Lonafarnib

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Identification

Summary

Lonafarnib is a potent farnesyl transferase inhibitor used to reduce mortality associated with Hutchinson-Gilford progeria syndrome (HGPS) and other progeroid laminopathies.

Brand Names

Zokinvy

Generic Name

Lonafarnib

DrugBank Accession Number

DB06448

Background

Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant disorder estimated to affect approximately one in 20 million individuals resulting in adverse symptoms associated with premature ageing: skeletal dysplasia, joint contractures, atherosclerosis, myocardial fibrosis/dysfunction, scleroderma-like cutaneous effects, lipoatrophy, alopecia, and a severe failure to thrive; HGPS is uniformly fatal.^1,2,3,4,5 Mechanistically, HGPS is underpinned by a single heterozygous C-to-T mutation at position 1824 of the LMNA gene, which results in the accumulation of an aberrant farnesylated form of lamin A called progerin in the inner nuclear membrane.^1,4 Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), which reduces the farnesylation of numerous cellular proteins, including progerin; as progerin farnesylation is important for localization to the nuclear membrane, lonafarnib inhibits progerin accumulation and improves symptoms in HGPS patients.^1,9,10,13

Merck originally developed Lonafarnib and subsequently licensed it to Eiger Biopharmaceuticals Inc., which currently markets it under the trademark ZOKINVY™.^13,14 Lonafarnib was granted FDA approval on November 20, 2020, and is the first FDA-approved treatment for HGPS and other related progeroid laminopathies.^13,15

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 638.822
Monoisotopic: 636.050229257
Chemical Formula: C₂₇H₃₁Br₂ClN₄O₂

Synonyms

Lonafarnib
Lonafarnibum

External IDs

SCH 66336
SCH-66336
SCH66336

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Pharmacology

Indication

Lonafarnib is a farnesyltransferase inhibitor indicated in patients aged 12 months and older with a body surface area of at least 0.39 m² to reduce the risk of mortality associated with Hutchinson-Gilford progeria syndrome (HGPS). It is also indicated in this same population for the treatment of processing-deficient progeroid laminopathies that either involve a heterozygous LMNA mutation resulting in the accumulation of a progerin-like protein or homozygous/compound heterozygous mutations in ZMPSTE24.¹³

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Associated Conditions

Indication Type	Indication	Approval Level	Patient Characteristics	Dose Form
Prevention of	Death	••••••••••••	•••• ••••••• •••• •• •••• •• ••• •••••	•••••••
Treatment of	Hutchinson-gilford progeria syndrome	••••••••••••		•••••••
Treatment of	Processing-deficient progeroid laminopathies	••••••••••••	•••• ••••••• •••• •• •••• •• ••• •••••	•••••••
Treatment of	Processing-deficient progeroid laminopathies	••••••••••••	•••• ••••••• •••• •• •••• •• ••• •••••	•••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Lonafarnib is a direct farnesyl transferase inhibitor that reduces the farnesylation of numerous cellular proteins, including progerin, the aberrantly truncated form of lamin A that accumulates in progeroid laminopathies such as Hutchinson-Gilford progeria syndrome. Treatment with lonafarnib has been associated with electrolyte abnormalities, myelosuppression, and increased liver enzyme levels (AST/ALT), although causation remains unclear. Also, lonafarnib is known to cause nephrotoxicity in rats and rod-dependent low-light vision decline in monkeys at plasma levels similar to those achieved under recommended dosing guidelines in humans; patients taking lonafarnib should undergo regular monitoring for both renal and ophthalmological function. In addition, based on observations from animal studies with rats, monkeys, and rabbits with plasma drug concentrations approximately equal to those attained in humans, lonafarnib may cause both male and female fertility impairment and embryo-fetal toxicity.¹³

