Toxicity of 1,25-dihydroxyvitamin D3, tacalcitol, and calcipotriol after topical treatment in rats.
To investigate and compare the effects on calcium metabolism of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the synthetic vitamin D analogs tacalcitol and calcipotriol after topical treatment, we treated groups of rats topically once daily with three dose levels of each test compound in a vehicle of propylene glycol plus ethanol for 28 d. The urinary calcium excretion was measured after 14 d, and serum calcium and parathyroid hormone were measured at termination. The rats were autopsied, and the kidneys were examined microscopically for mineralizations. Based on the urinary calcium excretion and the serum calcium level, calcipotriol was found to be 60 times less calcemic, and tacalcitol was slightly less calcemic, than 1,25(OH)2D3 after repeated topical application to rats. Serum parathyroid hormone was suppressed to a lower degree by calcipotriol and tacalcitol than by 1,25(OH)2D3, and the incidence and severity of renal corticomedullary mineralization were higher in rats treated with 1,25(OH)2D3 and tacalcitol than with calcipotriol. We conclude that calcipotriol is much less calcemic than 1,25(OH)2D3 or tacalcitol when applied topically to rats in a vehicle that enhances penetration into the skin. We attribute the lower calcemic effect of calcipotriol to the pharmacokinetic profile of the compound, particularly its rapid metabolization into inactive compounds.
Mortensen
J T
JT
Biological Research and Development, Leo Pharmaceutical Products, Ballerup, Denmark.
Lichtenberg
J
J
Binderup
L
L
D000287:Administration, Topical; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D004100:Dihydroxycholecalciferols / Q000633:toxicity*; D005260:Female; D051379:Mice; D010281:Parathyroid Hormone / Q000097:blood; D051381:Rats; D011917:Rats, Inbred Lew
D004100:Dihydroxycholecalciferols; D010281:Parathyroid Hormone; C055085:calcipotriene; C023850:1 alpha,24-dihydroxyvitamin D3; D002117:Calcitriol; D002118:Calcium