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Trastuzumab deruxtecan

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Identification

Summary

Trastuzumab deruxtecan is an antibody used to treat certain types of unresectable or metastatic HER2 positive breast cancer.

Brand Names
Enhertu
Generic Name
Trastuzumab deruxtecan
DrugBank Accession Number
DB14962
Background

Trastuzumab deruxtecan is a HER2-directed antibody attached to a topoisomerase inhibitor that is approved for use in certain types of treatment-resistant HER2-positive cancers.6 It is classified as an antibody-drug conjugate. The cleavable peptide linker used to bind the antibody and drug in this product distinguishes it from other members of its class.4

Trastuzumab deruxtecan was developed by Daiichi Sankyo in collaboration with AstraZeneca and was first approved by the FDA in 2019.6

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
Not Available
Synonyms
  • fam-trastuzumab deruxtecan-nxki
  • Trastuzumab deruxtecan
External IDs
  • DS-8201
  • DS-8201A
  • WHO 10516
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Pharmacology

Indication

Trastuzumab deruxtecan is indicated for the following conditions:

HER2-Positive Breast Cancer

  • This indication is approved in the US, Canada, and Europe.
  • It is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen.10,8,9 In the US and Canada, it is used either in the metastatic setting or in the neoadjuvant or adjuvant setting in patients who have developed disease recurrence during or within six months of completing therapy.10,8
  • In Canada, it is also used in patients who have received prior treatment with trastuzumab emtansine (T-DM1).8

HER2-Low Breast Cancer

  • This indication is approved in the US, Canada, and Europe.
  • It is indicated for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.10,8,9

Non-small cell lung cancer (NSCLC)

  • This indication is approved in the US and Europe.
  • It is indicated for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have activating HER2 (ERBB2) mutations and who have received prior systemic therapy.10,9 In Europe, it is used in patients who require systemic therapy following platinum-based chemotherapy with or without immunotherapy.9

Gastric cancer

  • This indication is approved in the US and Europe.
  • It is indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.10,9

Solid Tumors

  • This indication is approved in the US.
  • It is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours who have received prior systemic treatment and have no satisfactory alternative treatment options.10
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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofMetastatic breast cancer with her2 positive••••••••••••••••••••••••• ••••••••• •••• ••••••••••• •••••••••
Treatment ofMetastatic breast cancer with her2 positive•••••••••••••••••••••• ••••••••••••••• •••••••
Treatment ofMetastatic breast cancer with her2 positive•••••••••••••••••••••• ••••••••••••••• •••••••• •••• •••••••• •• ••••••••••• ••••••• •• •• •••••• • ••••••
Treatment ofMetastatic non-small cell lung cancer••••••••••••••••••••••••• •••••••••••••• ••••••••••••• ••••• •••• ••••••••• ••••••• •••••••• •••••••
Treatment ofMetastatic non-small cell lung cancer•••••••••••••••••••••••••••••• •••••••••••••• ••••••• •••••••• •••••••• ••••• •••• ••••••••• •••••••• •••••••••••••• ••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Trastuzumab demonstrates antitumor activity against certain types of HER2 positive breast cancer, however, clinical trials are still ongoing to confirm its efficacy.3,6,7 By exploiting both targeted antibody and cytotoxic effects, trastuzumab deruxtecan can effectively destroy tumors.4

The FDA label warns of a potential risk for neutropenia, interstitial lung disease/pneumonitis, and left ventricular dysfunction following the use of this drug.6

Mechanism of action

Trastuzumab deruxtecan is a humanized anti-HER2 IgG1 antibody, targeting cancer cause by mutation of the HER2 gene. In addition, the small molecule portion of this drug, deruxtecan (DXd), is a topoisomerase I inhibitor.1,6 It is attached to the antibody by a peptide linker. After trastuzumab deruxtecan binds to HER2 found on malignant cells, it is internalized and linker cleavage occurs through the actions of lysosomal enzymes. After it is released through cleavage, DXd causes targeted DNA damage and apoptosis in cancer cells, due to the ability to cross cell membranes.4,6

Normally, drugs in this class (antibody-drug conjugates) present a challenge. The monoclonal antibody accurately targets cancer cells, however exert limited killing action. The addition of a cytotoxic agent (a topoisomerase I inhibitor in this case) effectively kills dividing cancer cells, including those in the healthy tissues, leading to various adverse effects. The peptide linker used to formulate this drug is cleavable, which is unique to other antibody-drug conjugates, allowing for increased efficacy and reduced drug resistance to topoisomerase.4

TargetActionsOrganism
AHigh affinity immunoglobulin gamma Fc receptor I
antibody
Humans
ADNA topoisomerase 1
inhibitor
Humans
Absorption

