Details of the Drug

General Information of Drug (ID: DMYP4XC)

• Drug Name: Norgestimate
• Synonyms: Norgestimato; Norgestimatum; Dexnorgestrel acetime; Norgestrel oxime acetate; D 138; ORF 10131; RWJ 10131; Norgestimato [INN-Spanish]; Norgestimatum [INN-Latin]; ORF-10131; Ortho-Prefest; RWJ-10131; Norgestimate (USP/INN); Norgestimate [USAN:INN:BAN]; D-13beta-Ethyl-17alpha-ethynyl-17beta-acetoxygon-4-en-3-oneoxime; D-13-beta-Ethyl-17-alpha-ethynyl-17-beta-acetoxygon-4-en-3-one oxime; [(3E,8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-3-hydroxyimino-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate; (+)-13-Ethyl-17-hydroxy-18,19-dinor-17alpha-pregn-4-en-20-yn-3-one oxime acetate (ester); (17-alpha)-17-(Acetyloxy)-13-ethyl-18,19-dinorpregn-4-en-20-yn-3-one 3-oxime; (17alpha)-17-(Acetyloxy)-13-ethyl-18,19-dinorpregn-4-en-20-yn-3-one 3-oxime; (3E)-17alpha-ethynyl-3-(hydroxyimino)-18a-homoestr-4-en-17beta-yl acetate

Indication

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[1]
Contraception	QA21	Approved	[2]
Hot flushes	GA30	Approved	[1]
Obsolete atrophic vulva	N.A.	Approved	[1]

• Therapeutic Class: Contraceptive Agents
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 369.5
  Logarithm of the Partition Coefficient (xlogp); 4.1
  Rotatable Bond Count (rotbonds); 4
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 4
• ADMET Property:
  Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 16.1 mcgh/L [3]
  Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 1.82 mcg/L [3]
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 1.5 h [3]
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [4]
  Elimination: Norgestimate is 45-49% eliminated in urine and 16-49% eliminated in feces [5]
  Metabolism: The drug is metabolized via the CYP3A4 and to a lesser extend by CYP2B6 and CYP2C9 [6]
  Water Solubility: The ability of drug to dissolve in water is measured as 0.02 mg/mL [4]
• Chemical Identifiers:
  Formula: C23H31NO3
  IUPAC Name: [(3E,8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-3-hydroxyimino-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate
  Canonical SMILES: CC[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)OC(=O)C)CCC4=C/C(=N/O)/CC[C@H]34
  InChI: InChI=1S/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1
  InChIKey: KIQQMECNKUGGKA-NMYWJIRASA-N
• Cross-matching ID:
  PubChem CID: 6540478
  ChEBI ID: CHEBI:50815
  CAS Number: 20799-27-3
  DrugBank ID: DB00957
  TTD ID: D09QZI
  INTEDE ID: DR1178
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Progesterone receptor (PGR)	TTUV8G9	PRGR_HUMAN	Agonist	[7]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[8]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Gene/Protein Processing	[9]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Gene/Protein Processing	[10]

Molecular Expression Atlas of This Drug

• The Studied Disease: Acne vulgaris
• ICD Disease Classification: ED80

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Progesterone receptor (PGR)	DTT	PGR	3.26E-38	-3.79	-2.5
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	2.20E-02	-1.08E-01	-2.31E-01

