Details of the Drug

General Information of Drug (ID: DM8ZVJ7)

• Drug Name: Calcitriol
• Synonyms: calcitriol; Rocaltrol; 32222-06-3; Calcijex; Topitriol; 1alpha,25-Dihydroxyvitamin D3; Silkis; Soltriol; 1alpha,25-Dihydroxycholecalciferol; Calcitriolum; Dihydroxyvitamin D3; 1,25-DHCC; 1,25-Dihydroxyvitamin D; Vectical; 1,25-DIHYDROXYCHOLECALCIFEROL; 1,25-Dihydroxyvitamin D3; 1alpha,25-Dihydroxyvitamin D; 1-alpha,25-Dihydroxyvitamin D3; Calcitriolum [INN-Latin]; UNII-FXC9231JVH; 1alpha,25(OH)2D3; DN-101; 1,25-Dihydroxycholecaliferol; CCRIS 5522; Ro 21-5535; HSDB 3482; 1-alpha,25-Dihydroxycholecalciferol; EINECS 250-963-8; DN 101; Calcitriol (chemotherapy-induced alopecia); Calcitriol (chemotherapy-induced alopecia), Cytotech Labs; Calcitriol (API-31543, drug-induced alopecia), Cytotech Labs; 1alpha,25 dihydroxyvitamin D(3)

Indication

Disease Entry	ICD 11	Status	REF
Congenital alopecia	LC30	Approved	[1], [2]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 416.6
  Topological Polar Surface Area (xlogp); 5.1
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 3
  Hydrogen Bond Acceptor Count (hbondacc); 3
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 2: low solubility and high permeability [3]
  Bioavailability: 61% of drug becomes completely available to its intended biological destination(s) [4]
  Clearance: The clearance of drug is 23.5 +/- 4.34 mL/min [5]
  Elimination: In normal subjects, approximately 27% and 7% of the radioactivity appeared in the feces and urine, respectively, within 24 hours [6]
  Half-life: The concentration or amount of drug in body reduced by one-half in 5 - 8 hours [7]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.000103 micromolar/kg/day [8]
  Vd: The volume of distribution (Vd) of drug is 0.49 +/- 0.14 L/kg [5]
• Chemical Identifiers:
  Formula: C27H44O3
  IUPAC Name: (1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol
  Canonical SMILES: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@@H]\\2[C@@]1(CCC/C2=C\\C=C/3\\C[C@H](C[C@@H](C3=C)O)O)C
  InChI: InChI=1S/C27H44O3/c1-18(8-6-14-26(3,4)30)23-12-13-24-20(9-7-15-27(23,24)5)10-11-21-16-22(28)17-25(29)19(21)2/h10-11,18,22-25,28-30H,2,6-9,12-17H2,1,3-5H3/b20-10+,21-11-/t18-,22-,23-,24+,25+,27-/m1/s1
  InChIKey: GMRQFYUYWCNGIN-NKMMMXOESA-N
• Cross-matching ID:
  PubChem CID: 5280453
  ChEBI ID: CHEBI:17823
  CAS Number: 32222-06-3
  DrugBank ID: DB00136
  TTD ID: D0T2PL
  INTEDE ID: DR0260
  ACDINA ID: D00090

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Vitamin D3 receptor (VDR)	TTK59TV	VDR_HUMAN	Agonist	[9]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[10]
Vitamin D(3) 24-hydroxylase (CYP24A1)	DEFI12S	CP24A_HUMAN	Substrate	[11]
UDP-glucuronosyltransferase 1A4 (UGT1A4)	DELOY3P	UD14_HUMAN	Substrate	[12]

Molecular Expression Atlas of This Drug

• The Studied Disease: Congenital alopecia
• ICD Disease Classification: LC30

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Vitamin D3 receptor (VDR)	DTT	VDR	1.69E-02	-0.23	-0.66
Vitamin D(3) 24-hydroxylase (CYP24A1)	DME	CYP24A1	7.29E-01	1.85E-01	9.48E-02
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	1.10E-01	-1.23E-01	-2.88E-01