Mechanism of action

Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant disorder estimated to affect approximately one in 20 million individuals resulting in premature ageing, associated cardiovascular, cerebrovascular, and musculoskeletal effects and early death around 14 years of age.^1,2,3,4 The LMNA gene encodes lamin A and lamin C, two proteins involved in nuclear integrity and function at the inner nuclear membrane. Under normal conditions, the 12-exon LMNA gene produces full-length prelamin A, which undergoes farnesylation of the C-terminal CaaX motif, followed by proteolytic cleavage of the terminal three amino acids (aaX) by the metalloproteinase ZMPSTE24, subsequent carboxymethylation, and finally removal of the last 15 amino acids to yield mature, unfarnesylated, lamin A protein.^1,4 In HGPS, a single heterozygous C-to-T mutation at position 1824 results in a cryptic splice site that removes the last 150 nucleotides of exon 11 and a concomitant 50-amino acid deletion in the C-terminus of the prelamin A protein. This aberrant prelamin A protein, often called progerin, is permanently farnesylated but unable to complete maturation due to the removal of the second endoproteolytic cleavage site.^1,4

Although the exact mechanism is unclear, progerin accumulation results in a host of adverse symptoms associated with ageing such as skeletal dysplasia, joint contractures, atherosclerosis, myocardial fibrosis/dysfunction, scleroderma-like cutaneous effects, lipoatrophy, alopecia, and a severe failure to thrive.^1,2,3,4,5 An additional notable effect of HGPS is increased vascular and peripheral calcification.⁶ Children affected by HGPS typically die due to myocardial infarction or stroke.⁵ Mechanistic understanding of HGPS remains unclear, although a recent study correlated progerin accumulation, telomere dysfunction, DNA damage-mediated inflammatory cytokine release, and HGPS symptoms, suggesting that the nuclear effects of progerin accumulation may result in pleiotropic downstream effects.⁷

Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), with a reported IC₅₀ value of 1.9 nM; lonafarnib is specific for FTase, as it does not appreciably inhibit the related GGPT-1 enzyme at concentrations up to 50 μM.⁸ Inhibition of progerin farnesylation reduces progerin accumulation in the inner nuclear membrane, which subsequently slows the progression of HGPS and other progeroid laminopathies.^1,9,10,13

Target	Actions	Organism
AProtein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	inhibitor	Humans
AProtein farnesyltransferase subunit beta	inhibitor	Humans

Absorption

The absolute oral bioavailability of lonafarnib is unknown; in healthy subjects administration of either 75 or 100 mg of lonafarnib twice daily resulted in mean peak plasma concentrations (%CV) of 834 (32%) and 964 (32%) ng/mL, respectively. Twice daily administration of 115 mg/m² lonafarnib in HGPS patients resulted in a median t_max of 2 hours (range 0-6), mean C_max of 1777 ± 1083 ng/mL, mean AUC_0-8hr of 9869 ± 6327 ng*hr/mL, and a mean AUC_tau of 12365 ± 9135 ng*hr/mL. The corresponding values for a dose of 150 mg/m² are: 4 hours (range 0-12), 2695 ± 1090 ng/mL, 16020 ± 4978 ng*hr/mL, and 19539 ± 6434 ng*hr/mL, respectively.¹³

Following a single oral dose of 75 mg in healthy subjects, the C_max of lonafarnib decreased by 55% and 25%, and the AUC decreased by 29% and 21% for a high/low-fat meal compared to fasted conditions.¹³

Volume of distribution

In healthy patients administered either 75 or 100 mg lonafarnib twice daily, the steady-state apparent volumes of distribution were 97.4 L and 87.8 L, respectively.¹³

Protein binding

Lonafarnib exhibits in vitro plasma protein binding of ≥99% over a concentration range of 0.5-40.0 μg/mL.¹³

Metabolism

Lonafarnib is metabolized in vitro primarily by CYP3A4/5 and partially by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1.^11,13 Formation of the primary metabolites involves oxidation and subsequent dehydration in the pendant piperidine ring.^11,12

