METABOLISM OF 1-ALPHA-HYDROXYVITAMIN D-2 TO ACTIVATED DIHYDROXYVITAMIN D-2 METABOLITES DECREASES ENDOGENOUS 1-ALPHA-25-DIHYDROXYVITAMIN D-3IN RATS AND MONKEYS

The vitamin D analog 1 alpha-hydroxyvitamin D-2 (1 alpha-OHD2) is unde r development for the treatment of secondary hyperparathyroidism and m etabolic bone disease. This analog is metabolized in vivo to the natur al active dihydroxylated metabolite of vitamin D-2, 1 alpha,25-dihydro xyvitamin D-2 [1 alpha,25-(OH)(2)D-2]. To study the metabolism of this analog, an assay involving HPLC separation and purification of metabo lites followed by RRA with the vitamin D receptor was developed to qua ntitate the active metabolites of the analog and the endogenous active metabolite of vitamin D-3, 1 alpha,25-(OH)(2)D-3, from the same blood sample. This assay was used to determine blood levels of active dihyd roxylated vitamin D compounds in rats and monkeys treated with oral 1 alpha-OHD2. As the circulating 1 alpha,25-(OH)(2)D-2 level increased d ose dependently in these rats and monkeys, a concomitant decrease in t he endogenous 1 alpha,25-(OH)(2)D-3 was observed. In rats orally admin istered more than 2.5 mu g 1 alpha-OHD2/kg . day, a second active meta bolite of 1 alpha-OHD2, 1 alpha,24-(OH)(2)D-2, was detected in concent rations similar to those of 1 alpha,25-(OH)(2)D-2. These results indic ate that the regulatory control of endogenous vitamin D metabolism as well as analog metabolism must be considered when assessing the therap eutic potential of a vitamin D analog.