Drug-Drug Interaction (DDI) Information of This Drug

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

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Metreleptin	DM1NOEK	Moderate	Decreased metabolism of Norgestimate caused by Metreleptin mediated inhibition of CYP450 enzyme.	Acute diabete complication [5A2Y]	[11]
Emapalumab	DMZG5WL	Moderate	Altered metabolism of Norgestimate due to Emapalumab alters the formation of CYP450 enzymes.	Adaptive immunity immunodeficiency [4A01]	[12]
Siltuximab	DMGEATB	Moderate	Altered metabolism of Norgestimate due to Siltuximab alters the formation of CYP450 enzymes.	Anemia [3A00-3A9Z]	[12]
Ag-221	DMS0ZBI	Moderate	Increased metabolism of Norgestimate caused by Ag-221 mediated induction of CYP450 enzyme.	BCR-ABL1-negative chronic myeloid leukaemia [2A41]	[11]
Pexidartinib	DMS2J0Z	Major	Increased metabolism of Norgestimate caused by Pexidartinib mediated induction of CYP450 enzyme.	Bone/articular cartilage neoplasm [2F7B]	[13]
MK-8228	DMOB58Q	Moderate	Decreased metabolism of Norgestimate caused by MK-8228 mediated inhibition of CYP450 enzyme.	Cytomegaloviral disease [1D82]	[14]
Selegiline	DM6034S	Moderate	Decreased metabolism of Norgestimate caused by Selegiline mediated inhibition of CYP450 enzyme.	Depression [6A70-6A7Z]	[15]
Fosphenytoin	DMOX3LB	Major	Increased metabolism of Norgestimate caused by Fosphenytoin mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[16]
Brivaracetam	DMSEPK8	Minor	Increased metabolism of Norgestimate caused by Brivaracetam mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[17]
Phenobarbital	DMXZOCG	Major	Increased metabolism of Norgestimate caused by Phenobarbital mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[16]
Eslicarbazepine	DMZREFQ	Major	Increased metabolism of Norgestimate caused by Eslicarbazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[16]
Boceprevir	DMBSHMF	Major	Increased metabolism of Norgestimate caused by Boceprevir mediated induction of CYP450 enzyme.	Hepatitis virus infection [1E50-1E51]	[18]
Telaprevir	DMMRV29	Major	Increased metabolism of Norgestimate caused by Telaprevir mediated induction of CYP450 enzyme.	Hepatitis virus infection [1E50-1E51]	[18]
Rifampin	DMA8J1G	Major	Increased metabolism of Norgestimate caused by Rifampin mediated induction of CYP450 enzyme.	HIV-infected patients with tuberculosis [1B10-1B14]	[19]
Rifapentine	DMCHV4I	Major	Increased metabolism of Norgestimate caused by Rifapentine mediated induction of CYP450 enzyme.	HIV-infected patients with tuberculosis [1B10-1B14]	[19]
Darunavir	DMN3GCH	Moderate	Decreased metabolism of Norgestimate caused by Darunavir mediated inhibition of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[20]
Atazanavir	DMSYRBX	Moderate	Decreased metabolism of Norgestimate caused by Atazanavir mediated inhibition of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[11]
BMS-201038	DMQTAGO	Moderate	Decreased metabolism of Norgestimate caused by BMS-201038 mediated inhibition of CYP450 enzyme.	Hyper-lipoproteinaemia [5C80]	[21]
Lesinurad	DMUR64T	Moderate	Increased metabolism of Norgestimate caused by Lesinurad mediated induction of CYP450 enzyme.	Inborn purine/pyrimidine/nucleotide metabolism error [5C55]	[11]
Miltefosine	DMND304	Moderate	Altered absorption of Norgestimate caused by Miltefosine.	Leishmaniasis [1F54]	[11]
Brigatinib	DM7W94S	Major	Increased metabolism of Norgestimate caused by Brigatinib mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[21]
Calaspargase pegol	DMQZBXI	Moderate	Decreased metabolism of Norgestimate caused by Calaspargase pegol mediated hepatotoxicity.	Malignant haematopoietic neoplasm [2B33]	[14]
LGX818	DMNQXV8	Major	Increased metabolism of Norgestimate caused by LGX818 mediated induction of CYP450 enzyme.	Melanoma [2C30]	[21]
Dabrafenib	DMX6OE3	Major	Increased metabolism of Norgestimate caused by Dabrafenib mediated induction of CYP450 enzyme.	Melanoma [2C30]	[18]
E-2007	DMJDYNQ	Moderate	Increased metabolism of Norgestimate caused by E-2007 mediated induction of CYP450 enzyme.	Neuropathy [8C0Z]	[22]
Olaparib	DM8QB1D	Moderate	Increased metabolism of Norgestimate caused by Olaparib mediated induction of CYP450 enzyme.	Ovarian cancer [2C73]	[22]
Ustekinumab	DMHTYK3	Moderate	Altered metabolism of Norgestimate due to Ustekinumab alters the formation of CYP450 enzymes.	Psoriasis [EA90]	[12]
Ixekizumab	DMXW92T	Moderate	Altered metabolism of Norgestimate due to Ixekizumab alters the formation of CYP450 enzymes.	Psoriasis [EA90]	[12]
Tocilizumab	DM7J6OR	Moderate	Altered metabolism of Norgestimate due to Tocilizumab alters the formation of CYP450 enzymes.	Rheumatoid arthritis [FA20]	[12]
Canakinumab	DM8HLO5	Moderate	Altered metabolism of Norgestimate due to Canakinumab alters the formation of CYP450 enzymes.	Rheumatoid arthritis [FA20]	[12]
Rilonacept	DMGLUQS	Moderate	Altered metabolism of Norgestimate due to Rilonacept alters the formation of CYP450 enzymes.	Rheumatoid arthritis [FA20]	[12]
Golimumab	DMHZV7X	Moderate	Altered metabolism of Norgestimate due to Golimumab alters the formation of CYP450 enzymes.	Rheumatoid arthritis [FA20]	[12]
Sarilumab	DMOGNXY	Moderate	Altered metabolism of Norgestimate due to Sarilumab alters the formation of CYP450 enzymes.	Rheumatoid arthritis [FA20]	[12]
Armodafinil	DMGB035	Moderate	Increased metabolism of Norgestimate caused by Armodafinil mediated induction of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[18]
Pitolisant	DM8RFNJ	Moderate	Increased metabolism of Norgestimate caused by Pitolisant mediated induction of CYP450 enzyme.	Somnolence [MG42]	[22]

