These same factors may have also caused the almost complete and sustained suppression of renal CYP27B1. Although, at the end of the treatment period, serum calcitriol returned to baseline levels, FGF23 remained elevated. We do not presently know the mechanism selleck chemical sustaining FGF23 levels; however, this would likely continue to suppress CYP27B1 expression and maintain CYP24A1 elevation. This FGF23 “memory” effect would be expected to have an impact on the efficacy of subsequent dosing, further supporting gradual repletion over bolus treatments. Previous studies have demonstrated that increased

expression of CYP24A1 in kidney and extra-renal target tissues is differentially regulated following increased calcitriol production [21], [22] and [23]. This differential regulation may depend on whether the target tissue in question can respond to FGF23 and whether FGF23

levels have been increased by vitamin D treatment. The observed PTH lowering in rats was equivalent at 24 h post-dose JQ1 manufacturer after both IV and MR dosing. However, we postulate that PTH suppression would not have been sustained for much longer after IV dosing because CYP24A1 was increased in both kidney and parathyroid gland, serum FGF23 was elevated and CYP27B1 was suppressed. This is supported by the greater and more sustained PTH suppression observed in CKD patients between 24 and 72 h after the 900 μg MR dose. Bolus IV administration of calcifediol induced a 40-fold surge in kidney CYP24A1 expression by 8 h post-dose. This rapid induction of CYP24A1 was similar to that observed previously in rats (46-fold increase in kidney and 25-fold increase in intestine) following Lacidipine 2.5 weeks of high-dose vitamin D (three treatments per week of 25,000 IU each) [23]. This previous study demonstrated that consecutive rapid administrations of vitamin D progressively raise CYP24A1 levels, attenuating the intended impact of treatment. Recent clinical studies have shown that treatment of CKD patients with bolus cholecalciferol

results in a shift of vitamin D balance to net degradation with increased production of 24,25-dihydroxyvitamin D3, reduced production of 1,25-dihydroxyvitamin D and increased FGF23 expression [24]. Consistent with our findings, bolus cholecalciferol was not effective at suppressing iPTH. In our study, patients receiving bolus calcifediol exhibited elevated and sustained production of 24,25-dihydroxyvitamin D3. This likely reflects elevated CYP24A1 expression both in the kidney as well as in other vitamin D target tissues, but the mechanism underlying continued production of 24,25-dihydroxyvitamin D3 over 42 days is unknown. It is notable that both rat and patient responses to different rates of calcifediol administration were similar.