amounts of vitamin D from diet, results in hypocalcemia and hypophosphatemia and corresponding secondary hyperparathyroidism (Holick, M. F. et al. (1986)). Vitamin D-deficiency is best determined in a clinical setting by measuring 25-OH-D in blood. When the 25-OH-D concentration is below the low limit of the normal range, the patient is considered to be deficient in vitamin D. Hypovitaminosis D also results in disturbances in mineral metabolism (i.e., rickets and osteomalacia in children and adults, respectively).
Serum 25-OH-D-levels are also found to be lower than normal in intestinal malabsorption syndromes, liver disorders (chronic and acute), and nephrotic syndromes. In osteopenia in the aged, serum 25-OH-D levels are often found to be lower than normal. In cases of vitamin D intoxication, serum 25-OH-D le

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