Comparative effects of doxercalciferol (1α-hydroxyvitamin D₂) versus calcitriol (1α,25-dihydroxyvitamin D₃) on the expression of transporters and enzymes in the rat in vivo

Effects of 1.28 nmol/kg doxercalciferol [1 alpha(OH)D(2)], a synthetic vitamin D(2) analog that undergoes metabolic activation to 1 alpha,25-dihydroxyvitamin D(2), the naturally occurring, biologically active form of vitamin D(2), on rat transporters and enzymes were compared with those of 1 alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3), active form of vitamin D(3); 4.8 and 6.4 nmol/kg] given on alternate days intraperitoneally for 8 days. Changes were mostly confined to the intestine and kidney where the vitamin D receptor (VDR) was highly expressed: increased intestinal Cyp24 and Cyp3a1 messenger RNA (mRNA) and a modest elevation of apical sodium-dependent bile salt transporter (Asbt) and P-glycoprotein (P-gp) protein; increased renal VDR, Cyp24, Cyp3a9, Mdr1a, and Asbt mRNA, as well as Asbt and P-gp protein expression; and decreased renal PepT1 and Oat1 mRNA expression. In comparison, 1 alpha(OH)D(2) treatment exerted a greater effect than 1,25(OH)(2)D(3) on Cyp3a and Cyp24 mRNA. However, the farnesoid X receptor -related repressive effects on liver Cyp7a1 were absent because intestinal Asbt, FGF15 and portal bile acid concentrations were unchanged. Rats on the alternate day regimen showed milder changes and lessened signs of hypercalcemia and weight loss compared with rats receiving daily injections (similar or greater amounts of 0.64-2.56 nmol/kg daily x4) described in previous reports, showing that the protracted pretreatment regimen was associated with milder inductive and lesser toxic effects in vivo. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100: 1594-1604, 2011