References

• [1] Norgestimate FDA Label
• [2] 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: 7091).
• [3] Quantification of 17-desacetyl norgestimate in human plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application to bioequivalence study. J Pharm Anal. 2015 Apr;5(2):93-100. doi: 10.1016/j.jpha.2014.09.004. Epub 2014 Sep 22.
• [4] BDDCS applied to over 900 drugs
• [5] FDA Approved Drug Products: Ortho Tri-Cyclen Norgestimate and Ethinyl Estradiol Oral Tablets
• [6] Valitalo PA, Kemppainen H, Kulo A, Smits A, van Calsteren K, Olkkola KT, de Hoon J, Knibbe CAJ, Allegaert K: Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics. Br J Clin Pharmacol. 2017 Sep;83(9):1966-1975. doi: 10.1111/bcp.13311. Epub 2017 May 14.
• [7] Pharmacological profile of progestins. Maturitas. 2008 Sep-Oct;61(1-2):151-7.
• [8] Metabolite identification, reaction phenotyping, and retrospective drug-drug interaction predictions of 17-deacetylnorgestimate, the active component of the oral contraceptive norgestimate. Drug Metab Dispos. 2017 Jun;45(6):676-685.
• [9] Antiandrogenic activity of norgestimate in a human androgen-dependent stable-transfected cell line. Gynecol Endocrinol. 2007 Apr;23(4):193-7. doi: 10.1080/09513590701214414.
• [10] Interaction of progestins with the human multidrug resistance-associated protein 2 (MRP2). Drug Metab Dispos. 2005 Nov;33(11):1576-9.
• [11] Bailey DG, Arnold JMO, Spence JD "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet 26 (1994): 91-8. [PMID: 8162660]
• [12] Product Information. Cosentyx (secukinumab). Novartis Pharmaceuticals, East Hanover, NJ.
• [13] Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
• [14] Cerner Multum, Inc. "Australian Product Information.".
• [15] Ito D, Amano T, Sato H, Fukuuchi Y "Paroxysmal hypertensive crises induced by selegiline in a patient with Parkinson's disease." J Neurol 248 (2001): 533-4. [PMID: 11499649]
• [16] Back DJ, Grimmer SF, Orme ML, Proudlove D, Mann RD, Breckenridge AM "Evaluation of Committee on Safety of Medicines yellow card reports on oral contraceptive-drug interactions with anticonvulsants and antibiotics." Br J Clin Pharmacol 25 (1988): 527-32. [PMID: 3408633]
• [17] Product Information. Briviact (brivaracetam). UCB Pharma Inc, Smyrna, GA.
• [18] Faculty of Sexual & Reproductive Healthcare "FSRH Clinical Guidance: Drug Interactions with Hormonal Contraception.".
• [19] Back DJ, Breckenridge AM, Crawford F, et al. "The effect of rifampicin on norethisterone pharmacokinetics." Eur J Clin Pharmacol 15 (1979): 193-7. [PMID: 37091]
• [20] Product Information. Prezista (darunavir). Ortho Biotech Inc, Bridgewater, NJ.
• [21] Gunston GD, Mehta U "Potentially serious drug interactions with grapefruit juice." S Afr Med J 90 (2000): 41. [PMID: 10721388]
• [22] Cerner Multum, Inc. "UK Summary of Product Characteristics.".