Hover over products below to view reaction partners

Lonafarnib
- Lonafarnib metabolite M1
  - Lonafarnib metabolite M2

Route of elimination

Up to 240 hours following oral administration of 104 mg [14C]-lonafarnib in fasted healthy subjects, approximately 62% and <1% of the initial radiolabeled dose was recovered in feces and urine, respectively. The two most prevalent metabolites were the active HM21 and HM17, which account for 14% and 15% of plasma radioactivity.¹³

Half-life

Lonafarnib has a mean half-life of approximately 4-6 hours following oral administration of 100 mg twice daily in healthy subjects.¹³

Clearance

Not Available

Adverse Effects

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Toxicity

Toxicity information regarding lonafarnib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as altered electrolyte, blood cell, and liver enzyme levels, retinal toxicity, nephrotoxicity, fertility impairment, and embryo-fetal toxicity. Symptomatic and supportive measures are recommended.¹³

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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1,2-Benzodiazepine	The metabolism of 1,2-Benzodiazepine can be decreased when combined with Lonafarnib.
Abametapir	The serum concentration of Lonafarnib can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Lonafarnib can be increased when combined with Abatacept.
Abemaciclib	The metabolism of Abemaciclib can be decreased when combined with Lonafarnib.
Abiraterone	The metabolism of Abiraterone can be decreased when combined with Lonafarnib.

Food Interactions

Avoid grapefruit products. Co-administration with strong or moderate CYP3A inhibitors is contraindicated; avoid consuming grapefruit or Seville oranges.
Take with food. Administration with food is recommended to reduce gastrointestinal adverse reactions. However, co-administration with food does affect lonafarnib absorption.

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International/Other Brands

Sarasar

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Zokinvy	Capsule	75 mg/1	Oral	Eiger BioPharmaceuticals, Inc.	2020-11-20	Not applicable
Zokinvy	Capsule	75 mg	Oral	Eiger Bio Europe Limited	2022-08-02	Not applicable
Zokinvy	Capsule	50 mg/1	Oral	Eiger BioPharmaceuticals, Inc.	2020-11-20	Not applicable
Zokinvy	Capsule	50 mg	Oral	Eiger Bio Europe Limited	2022-08-02	Not applicable

Chemical Identifiers

UNII: IOW153004F
CAS number: 193275-84-2
InChI Key: DHMTURDWPRKSOA-RUZDIDTESA-N
InChI: InChI=1S/C27H31Br2ClN4O2/c28-20-12-19-2-1-18-13-21(30)14-22(29)24(18)25(26(19)32-15-20)17-5-9-33(10-6-17)23(35)11-16-3-7-34(8-4-16)27(31)36/h12-17,25H,1-11H2,(H2,31,36)/t25-/m1/s1
IUPAC Name: 4-(2-{4-[(2R)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl]piperidin-1-yl}-2-oxoethyl)piperidine-1-carboxamide
SMILES: NC(=O)N1CCC(CC(=O)N2CCC(CC2)[C@H]2C3=C(CCC4=C2C(Br)=CC(Cl)=C4)C=C(Br)C=N3)CC1

References

Synthesis Reference

Njoroge FG, Taveras AG, Kelly J, Remiszewski S, Mallams AK, Wolin R, Afonso A, Cooper AB, Rane DF, Liu YT, Wong J, Vibulbhan B, Pinto P, Deskus J, Alvarez CS, del Rosario J, Connolly M, Wang J, Desai J, Rossman RR, Bishop WR, Patton R, Wang L, Kirschmeier P, Ganguly AK, et al.: (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem. 1998 Nov 19;41(24):4890-902.