The Cmax of trastuzumab deruxtecan at normal therapeutic doses was 122 μg/mL (20%). The AUC of trastuzumab deruxtecan was 735 μg·day/mL (31%).6

Volume of distribution

The estimated volume of distribution of trastuzumab deruxtecan in the central compartment is 2.77 L, according to a population based pharmacokinetic study.6 Pharmacokinetic studies found that the unchanged drug is distributed in the blood and is not significantly retained in tissues.2

Protein binding

The Dxd portion of the drug has a plasma protein binding estimated at 97%.6

Metabolism

Trastuzumab deruxtecan is likely broken down into small peptides and amino acids through catabolism, just as the metabolism of endogenous IgG.5,6 Cathepsin B and L enzymes are thought to be involved in the cleavage of the peptide linker that joins the topoisomerase I inhibitor and the antibody.4 In vitro, DXd, the topoisomerase inhibitor portion of the drug, is found to be metabolized by CYP3A4.6

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Route of elimination

A pharmacokinetic study revealed that this drug was mainly excreted in the feces. Another study determined that 67% of a dose was excreted in the feces.2,4 Unmetabolized DXd was found in the urine during a pharmacokinetic study.2

Half-life

In a pharmacokinetic study, the median elimination half-life of trastuzumab deruxtecan was about 5.8 days.6

Clearance

Trastuzumab deruxtecan is rapidly cleared from systemic circulation.2 Estimated systemic clearance of trastuzumab deruxtecan is 0.42 L/day, according to a population pharmacokinetic analysis. DXd showed a systemic clearance of about 19.2 L/h.6

Adverse Effects
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Toxicity

LD50 and overdose information are not currently available, but effects of an overdose are likely to impact the lungs, heart, and circulatory system, leading to significant toxicity.6

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.
DrugInteraction
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interactions in your software
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Trastuzumab deruxtecan.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Trastuzumab deruxtecan.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Trastuzumab deruxtecan.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Trastuzumab deruxtecan.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Trastuzumab deruxtecan.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EnhertuInjection, powder, lyophilized, for solution100 mg/5mLIntravenousDaiichi Sankyo Inc.2019-12-20Not applicableUS flag
EnhertuInjection, powder, for solution100 mgIntravenousDaiichi Sankyo Europe, Gmb H2021-03-03Not applicableEU flag
EnhertuPowder, for solution100 mg / vialIntravenousAstra Zeneca2021-07-09Not applicableCanada flag

Categories

ATC Codes
L01FD04 — Trastuzumab deruxtecan
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
5384HK7574
CAS number
1826843-81-5

References

Synthesis Reference

Nakada T, Masuda T, Naito H, Yoshida M, Ashida S, Morita K, Miyazaki H, Kasuya Y, Ogitani Y, Yamaguchi J, Abe Y2, Honda T2. (2016).Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg Med Chem Lett.,Mar 15;26(6):1542-1545

General References
  1. Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, Sagara Y, Doi T, Park H, Murthy RK, Redman RA, Jikoh T, Lee C, Sugihara M, Shahidi J, Yver A, Modi S: Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 2019 Jun;20(6):816-826. doi: 10.1016/S1470-2045(19)30097-X. Epub 2019 Apr 29. [Article]
  2. Nagai Y, Oitate M, Shiozawa H, Ando O: Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys. Xenobiotica. 2019 Sep;49(9):1086-1096. doi: 10.1080/00498254.2018.1531158. Epub 2019 Jan 4. [Article]
  3. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I: Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2019 Dec 11. doi: 10.1056/NEJMoa1914510. [Article]
  4. Xu Z, Guo D, Jiang Z, Tong R, Jiang P, Bai L, Chen L, Zhu Y, Guo C, Shi J, Yu D: Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019 Dec 1;183:111682. doi: 10.1016/j.ejmech.2019.111682. Epub 2019 Sep 6. [Article]
  5. Kendrick F, Evans ND, Arnulf B, Avet-Loiseau H, Decaux O, Dejoie T, Fouquet G, Guidez S, Harel S, Hebraud B, Javaugue V, Richez V, Schraen S, Touzeau C, Moreau P, Leleu X, Harding S, Chappell MJ: Analysis of a Compartmental Model of Endogenous Immunoglobulin G Metabolism with Application to Multiple Myeloma. Front Physiol. 2017 Mar 17;8:149. doi: 10.3389/fphys.2017.00149. eCollection 2017. [Article]
  6. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]
  7. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies [Link]
  8. Health Canada Approved Drug Products: Enhertu (trastuzumab deruxtecan) powder for concentrate for intravenous infusion [Link]
  9. EMA Approved Drug Products: Enhertu (Trastuzumab deruxtecan) Powder for concentrate for solution for infusion. [Link]
  10. FDA Approved Drug Products: ENHERTU (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use (April 2024) [Link]
RxNav
2267574
Wikipedia
Trastuzumab_deruxtecan

