Paricalcitol

Product Overview

Paricalcitol (development codes ABT-358 / Compound 49510) was developed by Abbott and marketed as Zemplar; it was approved by the US FDA in 1998, with ATC code H05BX02.

Structural essence: It is 19-nor-1α,25-dihydroxyvitamin D₂ (19-nor-1,25-(OH)₂D₂) — the vitamin D₂ (ergocalciferol) scaffold with the C-19 methylene removed and a hydroxyl group introduced at each of the 1α and 25 positions. The “19-nor” modification is the structural origin of its selectivity advantage.

Mechanism of action: It is a selective vitamin D receptor (VDR) agonist. Unlike calcitriol (active vitamin D₃), paricalcitol selectively acts on VDR in the parathyroid gland, directly suppressing PTH gene transcription and PTH secretion while also inhibiting parathyroid cell proliferation.

Why it is clinically superior: Conventional VDR agonists (e.g., calcitriol), while suppressing PTH, markedly promote intestinal calcium and phosphate absorption and bone calcium mobilization, readily causing hypercalcemia and hyperphosphatemia (and the resulting increased risk of vascular calcification). The 19-nor structure of paricalcitol means that at doses that effectively suppress PTH, its stimulatory effect on intestinal calcium/phosphate transport and bone resorption is relatively weak, so the incidence of hypercalcemia / hyperphosphatemia is lower — this is the core reason it is preferred for treating CKD-associated secondary hyperparathyroidism. Literature also suggests it is associated with lower morbidity and improved survival, and it may have certain anti-inflammatory effects.

Pharmacokinetic profile: Oral bioavailability approximately 72%; plasma protein binding approximately 99.8% (free fraction approximately 0.0016); steady-state volume of distribution approximately 0.41 L/kg; metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, CYP3A4 and UGT1A4; half-life approximately 4–6 hours (other literature reports 5–7 hours, 5.3 hours); excreted mainly via the hepatobiliary route; clearance approximately 0.89 mL/min/kg (CKD stage 5 data: hemodialysis 1.49 L/h, peritoneal dialysis 1.54 L/h).

The “isomer trap” that must be distinguished: Paricalcitol and calcitriol (CAS 32222-06-3) have exactly the same molecular formula, both C₂₇H₄₄O₃, and almost the same molecular weight (416.64) — yet one is a 19-nor vitamin D₂ analogue and the other is active vitamin D₃; they are two completely different drugs, with different indications, selectivity and safety profiles. The reliable distinguishing metric is melting point: paricalcitol 172–174 °C versus calcitriol 119–121 °C — a difference of more than 50 °C. Molecular formula and molecular weight alone cannot distinguish them; the CAS number and chemical name must be verified.

Technical Specifications

• Standards: CHP / USP / EP

• Specification: 0.99 (purity ≥99.0%, HPLC); reagent grade commonly ≥98% (HPLC, Sigma)

• CAS No.: 131918-61-1 (EC 658-064-6; UNII 6702D36OG5; ChEBI 7931; ChEMBL CHEMBL1200622; DrugBank DB00910; KEGG C08127 / D00930; PubChem CID 5281104; MDL MFCD08067734)

• Molecular formula: C₂₇H₄₄O₃

• Molecular weight: 416.64 (PubChem 416.6; ChemicalBook 416.65; Guidechem 416.63646; Xiamen University database 416.6365; CliniSciences / TRC / Sigma 416.64); exact mass calculated according to isotopic composition

• Appearance: White to light yellow solid; Sigma describes it as a white to beige powder; ChemicalBook records a white to off-white solid

• Purity (HPLC): ≥ 99.0%

• Melting point: 172–174 °C (TRC, recommended); another source records 172–176 °C (CliniSciences) — a slightly wider expression of the same range; the two are compatible. This is a key identification point: it contrasts sharply with calcitriol (melting point 119–121 °C), which shares the same molecular formula, and can be used to rapidly distinguish the two substances. The above values come from suppliers / reference standards, not from publicly available official pharmacopoeial melting points

• Specific rotation: No official pharmacopoeial specific rotation is publicly available; the molecule contains multiple defined stereocenters (SMILES shows 1R,3R,3aS,7aR,2R,5S etc.), and quality control is typically achieved through chiral HPLC / stereoisomer purity and structural confirmation (NMR, MS)

• Chemical name: (1R,3R)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(E,2R,5S)-6-hydroxy-5,6-dimethylhept-3-en-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]cyclohexane-1,3-diol; i.e., 19-nor-1α,25-dihydroxyvitamin D₂, (1α,3β,7E,22E)-19-nor-9,10-secoergosta-5,7,22-triene-1,3,25-triol

• Stereochemistry: Multiple defined stereocenters (1R, 3R, 3aS, 7aR, 2R, 5S and two E-configured double bonds); a steroidal scaffold of the vitamin D series

• Solubility: Soluble in DMSO (approx. 100 mg/mL, with sonication; Sigma records 2 mg/mL clear); slightly soluble in methanol (approx. 12.5 mg/mL, with sonication) and ethanol; practically insoluble in water (<0.1 mg/mL, insoluble)

