COMPARISON OF EFFECTS OF 1-ALPHA-HYDROXY-VITAMIN-D3 AND 1,25-DIHYDROXY-VITAMIN-D3 IN MAN

The effects of short-term treatment with 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] or 1.alpha.-hydroxy-vitamin D3 [1.alpha.(OH)D3] on intestinal absorption of 47Ca were compared in 41 experiments in normals and 72 experiments in patients with chronic renal failure. Eleven patients were studied a 2nd time after treatment for 2-5 mo. Doses varied from 0.14-5.4 .mu.g/day to establish dose-response relationships. Urinary Ca was monitored in normal subjects, 9 of whom received a constant Ca intake on a metabolic unit. There was an increase in intestinal absorption of 47Ca and urinary Ca in normals receiving 1,25(OH)2D3, 0.14 .mu.g/day or greater, and 0.28 .mu.g/day or greater augmented intestinal absorption of 47Ca in chronic renal failure. In contrast, 2.6 .mu.g/day of 1.alpha.(OH)D3 was required to increase intestinal absorption of 47Ca in both groups. The increase in urinary Ca to maximal levels was delayed during treatment with 1.alpha.(OH)D3, 5-10 days vs. 2-5 days with 1,25(OH)2D3. Half-times for urinary Ca to decrease to pretreatment levels after stopping treatment were greater after 1.alpha.-(OH)D3 (1.5-2.7 days) than 1,25(OH)2D3 (1.1-2.0 days). With long-term administration there was a progressive increase in intestinal absorption of 47Ca in patients receiving 1.alpha.(OH)D3; this was not observed with 1,25(OH)2D3. Pharmacologic differences between 1.alpha.(OH)D3 and 1,25(OH)2D3 may be explained by the requirement for 25-hydroxylation of 1.alpha.(OH)D3 before biologic effects occur; at low doses (< 1 .mu.g/day), 1.alpha.(OH)D3 competes with vitamin D3 for 25-hydroxylation. With prolonged treatment or larger doses (> 2 .mu.g/day), 1.alpha.(OH)D3 could accumulate and then be hydroxylated resulting in production of higher levels of 1,25(OH)2D3.