General References

Cubria MB, Suarez S, Masoudi A, Oftadeh R, Kamalapathy P, DuBose A, Erdos MR, Cabral WA, Karim L, Collins FS, Snyder BD, Nazarian A: Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups. Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12029-12040. doi: 10.1073/pnas.1906713117. Epub 2020 May 13. [Article]
Prakash A, Gordon LB, Kleinman ME, Gurary EB, Massaro J, D'Agostino R Sr, Kieran MW, Gerhard-Herman M, Smoot L: Cardiac Abnormalities in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA Cardiol. 2018 Apr 1;3(4):326-334. doi: 10.1001/jamacardio.2017.5235. [Article]
Ullrich NJ, Kieran MW, Miller DT, Gordon LB, Cho YJ, Silvera VM, Giobbie-Hurder A, Neuberg D, Kleinman ME: Neurologic features of Hutchinson-Gilford progeria syndrome after lonafarnib treatment. Neurology. 2013 Jul 30;81(5):427-30. doi: 10.1212/WNL.0b013e31829d85c0. Epub 2013 Jun 28. [Article]
Young SG, Yang SH, Davies BS, Jung HJ, Fong LG: Targeting protein prenylation in progeria. Sci Transl Med. 2013 Feb 6;5(171):171ps3. doi: 10.1126/scitranslmed.3005229. [Article]
Xu S, Jin ZG: Hutchinson-Gilford Progeria Syndrome: Cardiovascular Pathologies and Potential Therapies. Trends Biochem Sci. 2019 Jul;44(7):561-564. doi: 10.1016/j.tibs.2019.03.010. Epub 2019 Apr 26. [Article]
Gordon CM, Cleveland RH, Baltrusaitis K, Massaro J, D'Agostino RB Sr, Liang MG, Snyder B, Walters M, Li X, Braddock DT, Kleinman ME, Kieran MW, Gordon LB: Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome. Bone. 2019 Aug;125:103-111. doi: 10.1016/j.bone.2019.05.008. Epub 2019 May 8. [Article]
Li Y, Zhou G, Bruno IG, Zhang N, Sho S, Tedone E, Lai TP, Cooke JP, Shay JW: Transient introduction of human telomerase mRNA improves hallmarks of progeria cells. Aging Cell. 2019 Aug;18(4):e12979. doi: 10.1111/acel.12979. Epub 2019 May 31. [Article]
Njoroge FG, Taveras AG, Kelly J, Remiszewski S, Mallams AK, Wolin R, Afonso A, Cooper AB, Rane DF, Liu YT, Wong J, Vibulbhan B, Pinto P, Deskus J, Alvarez CS, del Rosario J, Connolly M, Wang J, Desai J, Rossman RR, Bishop WR, Patton R, Wang L, Kirschmeier P, Ganguly AK, et al.: (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem. 1998 Nov 19;41(24):4890-902. [Article]
Gordon LB, Shappell H, Massaro J, D'Agostino RB Sr, Brazier J, Campbell SE, Kleinman ME, Kieran MW: Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA. 2018 Apr 24;319(16):1687-1695. doi: 10.1001/jama.2018.3264. [Article]
Gordon LB, Kleinman ME, Massaro J, D'Agostino RB Sr, Shappell H, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland RH, Nazarian A, Snyder BD, Ullrich NJ, Silvera VM, Liang MG, Quinn N, Miller DT, Huh SY, Dowton AA, Littlefield K, Greer MM, Kieran MW: Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Circulation. 2016 Jul 12;134(2):114-25. doi: 10.1161/CIRCULATIONAHA.116.022188. [Article]
Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, Zbaida S: Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006 Apr;34(4):628-35. doi: 10.1124/dmd.105.007906. Epub 2006 Jan 27. [Article]
Tong W, Chowdhury SK, Su AD, Feng W, Ghosal A, Alton KB: Identification of unstable metabolites of Lonafarnib using liquid chromatography-quadrupole time-of-flight mass spectrometry, stable isotope incorporation and ion source temperature alteration. J Mass Spectrom. 2006 Nov;41(11):1430-41. doi: 10.1002/jms.1114. [Article]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]
Eiger Bio: Lonafarnib license agreement [Link]
FDA Press Announcement: FDA Approves First Treatment for Hutchinson-Gilford Progeria Syndrome and Some Progeroid Laminopathies [Link]
Cayman Chemical: lonafarnib MSDS [Link]
EMA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