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Calcitriol (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Magnesium Sulfate	DMVEK07	Moderate	Increased risk of hypermagnesemia by the combination of Calcitriol and Magnesium Sulfate.	Acute pain [MG31]	[37]
Butalbital	DM9J04X	Moderate	Increased metabolism of Calcitriol caused by Butalbital mediated induction of CYP450 enzyme.	Anxiety disorder [6B00-6B0Z]	[37]
Methylphenobarbital	DMDSWAG	Moderate	Increased metabolism of Calcitriol caused by Methylphenobarbital mediated induction of CYP450 enzyme.	Anxiety disorder [6B00-6B0Z]	[37]
Secobarbital	DM14RF5	Moderate	Increased metabolism of Calcitriol caused by Secobarbital mediated induction of CYP450 enzyme.	Chronic insomnia [7A00]	[37]
Primidone	DM0WX6I	Moderate	Increased metabolism of Calcitriol caused by Primidone mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[37]
Felbamate	DM1V5ZS	Moderate	Increased metabolism of Calcitriol caused by Felbamate mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[37]
Oxcarbazepine	DM5PU6O	Moderate	Increased metabolism of Calcitriol caused by Oxcarbazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[37]
Phenytoin	DMNOKBV	Moderate	Increased metabolism of Calcitriol caused by Phenytoin mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[37]
Fosphenytoin	DMOX3LB	Moderate	Increased metabolism of Calcitriol caused by Fosphenytoin mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[37]
Rufinamide	DMWE60C	Moderate	Increased metabolism of Calcitriol caused by Rufinamide mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[37]
Phenobarbital	DMXZOCG	Moderate	Increased metabolism of Calcitriol caused by Phenobarbital mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[37]
Carbamazepine	DMZOLBI	Moderate	Increased metabolism of Calcitriol caused by Carbamazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[37]
Isoniazid	DM5JVS3	Moderate	Increased metabolism of Calcitriol caused by Isoniazid mediated induction of CYP450 enzyme.	HIV-infected patients with tuberculosis [1B10-1B14]	[37]
Rifampin	DMA8J1G	Moderate	Increased metabolism of Calcitriol caused by Rifampin mediated induction of CYP450 enzyme.	HIV-infected patients with tuberculosis [1B10-1B14]	[37]
Rifapentine	DMCHV4I	Moderate	Increased metabolism of Calcitriol caused by Rifapentine mediated induction of CYP450 enzyme.	HIV-infected patients with tuberculosis [1B10-1B14]	[37]
Amobarbital	DM0GQ8N	Moderate	Increased metabolism of Calcitriol caused by Amobarbital mediated induction of CYP450 enzyme.	Insomnia [7A00-7A0Z]	[37]
Butabarbital	DMC5AST	Moderate	Increased metabolism of Calcitriol caused by Butabarbital mediated induction of CYP450 enzyme.	Insomnia [7A00-7A0Z]	[37]
Pentobarbital	DMFNH7L	Moderate	Increased metabolism of Calcitriol caused by Pentobarbital mediated induction of CYP450 enzyme.	Insomnia [7A00-7A0Z]	[37]
Orlistat	DMRJSP8	Minor	Decreased absorption of Calcitriol caused by Orlistat.	Obesity [5B80-5B81]	[38]

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Allura red AC dye	E00338	33258	Colorant
Butylated hydroxytoluene	E00336	31404	Antioxidant
Hydrazine yellow	E00409	164825	Colorant
Isopropyl alcohol	E00070	3776	Antimicrobial preservative; Solvent
Mannitol	E00103	6251	Diluent; Flavoring agent; Lyophilization aid; Plasticizing agent; Tonicity agent
methylparaben	E00149	7456	Antimicrobial preservative
Propyl 4-hydroxybenzoate	E00141	7175	Antimicrobial preservative
Propylparaben sodium	E00567	23679044	Antimicrobial preservative
Sodium methylparaben	E00543	23663626	Antimicrobial preservative
Sunset yellow FCF	E00255	17730	Colorant
Ammonia	E00007	222	Alkalizing agent
Butylhydroxyanisole	E00308	24667	Antimicrobial preservative; Antioxidant
Eisenoxyd	E00585	56841934	Colorant
FD&C red no. 3	E00629	Not Available	Colorant
Ferric hydroxide oxide yellow	E00539	23320441	Colorant
Ferrosoferric oxide	E00231	14789	Colorant
Glycerin	E00026	753	Antimicrobial preservative; Emollient; Flavoring agent; Humectant; Lubricant; Plasticizing agent; Solvent; Suppository base; Tonicity agent; Viscosity-controlling agent
Hexahydric alcohol	E00083	5780	Diluent; Flavoring agent; Humectant; Plasticizing agent
Medium-chain triglyceride	E00640	Not Available	Emollient; Lubricant; Surfactant
Propylene glycol	E00040	1030	Antimicrobial preservative; Humectant; Plasticizing agent; Solvent
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Water	E00035	962	Solvent