• Acidity coefficient (pKa): 14.34 ± 0.40 (calculated)

• Computed physicochemical parameters: Density approx. 1.121 ± 0.06 g/cm³ (predicted); boiling point approx. 564.8 ± 50.0 °C (predicted); flash point approx. 14 °C; LogP approx. 5.56; topological polar surface area approx. 60.69 Ų; H-bond donors 3 / acceptors 3

• Stability and storage: Light-sensitive, temperature-sensitive (Light Sensitive, Temperature Sensitive); unstable in solution — prepare fresh before use; recommended storage at −20 °C (TRC recommends freezing at −86 °C) under inert gas, in an amber vial protected from light; ChemicalBook recommends −20 °C, unstable in solution, prepare and use immediately

• Marketed dosage strengths: Injection (intravenous) and capsules, commonly 1 μg, 2 μg, 4 μg

Applications

• Prevention and treatment of CKD-associated secondary hyperparathyroidism (SHPT) (core indication): For the prevention and treatment of secondary hyperparathyroidism in patients with CKD stages 3 and 4, and for the treatment of SHPT in patients with CKD stage 5 (dialysis). Both intravenous injection and oral capsule routes are approved

• Mechanism-of-action research: For evaluation of vitamin D receptor (VDR) agonist activity, inhibition of PTH gene transcription and secretion, inhibition of parathyroid cell proliferation, and comparative studies of VDR selectivity (intestinal calcium/phosphate transport vs parathyroid PTH suppression)

• Comparative pharmacology research: Head-to-head comparisons with other VDR agonists such as calcitriol and doxercalciferol regarding hypercalcemia / hyperphosphatemia risk — this is the core evidence base for paricalcitol’s clinical positioning and a common use of the compound as a research tool

• Anti-inflammatory and renoprotection research: Literature suggests paricalcitol has certain anti-inflammatory effects that may benefit the management of CKD-associated inflammatory states; studies have also explored its effects on endpoints such as proteinuria and cardiovascular calcification — the above are largely investigational directions; specific approved indications are subject to the latest labeling in each jurisdiction

• Formulation and manufacturing: For formulation development of injections and soft / hard capsules; the API is light-sensitive, temperature-sensitive and unstable in solution, so the entire manufacturing process must focus on light protection, inert gas protection, low temperature and immediate use after preparation, with strict monitoring of related substances (the vitamin D series is prone to isomerization and oxidative degradation); attention must also be paid to identity discrimination from calcitriol (identical molecular formula and molecular weight) — dual identification by melting point, chiral chromatography and characteristic spectra is recommended; suitable for analytical method development and validation, stability studies, and GMP scale-up with CMO / CDMO contract manufacturing

Safety notice: This product is an active pharmaceutical ingredient (API) intended solely for compliant industrial, research and pharmaceutical manufacturing use; it is not for end clinical use or guidance for self-administration. The finished product is a prescription drug and must be prescribed by a physician experienced in the management of chronic kidney disease–mineral and bone disorder, with regular monitoring of serum calcium, serum phosphate, calcium–phosphate product (Ca × P) and intact PTH (iPTH) levels. Key warnings: ① Hypercalcemia — a class effect of vitamin D compounds; although the risk with paricalcitol is lower than with non-selective VDR agonists, it can still occur; the risk increases when combined with calcium-containing preparations, thiazide diuretics or high-dose vitamin D — reduce the dose or discontinue if hypercalcemia occurs; ② Hyperphosphatemia and elevated calcium–phosphate product — may increase the risk of soft-tissue and vascular calcification; monitoring throughout treatment is required, together with phosphate binders and dietary phosphate control; ③ Digitalis interaction — hypercalcemia caused by vitamin D compounds can precipitate digitalis toxicity (arrhythmia); serum calcium and ECG must be closely monitored when used concomitantly; ④ Aluminum-containing preparations interaction — long-term concomitant use with aluminum-containing preparations (e.g., certain phosphate binders) may increase aluminum accumulation toxicity. Overdose management: Acute overdose may cause hypercalcemia; management includes discontinuation, a low-calcium diet, adequate hydration and, if necessary, loop diuretics or glucocorticoids; due to high protein binding, hemodialysis is not expected to effectively remove the drug. Adverse reactions: Common events include hypercalcemia, hyperphosphatemia, nausea, vomiting, dizziness and edema; serious adverse reactions include hypercalcemic crisis, ectopic calcification and hypersensitivity reactions (injection). Special populations: Use in pregnancy and lactation requires a physician’s benefit–risk assessment; safety and efficacy data in children are limited. API handling warning: This is a light-sensitive, temperature-sensitive, solution-unstable, highly potent steroidal compound, and GHS data indicate a flash point of approximately 14 °C; wear protective gloves, protective clothing, and respiratory, eye and face protection during handling; protect from light throughout (amber containers) and use inert gas protection; avoid dust inhalation; store at −20 °C or below. It must be strictly distinguished from calcitriol (CAS 32222-06-3) — the two have the same molecular formula and molecular weight but are different drugs; mix-ups can cause serious medication errors.

Product information: please contact us. This information is for reference only.