Modified-release calcifediol effectively controls secondary hyperparathyroidism associated with vitamin D insufficiency in chronic kidney disease.

Background/aims: Vitamin D insufficiency drives secondary hyperparathyroidism (SHPT) and is associated with increased cardiovascular mortality in patients with chronic kidney disease (CKD). SHPT is poorly addressed by current vitamin D repletion options. The present study evaluated a novel investigational vitamin D repletion therapy: a modified-release (MR) formulation of calcifediol designed to raise serum 25-hydroxyvitamin D in a gradual manner to minimize the induction of CYP24 and, thereby, improve the SHPT control.

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

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.

Dysregulation of renal vitamin D metabolism in the uremic rat.

The progressive decline in kidney function and concomitant loss of renal 1alpha-hydroxylase (CYP27B1) in chronic kidney disease (CKD) are associated with a gradual loss of circulating 25-hydroxyvitamin D(3) (25(OH)D(3)) and 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)). However, only the decrease in 1alpha,25(OH)(2)D(3) can be explained by the decline of CYP27B1, suggesting that insufficiency of both metabolites may reflect their accelerated degradation by the key catabolic enzyme 24-hydroxylase (CYP24). To determine whether CYP24 is involved in causing vitamin D insufficiency and/or resistance to vitamin D therapy in CKD, we determined the regulation of CYP24 and CYP27B1 in normal rats and rats treated with adenine to induce CKD.

CYP1A induction and blue sac disease in early developmental stages of rainbow trout (Oncorhynchus Mykiss) exposed to retene.

Early life stages of rainbow trout were exposed to different regimes of water-borne retene (7-isopropyl-1-methylphenanthrene) to determine if there is an ontogenic stage particularly sensitive to retene toxicity, and if cytochrome P-4501A (CYP1A) induction is a forerunner to blue sac disease (BSD), the syndrome of toxicity. CYP1A protein concentrations, measured by immunohistochemistry, were first detected during organogenesis, when organ and enzyme systems are first being developed, and steadily increased until swim-up. The prevalence of signs of BSD rose 1 wk following a marked increase in CYP1A activity after hatch, suggesting that CYP1A induction is related to BSD.

CYP1A Induction and Blue SAC Disease in Early Developmental Stages of Rainbow Trout (Oncorhynchus Mykiss) Exposed to Retene.

Early life stages of rainbow trout were exposed to different regimes of water-borne retene (7-isopropyl-1-methylphenanthrene) to determine if there is an ontogenic stage particularly sensitive to retene toxicity, and if cytochrome P-4501A (CYP1A) induction is a forerunner to blue sac disease (BSD), the syndrome of toxicity. CYP1A protein concentrations, measured by immunohistochemistry, were first detected during organogenesis, when organ and enzyme systems are first being developed, and steadily increased until swim-up. The prevalence of signs of BSD rose 1 wk following a marked increase in CYP1A activity after hatch, suggesting that CYP1A induction is related to BSD.

Altering cytochrome P4501A activity affects polycyclic aromatic hydrocarbon metabolism and toxicity in rainbow trout (Oncorhynchus mykiss).

The polycyclic aromatic hydrocarbons (PAHs) phenanthrene and retene (7-isopropyl-1-methyl phenanthrene) are lethal to rainbow trout (Oncorhynchus mykiss) larvae during chronic exposures. Phenanthrene is a low-toxicity, non-cytochrome P4501A (CYP1A)-inducing compound that accumulates in fish tissues during exposure to lethal concentrations in water. Retene is a higher toxicity CYP1A-inducing compound that is not detectable in tissue at lethal exposure concentrations.