パリカルシトール

Corticosteroids counteract the effects of vitamin D analogs. /Vitamin D analogs/

Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with /paricalcitol/. Adynamic bone lesions may develop if PTH levels are suppressed to abnormal levels.

Concurrent administration of thiazide diuretics and pharmacologic doses of vitamin D analogs in patients with hypoparathyroidism may result in hypercalcemia which may be transient and self-limited or may require discontinuance of vitamin D analogs. Thiazide-induced hypercalcemia in hypoparathyroid patients is probably caused by increased release of calcium from bone. /Vitamin D analogs/

Excessive use of mineral oil may interfere with intestinal absorption of vitamin D analogs. /Vitamin D analogs/

For more Interactions (Complete) data for PARICALCITOL (9 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.1X10+5(SRC), determined from a structure estimation method(2), indicates that paricalcitol is expected to be immobile in soil(SRC). Volatilization of paricalcitol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.8X10-7 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Paricalcitol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.6X10-14 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.1X10+5(SRC), determined from a structure estimation method(2), indicates that paricalcitol is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.8X10-7 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 1900(SRC), from an estimated log Kow of 7.4(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is very high(SRC). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), paricalcitol, which has a an estimated vapor pressure of 8.6X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase paricalcitol may be removed from the air by wet or dry deposition(SRC). Paricalcitol does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of paricalcitol can be estimated to be 1.1X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that paricalcitol is expected to be immobile in soil.

/SIGNS AND SYMPTOMS/ Patients should be informed of the dangers and symptoms of vitamin D intoxication. Early symptoms of hypercalcemia may include weakness, fatigue, somnolence, headache, anorexia, dry mouth, metallic taste, nausea, vomiting, abdominal cramps, constipation, diarrhea, vertigo, tinnitus, ataxia, exanthema, hypotonia (in infants), muscle pain, bone pain, and irritability. Later and sometimes more serious consequences of hypercalcemia may include rhinorrhea, pruritus, decreased libido, nephrocalcinosis, impairment of renal function (resulting in polyuria, nocturia, polydipsia, hyposthenuria, and proteinuria), osteoporosis in adults, decreased growth in children, weight loss, anemia, calcific conjunctivitis, photophobia, metastatic calcification, pancreatitis, generalized vascular calcification, and seizures. Rarely, patients may develop hypertension or overt psychosis. Urinary calcium, phosphate, and albumin; BUN; and serum cholesterol, AST (SGOT), and ALT (SGPT) concentrations may increase. Serum alkaline phosphatase concentrations may decrease. Serum electrolyte imbalances along with mild acidosis may result in cardiac arrhythmias. /Vitamin D/

/SIGNS AND SYMPTOMS/ The initial signs and symptoms of vitamin D toxicity are those associated with hypercalcemia. ... Hypercalcemia with hypervitaminosis D is due generally to very high circulating levels or 25-OHD (25-hydroxycholecalciferol), and plasma concentrations of PTH (parathyroid hormone) and calcitriol are typically but not uniformly suppressed. /Vitamin D/

/SIGNS AND SYMPTOMS/ Vitamin D toxicity may be manifested in the fetus. There is a relationship between excess maternal vitamin D intake or extreme sensitivity and nonfamilial congenital supravalvular aortic stenosis. In infants, this anomaly is often associated with other stigmata of hypercalcemia. Maternal hypercalcemia also may result in suppression of parathyroid function in the newborn, with resultant hypocalcemia, tetany, and seizures. /Vitamin D/

/SIGNS AND SYMPTOMS/ Acute overdose of /paricalcitol/ may cause hypercalcemia, and require emergency attention. ... Chronic administration of /paricalcitol/ may place patients at risk of hypercalcemia, elevated Ca x P product, and metastatic calcification. Signs and symptoms of vitamin D intoxication associated with hypercalcemia include: Early: Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, and metallic taste. Late: Anorexia, weight loss, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, hypercholesterolemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias, somnolence, death, and rarely, overt psychosis.

For more Human Toxicity Excerpts (Complete) data for PARICALCITOL (6 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Paricalcitol

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

An estimated BCF of 1900 was calculated for paricalcitol(SRC), using an estimated log Kow of 7.4(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC).

