Vitamin D levels in humans depend on two sources: (1) exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol in the skin to vitamin D₃ (cholecalcif-erol) and (2) dietary intake of either vitamin D₂ (ergocalciferol) or vitamin D₃. Vitamin D₂ and vitamin D₃ must be metabolically activated in the liver and the kidney before becoming fully active on target tissues. The initial step in the activation process is the introduction of a hydroxyl group in the side chain at C-25 by the hepatic enzyme, CYP 27 (a vitamin D-25-hydroxylase). The products of this reaction are 25-(OH)D₂ and 25-(OH)D₃, respectively. Further hydroxylation of these metabolites occurs in the mitochondria of kidney tissue, catalyzed by renal 25-hydroxyvitamin D-1-a-hydroxylase to produce 1a,25-(OH)₂D₂, the primary biologically active form of vitamin D₂, and 1a,25-(OH)₂D₃ (calcitriol), the biologically active form of vitamin D₃.

Calcitriol (1a,25-(OH)₂D₃) and 1a,25-(OH)₂D₂ regulate blood calcium at levels required for essential body functions. Specifically, the biologically active vitamin D metabolites control the intestinal absorption of dietary calcium, the tubular reabsorption of calcium by the kidney and, in conjunction with parathyroid hormone (PTH), the mobilization of calcium from the skeleton. They act directly on bone cells (osteoblasts) to stimulate skeletal growth, and on the parathyroid glands to suppress PTH synthesis and secretion. These functions are mediated by the interaction of these biologically active metabolites with specific receptor proteins in the various target tissues. In patients with chronic kidney disease (CKD), deficient production of biologically active vitamin D metabolites (due to lack of or insufficient 25-hydroxyvitamin D-1-alpha-hydroxylase activity) leads to secondary hyper-parathyroidism, which contributes to the development of metabolic bone disease.

Doxercalciferol is absorbed from the gastrointestinal tract and activated by CYP 27 in the liver to form 1a,25-(OH)₂D₂ (major metabolite) and 1a,24-dihydroxyvitamin D₂ (minor metabolite). Activation of doxercalciferol does not require the involvement of the kidneys. In healthy volunteers, peak blood levels of 1a,25-(OH)₂D₂, the major metabolite of dox-ercalciferol, are attained at 11-12 hours after repeated oral doses of 5 to 15 mcg of Hectorol^Ò and the mean elimination half-life of 1a,25-(OH)₂D₂ is approximately 32 to 37 hours with a range of up to 96 hours. The mean elimination half-life in patients with end-stage renal disease (ESRD) on dialysis appears to be similar. Hemodialysis causes a temporary increase in 1a,25-(OH)₂D₂ mean concentrations, presumably due to volume contraction. 1a,25-(OH)₂D₂ is not removed from blood during hemodialysis.

Brand Name: Hectorol
Generic Name: Doxercalciferol

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