External Links

Human Metabolome Database: HMDB0304871
PubChem Compound: 148195
ChemSpider: 130645
BindingDB: 14459
RxNav: 2467553
ChEBI: 47097
ChEMBL: CHEMBL298734
ZINC: ZINC000003950115
PharmGKB: PA166129466
PDBe Ligand: 336
Wikipedia: Lonafarnib

PDB Entries

1o5m / 8kg5 / 8phi

Clinical Trials

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
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3	Active Not Recruiting	Treatment	Hepatitis D, Chronic	1	somestatus	stop reason	just information to hide
3	Completed	Treatment	Hepatitis Delta Virus	1	somestatus	stop reason	just information to hide
3	Terminated	Treatment	Chronic Myelomonocytic Leukemia / Myelodysplastic Syndrome / Myelomonocytic	1	somestatus	stop reason	just information to hide
3	Terminated	Treatment	Metastatic Cancer / Non-Small Cell Lung Carcinoma	1	somestatus	stop reason	just information to hide
2	Active Not Recruiting	Treatment	Hutchinson-Gilford Progeria Syndrome	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	50 mg
Capsule	Oral	50 mg/1
Capsule	Oral	75 mg
Capsule	Oral	75 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8828356	No	2014-09-09	2023-10-17
US7838531	No	2010-11-23	2024-07-26

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	~3mg/ml	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.000829 mg/mL	ALOGPS
logP	5.34	ALOGPS
logP	4.74	Chemaxon
logS	-5.9	ALOGPS
pKa (Strongest Acidic)	15.75	Chemaxon
pKa (Strongest Basic)	3.28	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	3	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	79.53 Å²	Chemaxon
Rotatable Bond Count	3	Chemaxon
Refractivity	149.31 m³·mol^-1	Chemaxon
Polarizability	60.09 Å³	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9971
Blood Brain Barrier	+	0.9837
Caco-2 permeable	-	0.6451
P-glycoprotein substrate	Substrate	0.6145
P-glycoprotein inhibitor I	Inhibitor	0.8218
P-glycoprotein inhibitor II	Non-inhibitor	0.7588
Renal organic cation transporter	Inhibitor	0.6161
CYP450 2C9 substrate	Non-substrate	0.849
CYP450 2D6 substrate	Non-substrate	0.6877
CYP450 3A4 substrate	Substrate	0.5869
CYP450 1A2 substrate	Non-inhibitor	0.6897
CYP450 2C9 inhibitor	Non-inhibitor	0.6924
CYP450 2D6 inhibitor	Non-inhibitor	0.8235
CYP450 2C19 inhibitor	Inhibitor	0.5078
CYP450 3A4 inhibitor	Inhibitor	0.5372
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.776
Ames test	Non AMES toxic	0.6428
Carcinogenicity	Non-carcinogens	0.9177
Biodegradation	Not ready biodegradable	0.9858
Rat acute toxicity	2.6286 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.7635
hERG inhibition (predictor II)	Inhibitor	0.8517

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-000l-0000069000-40de4d56d77366084884
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-000i-0000009000-ce8f14e33f84045cea7a
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-000i-0000339000-9722b4bd15ca9e5be1f2
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-000f-3200098000-fda27ff9b087a8c5ffb8
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-01tc-9000171000-f7a7c8d5df19d3852ea3
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-2000192000-989a8d5990a79cc53e6e

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	214.94221	predicted	DeepCCS 1.0 (2019)
[M+H]+	217.33778	predicted	DeepCCS 1.0 (2019)
[M+Na]+	223.25032	predicted	DeepCCS 1.0 (2019)

Targets

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Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	1.9	7.5	22	A30625
IC 50 (nM)	1.9	N/A	N/A	A30626 / A30628 / A30629 / A30630
IC 50 (nM)	1900	N/A	N/A	A30627
IC 50 (nM)	10	N/A	N/A	A30628
IC 50 (nM)	2	N/A	N/A	A30631 / A30632
IC 50 (nM)	500000	N/A	N/A	A30632

Details1. Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor
Curator comments: Lonafarnib inhibits farnesyl transferase with an IC50 of 1.9nM.

