CALCIPOTRIOL (MC-903) - PHARMACOKINETICS IN RATS AND BIOLOGICAL-ACTIVITIES OF METABOLITES - A COMPARATIVE-STUDY WITH 1,25(OH)2D3

Calcipotriol (MC 903) is a novel analogue of the physiologically active metabolite of vitamin D3, 1-alpha,25-dihydroxycholecalciferol [1,25(OH)2D3]. MC 903 and 1,25(OH)2D3 have similar effects on cell proliferation and cell differentiation in vitro using the human histiocytic lymphoma cell line U 937, but in vivo MC 903 has 100-200 times less effect on calcium metabolism. To elucidate this difference, the pharmacokinetic profiles after a single intravenous dose (50-mu-g/kg) of the two compounds to rats were compared. The area under the serum level/time curve (AUC) was more than 100 times higher for 1,25(OH)2D3 than for MC 903 and the rate of clearance was more than 100 times higher for MC 903 than for 1,25(OH)D3. Serum from MC 903 or 1,25(OH)2D3 dosed rats (i.v. 10-mu-g/kg) was investigated for biological activities by incubation of U 937 cells with serum collected 0-24 hr after drug administration. Serum from MC 903 dosed rats had an effect only when collected shortly after dosing, whereas serum from 1,25(OH)2D3 dosed rats had an effect when collected up to 4 hr after dosing. The biological effects on the U 937 cells of the two major metabolites of MC 903 (MC 1046 and MC 1080) were investigated. The metabolites had effects that were more than 100 times weaker than those of the parent compound. The effect of MC 903 on proliferative disorders, its fast elimination and the formation of inactive metabolites makes MC 903 suitable for topical treatment of psoriasis.