The Henry's Law constant for paricalcitol is estimated as 3.8X10-7 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that paricalcitol is expected to be essentially nonvolatile from moist soil and water surfaces(2). Paricalcitol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.6X10-14 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a 104-week carcinogenicity study in CD-1 mice, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1 to 10 ug/kg (< 1 to 3 times the maximum recommended human weekly dose of 0.72 ug/kg, based on body surface area, mg/sq m). The incidence rate of uterine leiomyoma was significantly different than the control group at the highest dose of 10 ug/kg.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a 104-week carcinogenicity study in rats, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15 to 1.5 ug/kg (1 times the maximum recommended human weekly dose of 0.72 ug/kg, based on body surface area, mg/sq m). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol. In carcinogenicity studies in rats and mice, paricalcitol did not affect the incidences of tumors apart from benign rodent-specific lesions related to the effects of chronic hypercalcemia.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times the 0.24 ug/kg human dose (based on surface area, mg/sq m) and when administered to rats at a dose 2 times the 0.24 ug/kg human dose (based on plasma levels of exposure). At the highest dose tested (20 ug/kg 3 times per week in rats, 13 times the 0.24 ug/kg human dose based on surface area), there was a significant increase of the mortality of newborn rats at doses that were maternally toxic (hypercalcemia). No other effects on offspring development were observed. Paricalcitol was not teratogenic at the doses tested.

/GENOTOXICITY/ Paricalcitol did not exhibit genetic toxicity in vitro with or without metabolic activation in the microbial mutagenesis assay (Ames Assay), mouse lymphoma mutagenesis assay (L5178Y), or a human lymphocyte cell chromosomal aberration assay. There was also no evidence of genetic toxicity in an in vivo mouse micronucleus assay. /Paricalcitol/ had no effect on fertility (male or female) in rats at intravenous doses up to 20 ug/kg/dose (equivalent to 13 times the highest recommended human dose (0.24 ug/kg) based on surface area, mg/sq m).

Doses of vitamin D analogs that do not exceed the physiologic requirement are usually nontoxic. However, some infants and patients with sarcoidosis or hypoparathyroidism may have increased sensitivity to vitamin D analogs. /Vitamin D analogs/

Because administration of vitamin D analogs may increase phosphate absorption, patients with renal failure may require adjustment in the dosage of aluminum-containing antacids used to decrease phosphate absorption. /Vitamin D analogs/

Paricalcitol is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Paricalcitol does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to paricalcitol may occur through inhalation and dermal contact with this compound at workplaces where paricalcitol is produced or used(SRC). Exposure to paricalcitol among the general population may be limited to those administered the drug Zemplar(1).

Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Preclinical andin vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the VDR, which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.

Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the vitamin D receptor (VDR), which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.

4 to 6 hours

In healthy subjects, the mean elimination half-life of paricalcitol is 4 to 6 hours over the studied dose range of 0.06 to 0.48 mcg/kg. The pharmacokinetics of paricalcitol capsule have been studied in patients with chronic kidney disease (CKD) Stage 3 and 4 patients. After administration of 4 mcg paricalcitol capsule in CKD Stage 3 patients, the mean elimination half-life of paricalcitol is 17 hours. The mean half-life of paricalcitol is 20 hours in CKD Stage 4 patients when given 3 mcg of paricalcitol capsule.

Plasma half-life: 15 hours.

Metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4

After oral administration of a 0.48 mcg/kg dose of 3 H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces, and no parent drug found in the urine. Several metabolites were detected in both the urine and feces. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.

In vitro data suggest that paricalcitol is metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation, 24,26- and 24,28-dihydroxylation and direct glucuronidation.

6702D36OG5

PARICALCITOL

Chemical Structure [CS] - Ergocalciferols

Established Pharmacologic Class [EPC] - Vitamin D2 Analog

Established Pharmacologic Class [EPC] - Vitamin D Analog

Paricalcitol is a Vitamin D2 Analog and Vitamin D Analog.

Well absorbed

Paricalcitol is excreted primarily by hepatobiliary excretion.

30.8 ± 7.5 L [CKD Stage 5-HD]

1.49 +/- 0.60 L/h [chronic kidney disease Stage 5 with hemodialysis]

Stored mainly in liver and other fat depots. /Vitamin D and analogs/

Many vitamin D analogs are readily absorbed from the GI tract following oral administration if fat absorption is normal. The presence of bile is required for absorption of ergocalciferol and the extent of GI absorption may be decreased in patients with hepatic, biliary, or GI disease (e.g., Crohn's disease, Whipple's disease, sprue). Because vitamin D is fat soluble, it is incorporated into chylomicrons and absorbed via the lymphatic system; approximately 80% of ingested vitamin D appears to be absorbed systemically through this mechanism, principally in the small intestine. Although some evidence suggested that intestinal absorption of vitamin D may be decreased in geriatric adults, other evidence did not show clinically important age-related alterations in GI absorption of the vitamin in therapeutic doses. It currently is not known whether aging alters the GI absorption of physiologic amounts of vitamin D. /Vitamin D analogs/