General Function: Essential subunit of both the farnesyltransferase and the geranylgeranyltransferase complex. Contributes to the transfer of a farnesyl or geranylgeranyl moiety from farnesyl or geranylgeranyl diphosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. May positively regulate neuromuscular junction development downstream of MUSK via its function in RAC1 prenylation and activation
Specific Function: Alpha-tubulin binding
Gene Name: FNTA
Uniprot ID: P49354
Uniprot Name: Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha
Molecular Weight: 44408.32 Da

References

Lee HY, Moon H, Chun KH, Chang YS, Hassan K, Ji L, Lotan R, Khuri FR, Hong WK: Effects of insulin-like growth factor binding protein-3 and farnesyltransferase inhibitor SCH66336 on Akt expression and apoptosis in non-small-cell lung cancer cells. J Natl Cancer Inst. 2004 Oct 20;96(20):1536-48. [Article]
Medeiros BC, Landau HJ, Morrow M, Lockerbie RO, Pitts T, Eckhardt SG: The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines. Leukemia. 2007 Apr;21(4):739-46. Epub 2007 Feb 1. [Article]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details2. Protein farnesyltransferase subunit beta

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor
Curator comments: Lonafarnib inhibits farnesyl transferase with an IC50 of 1.9nM.

General Function: Essential subunit of the farnesyltransferase complex. Catalyzes the transfer of a farnesyl moiety from farnesyl diphosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X
Specific Function: Protein farnesyltransferase activity
Gene Name: FNTB
Uniprot ID: P49356
Uniprot Name: Protein farnesyltransferase subunit beta
Molecular Weight: 48773.2 Da

References

FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function: 1,8-cineole 2-exo-monooxygenase activity
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, Zbaida S: Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006 Apr;34(4):628-35. doi: 10.1124/dmd.105.007906. Epub 2006 Jan 27. [Article]
Flockhart Table of Drug Interactions [Link]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]

Details2. Cytochrome P450 3A5

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
Specific Function: Aromatase activity
Gene Name: CYP3A5
Uniprot ID: P20815
Uniprot Name: Cytochrome P450 3A5
Molecular Weight: 57108.065 Da

References

Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, Zbaida S: Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006 Apr;34(4):628-35. doi: 10.1124/dmd.105.007906. Epub 2006 Jan 27. [Article]
Flockhart Table of Drug Interactions [Link]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]

Details3. Cytochrome P450 3A Subfamily (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor
Curator comments: Lonafarnib is primarily metabolized by CYP3A, and is also a potent time-dependent CYP3A inhibitor.

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function: 1,8-cineole 2-exo-monooxygenase activity

Components:

Name	UniProt ID
Cytochrome P450 3A4	P08684
Cytochrome P450 3A43	Q9HB55
Cytochrome P450 3A5	P20815
Cytochrome P450 3A7	P24462

References

Flockhart Table of Drug Interactions [Link]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details4. Cytochrome P450 2C8

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
Specific Function: Arachidonic acid epoxygenase activity
Gene Name: CYP2C8
Uniprot ID: P10632
Uniprot Name: Cytochrome P450 2C8
Molecular Weight: 55824.275 Da

References

Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, Zbaida S: Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006 Apr;34(4):628-35. doi: 10.1124/dmd.105.007906. Epub 2006 Jan 27. [Article]
Flockhart Table of Drug Interactions [Link]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details5. Cytochrome P450 2C9

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
Specific Function: (r)-limonene 6-monooxygenase activity
Gene Name: CYP2C9
Uniprot ID: P11712
Uniprot Name: Cytochrome P450 2C9
Molecular Weight: 55627.365 Da

References

Flockhart Table of Drug Interactions [Link]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details6. Cytochrome P450 2C19