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Calcitriol 0.00025 mg capsule	0.00025 mg	Oral Capsule	Oral
Calcitriol 0.0005 mg capsule	0.0005 mg	Oral Capsule	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2779).
• [2] ClinicalTrials.gov (NCT02186665) Plaque Psoriasis Study in Pediatric Subjects. U.S. National Institutes of Health.
• [3] BDDCS applied to over 900 drugs
• [4] Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
• [5] Brandi L, Egfjord M, Olgaard K: Pharmacokinetics of 1,25(OH)2D3 and 1(OH)D3 in normal and uraemic men Nephrology Dialysis Transplantation. 2002 May 1;17(5):829C842.
• [6] An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
• [7] FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
• [8] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [9] Kaposi sarcoma is a therapeutic target for vitamin D(3) receptor agonist. Blood. 2000 Nov 1;96(9):3188-94.
• [10] Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia. Mol Pharmacol. 2006 Jan;69(1):56-65.
• [11] The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014 May;14(5):342-57.
• [12] Identification of human UDP-glucuronosyltransferases catalyzing hepatic 1alpha,25-dihydroxyvitamin D3 conjugation. Biochem Pharmacol. 2008 Mar 1;75(5):1240-50.
• [13] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [14] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [15] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [16] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [17] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [18] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [19] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [20] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [21] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [22] Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway. Respir Res. 2006 Apr 6;7:60.
• [23] FDA label of Lorlatinib. The 2020 official website of the U.S. Food and Drug Administration.
• [24] Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica. 2009 Nov;39(11):826-35.
• [25] Human biotransformation of the nonnucleoside reverse transcriptase inhibitor rilpivirine and a cross-species metabolism comparison. Antimicrob Agents Chemother. 2013 Oct;57(10):5067-79.
• [26] Bevirimat: a novel maturation inhibitor for the treatment of HIV-1 infection. Antivir Chem Chemother. 2008;19(3):107-13.
• [27] Identification of aspartic acid and histidine residues mediating the reaction mechanism and the substrate specificity of the human UDP-glucuronosyltransferases 1A. J Biol Chem. 2007 Dec 14;282(50):36514-24.
• [28] Vitamin D in health and disease. Clin J Am Soc Nephrol. 2008 Sep;3(5):1535-41.
• [29] Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
• [30] Cellular and molecular mechanisms involved in the action of vitamin D analogs targeting vitiligo depigmentation. Curr Drug Targets. 2008 Apr;9(4):345-59.
• [31] Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3. Bioorg Med Chem. 2000 Aug;8(8):2157-66.
• [32] In vivo metabolism of the vitamin D analog, dihydrotachysterol. Evidence for formation of 1 alpha,25- and 1 beta,25-dihydroxy-dihydrotachysterol metabolites and studies of their biological activity. J Biol Chem. 1993 Jan 5;268(1):282-92.
• [33] [Vitamin D2 or vitamin D3]. Rev Med Interne. 2008 Oct;29(10):815-20.
• [34] New acquisitions in therapy of secondary hyperparathyroidism in chronic kidney disease and peritoneal dialysis patients: role of vitamin D receptor... Contrib Nephrol. 2009;163:219-226.
• [35] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [36] Evidence for tissue- and cell-type selective activation of the vitamin D receptor by Ro-26-9228, a noncalcemic analog of vitamin D3. J Cell Biochem. 2003 Feb 1;88(2):267-73.
• [37] Product Information. Hectorol (doxercalciferol). Genzyme Corporation, Cambridge, MA.
• [38] Product Information. Xenical (orlistat). Roche Laboratories, Nutley, NJ.