Knutson J C, Hollis B W, LeVan L W, Valliere C, Gould K G, Bishop C W
Bone Care International, Inc., Madison, Wisconsin 53713, USA.
Endocrinology. 1995 Nov;136(11):4749-53. doi: 10.1210/endo.136.11.7588202.
The vitamin D analog 1 alpha-hydroxyvitamin D2 (1 alpha-OHD2) is under development for the treatment of secondary hyperparathyroidism and metabolic bone disease. This analog is metabolized in vivo to the natural active dihydroxylated metabolite of vitamin D2, 1 alpha,25-dihydroxyvitamin D2 [1 alpha,25-(OH)2D2]. To study the metabolism of this analog, an assay involving HPLC separation and purification of metabolites followed by RRA with the vitamin D receptor was developed to quantitate the active metabolites of the analog and the endogenous active metabolite of vitamin D3, 1 alpha,25-(OH)2D3, from the same blood sample. This assay was used to determine blood levels of active dihydroxylated vitamin D compounds in rats and monkeys treated with oral 1 alpha-OHD2. As the circulating 1 alpha,25-(OH)2D2 level increased dose dependently in these rats and monkeys, a concomitant decrease in the endogenous 1 alpha,25-(OH)2D3 was observed. In rats orally administered more than 2.5 micrograms 1 alpha-OHD2/kg.day, a second active metabolite of 1 alpha-OHD2, 1 alpha,24-(OH)2D2, was detected in concentrations similar to those of 1 alpha,25-(OH)2D2. These results indicate that the regulatory control of endogenous vitamin D metabolism as well as analog metabolism must be considered when assessing the therapeutic potential of a vitamin D analog.
维生素D类似物1α-羟基维生素D2（1α-OHD2）正在研发用于治疗继发性甲状旁腺功能亢进和代谢性骨病。这种类似物在体内代谢为维生素D2的天然活性二羟基化代谢产物1α,25-二羟基维生素D2 [1α,25-(OH)2D2]。为了研究这种类似物的代谢，开发了一种分析方法，该方法包括通过高效液相色谱法分离和纯化代谢产物，然后用维生素D受体进行放射受体分析，以从同一血样中定量该类似物的活性代谢产物和维生素D3的内源性活性代谢产物1α,25-(OH)2D3。该分析方法用于测定口服1α-OHD2治疗的大鼠和猴子体内活性二羟基化维生素D化合物的血药浓度。随着这些大鼠和猴子体内循环的1α,25-(OH)2D2水平呈剂量依赖性增加，观察到内源性1α,25-(OH)2D3随之降低。在口服剂量超过2.5微克1α-OHD2/千克·天的大鼠中，检测到1α-OHD2的第二种活性代谢产物1α,24-(OH)2D2，其浓度与1α,25-(OH)2D2相似。这些结果表明，在评估维生素D类似物的治疗潜力时，必须考虑内源性维生素D代谢以及类似物代谢的调节控制。
