Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation

Autor: Samir P. Tabash, Charles W. Bishop, Jay A. White, Joel Z. Melnick, Stephen Strugnell, Martin Petkovich
Rok vydání: 2014
Předmět:
Male
24
25-Dihydroxyvitamin D 3
Endocrinology
Diabetes and Metabolism
Clinical Biochemistry
Administration
Oral
Biochemistry
Rats
Sprague-Dawley
chemistry.chemical_compound
Endocrinology
Bolus (medicine)
Chronic kidney disease
polycyclic compounds
Medicine
Vitamin D3 24-Hydroxylase
Vitamins
3. Good health
medicine.anatomical_structure
Parathyroid Hormone
Molecular Medicine
Secondary hyperparathyroidism
medicine.drug
Vitamin
medicine.medical_specialty
Calcitriol
Clinical study
Internal medicine
Vitamin D and neurology
Animals
Humans
RNA
Messenger
Renal Insufficiency
Chronic
Molecular Biology
Calcifediol
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Vitamin D insufficiency
business.industry
Cell Biology
medicine.disease
Vitamin D Deficiency
Rats
Fibroblast Growth Factors
Drug Liberation
Fibroblast Growth Factor-23
CYP24A1
chemistry
Gene Expression Regulation
Modified-release
Dietary Supplements
Rat
Parathyroid gland
Calcium
business
Kidney disease
Zdroj: The Journal of steroid biochemistry and molecular biology. 148
ISSN: 1879-1220
Popis: Vitamin D insufficiency is prevalent in chronic kidney disease (CKD) and associated with secondary hyperparathyroidism (SHPT) and increased risk of bone and vascular disease. Unfortunately, supplementation of stage 3 or 4 CKD patients with currently recommended vitamin D2 or D3 regimens does not reliably restore serum total 25-hydroxyvitamin D to adequacy (≥30ng/mL) or effectively control SHPT. Preclinical and clinical studies were conducted to evaluate whether the effectiveness of vitamin D repletion depends, at least in part, on the rate of repletion. A modified-release (MR) oral formulation of calcifediol (25-hydroxyvitamin D3) was developed which raised serum 25-hydroxyvitamin D3 and calcitriol levels gradually. Single doses of either bolus intravenous (IV) or oral MR calcifediol were administered to vitamin D deficient rats. Bolus IV calcifediol produced rapid increases in serum 25-hydroxyvitamin D3, calcitriol and FGF23, along with significant induction of CYP24A1 in both kidney and parathyroid gland. In contrast, oral MR calcifediol produced gradual increases in serum 25-hydroxyvitamin D3 and calcitriol and achieved similar hormonal exposure, yet neither CYP24A1 nor FGF23 were induced. A 10-fold greater exposure to bolus IV than oral MR calcifediol was required to similarly lower intact parathyroid hormone (iPTH). Single doses of oral MR (450 or 900μg) or bolus IV (450μg) calcifediol were administered to patients with stage 3 or 4 CKD, SHPT and vitamin D insufficiency. Changes in serum 25-hydroxyvitamin D3 and calcitriol and in plasma iPTH were determined at multiple time-points over the following 42 days. IV calcifediol produced abrupt and pronounced increases in serum 25-hydroxyvitamin D3 and calcitriol, but little change in plasma iPTH. As in animals, these surges triggered increased vitamin D catabolism, as evidenced by elevated production of 24,25-dihydroxyvitamin D3. In contrast, MR calcifediol raised serum 25-hydroxyvitamin D3 and calcitriol gradually, and meaningfully lowered plasma iPTH levels. Taken together, these studies indicate that rapid increases in 25-hydroxyvitamin D3 trigger CYP24A1 and FGF23 induction, limiting effective exposure to calcitriol and iPTH reduction in SHPT. They also support further investigation of gradual vitamin D repletion for improved clinical effectiveness.This article is part of a Special Issue entitled "17th Vitamin D Workshop".
Databáze: OpenAIRE
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