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
Specific Function: (r)-limonene 6-monooxygenase activity
Gene Name: CYP2C19
Uniprot ID: P33261
Uniprot Name: Cytochrome P450 2C19
Molecular Weight: 55944.565 Da

References

Flockhart Table of Drug Interactions [Link]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details7. Cytochrome P450 1A2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
Specific Function: Aromatase activity
Gene Name: CYP1A2
Uniprot ID: P05177
Uniprot Name: Cytochrome P450 1A2
Molecular Weight: 58406.915 Da

References

Flockhart Table of Drug Interactions [Link]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details8. Cytochrome P450 2A6

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity
Specific Function: Arachidonic acid epoxygenase activity
Gene Name: CYP2A6
Uniprot ID: P11509
Uniprot Name: Cytochrome P450 2A6
Molecular Weight: 56517.005 Da

References

FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details9. Cytochrome P450 2E1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of fatty acids (PubMed:10553002, PubMed:18577768). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10553002, PubMed:18577768). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates fatty acids specifically at the omega-1 position displaying the highest catalytic activity for saturated fatty acids (PubMed:10553002, PubMed:18577768). May be involved in the oxidative metabolism of xenobiotics (Probable)
Specific Function: 4-nitrophenol 2-monooxygenase activity
Gene Name: CYP2E1
Uniprot ID: P05181
Uniprot Name: Cytochrome P450 2E1
Molecular Weight: 56848.42 Da

References

Flockhart Table of Drug Interactions [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Transporters

Details1. ATP-dependent translocase ABCB1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function: Abc-type xenobiotic transporter activity
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: ATP-dependent translocase ABCB1
Molecular Weight: 141477.255 Da

References

Wang E, Casciano CN, Clement RP, Johnson WW: The farnesyl protein transferase inhibitor SCH66336 is a potent inhibitor of MDR1 product P-glycoprotein. Cancer Res. 2001 Oct 15;61(20):7525-9. [Article]
Wang EJ, Johnson WW: The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2. Chemotherapy. 2003 Dec;49(6):303-8. doi: 10.1159/000074531. [Article]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details2. Solute carrier organic anion transporter family member 1B1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
Specific Function: Bile acid transmembrane transporter activity
Gene Name: SLCO1B1
Uniprot ID: Q9Y6L6
Uniprot Name: Solute carrier organic anion transporter family member 1B1
Molecular Weight: 76447.99 Da

References

FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details3. Solute carrier organic anion transporter family member 1B3

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
Specific Function: Bile acid transmembrane transporter activity
Gene Name: SLCO1B3
Uniprot ID: Q9NPD5
Uniprot Name: Solute carrier organic anion transporter family member 1B3
Molecular Weight: 77402.175 Da

References

FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details4. Broad substrate specificity ATP-binding cassette transporter ABCG2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
Specific Function: Abc-type xenobiotic transporter activity
Gene Name: ABCG2
Uniprot ID: Q9UNQ0
Uniprot Name: Broad substrate specificity ATP-binding cassette transporter ABCG2
Molecular Weight: 72313.47 Da

References

FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Approved Drug Products: Zokinvy (lonafarnib) capsules [Link]

Details5. ATP-binding cassette sub-family C member 2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:11500505). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:16332456). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (PubMed:10220572, PubMed:11500505, PubMed:12441801). Confers resistance to several anti-cancer drugs including cisplatin, doxorubicin, epirubicin, methotrexate, etoposide and vincristine (PubMed:10220572, PubMed:11500505)
Specific Function: Abc-type glutathione s-conjugate transporter activity
Gene Name: ABCC2
Uniprot ID: Q92887
Uniprot Name: ATP-binding cassette sub-family C member 2
Molecular Weight: 174205.64 Da

References

Wang EJ, Johnson WW: The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2. Chemotherapy. 2003 Dec;49(6):303-8. doi: 10.1159/000074531. [Article]

Drug created at March 19, 2008 16:33 / Updated at September 05, 2022 12:50

Lonafarnib

Identification

Structure for Lonafarnib (DB06448)

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