Pharmacokinetics of 1,25(OH)2D3 and 1alpha(OH)D3 in normal and uraemic men

Abstract

The present study found a 57% lower metabolic clearance rate of 1,25(OH)(2)D(3) in uraemic patients, as compared with that of healthy volunteers (P<0.03). The bioavailability of 1,25(OH)(2)D(3) following administration of 1alpha(OH)D(3) i.v. and orally in both healthy volunteers and uraemic patients was markedly lower than after administration of oral 1,25(OH)(2)D(3) (P<0.03). In spite of lower plasma-1,25(OH)(2)D(3) levels after administration of 1alpha(OH)D(3), no significant difference was observed on the suppressive effect of 4 microg i.v. of either 1,25(OH)(2)D(3) or 1alpha(OH)D(3) on the plasma-PTH levels in the uraemic patients. This might suggest the existence of an effect of 1alpha(OH)D(3) on the parathyroid glands which is independent of the plasma-1,25(OH)(2)D(3) levels, that are achieved after oral or i.v. administration of 1alpha(OH)D(3).

Temporal changes in tissue 1α,25-dihydroxyvitamin D3, vitamin D receptor target genes, and calcium and PTH levels after 1,25(OH)2D3treatment in mice

“…2 D 3 to mice. The baseline plasma concentration of 1,25(OH) 2 D 3 for vehicle-treated C57BL/6 mouse, estimated as the mean of the determinations for the experimental duration, was 212 Ϯ 29 pM (fmol/ml), a value similar to the endogenous plasma concentration of 1,25(OH) 2 D 3 in the rat (51) but higher than that in humans (8,53). Basal levels of 1,25(OH) 2 D 3 in the kidney (70.5 Ϯ 10.4 pmol/kg tissue), intestine (93.5 Ϯ 7.2 pmol/kg tissue), and bone (36.5 Ϯ 33.8 pmol/kg tissue) were significantly lower than those in plasma (Fig.…”

“…The dose was based on a series of published reports, with doses ranging from 0.1 to 5 g/mouse or 0.25 to 5 g/kg for ip or oral administration, daily or every other day in mice (1,2,27,37,39,42,47,55). In humans, doses of 1,25(OH) 2D3 (0.5 g/kg or 38 g) furnished a similar clearance and exposure with minimal toxicity when used intermittently (8,38). Moreover, preliminary studies had shown that the chosen dosing regimen in mice elicited the desired pharmacological effect with only minor elevation of plasma calcium.…”

“…For the control group (treated with corn oil only), however, sampling was conducted at 0, 3, 6, and 12 h on day 0, and at 0 h on days 2,4,6,8, and 14. The mouse was rendered unconscious in a carbon dioxide chamber before blood collection by cardiac puncture using a 1-ml syringe-23G 3/4 inch.…”

PKPD modelling to predict altered disposition of 1α,25‐dihydroxyvitamin D3 in mice due to dose‐dependent regulation of CYP27B1 on synthesis and CYP24A1 on degradation

“…1,25(OH)2D3 is used extensively for the treatment of secondary hyperparathyroidism in uraemic patients (Slatopolsky et al, 1984;Kimura et al, 1991;Brandi et al, 2002) and has demonstrated therapeutic potential for anticancer therapy (Hershberger et al, 2002;Rassnick et al, 2008;Ramnath et al, 2013). The therapeutic use of 1,25(OH)2D3 is often limited by the propensity of 1,25(OH)2D3 to cause hypercalcaemia and adverse effects.…”

“…and i.v. doses of 4 μg 1,25(OH)2D3, a t1/2 of 26 h was observed, along with a plasma clearance (dose/AUC∞) of 0.17 mL·min −1 ·kg −1 and bioavailability of 0.71 after 72 h of sampling (Brandi et al, 2002). C3H/HeJ mice treated with 0.125 or 0.5 μg 1,25(OH)2D3 i.p., with sampling up to 24 h, produced an apparent clearance (dose/AUC0→24), but a debatable terminal t1/2 due to limited sampling (Muindi et al, 2004).…”