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
Not AvailableActive Not RecruitingNot AvailableBreast Cancer / Metastatic Cancer1somestatusstop reasonjust information to hide
Not AvailableRecruitingNot AvailableAdvanced Malignant Neoplasm / Breast Cancer / HER2-low Breast Cancer / HER2/Neu-positive Breast Cancer1somestatusstop reasonjust information to hide
Not AvailableRecruitingNot AvailableHER2-low Breast Cancer / HER2/Neu-positive Breast Cancer / Metastatic Breast Cancer / Unresectable Breast Cancer1somestatusstop reasonjust information to hide
4Not Yet RecruitingTreatmentBreast Cancer2somestatusstop reasonjust information to hide
4RecruitingDiagnosticAnatomic Stage IV Breast Cancer AJCC v8 / Brain Metastases / Metastatic Breast Carcinoma1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous100 MG
Injection, powder, lyophilized, for solutionIntravenous100 mg/5mL
Powder, for solutionIntravenous100 mg / vial
Injection, solution, concentrateIntravenous100 mg
SolutionIntravenous100 mg
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

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Details1. High affinity immunoglobulin gamma Fc receptor I
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
High affinity receptor for the Fc region of immunoglobulins gamma. Functions in both innate and adaptive immune responses. Mediates IgG effector functions on monocytes triggering antibody-dependent cellular cytotoxicity (ADCC) of virus-infected cells
Specific Function
High-affinity igg receptor activity
Gene Name
FCGR1A
Uniprot ID
P12314
Uniprot Name
High affinity immunoglobulin gamma Fc receptor I
Molecular Weight
42631.525 Da
References
  1. Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, Sagara Y, Doi T, Park H, Murthy RK, Redman RA, Jikoh T, Lee C, Sugihara M, Shahidi J, Yver A, Modi S: Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 2019 Jun;20(6):816-826. doi: 10.1016/S1470-2045(19)30097-X. Epub 2019 Apr 29. [Article]
  2. Nagai Y, Oitate M, Shiozawa H, Ando O: Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys. Xenobiotica. 2019 Sep;49(9):1086-1096. doi: 10.1080/00498254.2018.1531158. Epub 2019 Jan 4. [Article]
  3. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]
Details2. DNA topoisomerase 1
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the BMAL1 promoter
Specific Function
Atp binding
Gene Name
TOP1
Uniprot ID
P11387
Uniprot Name
DNA topoisomerase 1
Molecular Weight
90725.19 Da
References
  1. Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, Sagara Y, Doi T, Park H, Murthy RK, Redman RA, Jikoh T, Lee C, Sugihara M, Shahidi J, Yver A, Modi S: Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 2019 Jun;20(6):816-826. doi: 10.1016/S1470-2045(19)30097-X. Epub 2019 Apr 29. [Article]
  2. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]

Enzymes

Details1. Lysosomal alpha-glucosidase
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Lysosomal glucosidase is a popular lysosomal enzyme and likely participates in the breakdown of this drug, but other lysosomal enzymes also contribute.
General Function
Essential for the degradation of glycogen in lysosomes (PubMed:14695532, PubMed:18429042, PubMed:1856189, PubMed:7717400). Has highest activity on alpha-1,4-linked glycosidic linkages, but can also hydrolyze alpha-1,6-linked glucans (PubMed:29061980)
Specific Function
Alpha-1,4-glucosidase activity
Gene Name
GAA
Uniprot ID
P10253
Uniprot Name
Lysosomal alpha-glucosidase
Molecular Weight
105322.935 Da
References
  1. Xu Z, Guo D, Jiang Z, Tong R, Jiang P, Bai L, Chen L, Zhu Y, Guo C, Shi J, Yu D: Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019 Dec 1;183:111682. doi: 10.1016/j.ejmech.2019.111682. Epub 2019 Sep 6. [Article]
  2. Wolska-Washer A, Robak T: Safety and Tolerability of Antibody-Drug Conjugates in Cancer. Drug Saf. 2019 Feb;42(2):295-314. doi: 10.1007/s40264-018-0775-7. [Article]
  3. Pernas S, Tolaney SM: HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019 Mar 19;11:1758835919833519. doi: 10.1177/1758835919833519. eCollection 2019. [Article]
  4. Rinnerthaler G, Gampenrieder SP, Greil R: HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer. Int J Mol Sci. 2019 Mar 5;20(5). pii: ijms20051115. doi: 10.3390/ijms20051115. [Article]
Details2. DNA topoisomerase 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the BMAL1 promoter
Specific Function
Atp binding
Gene Name
TOP1
Uniprot ID
P11387
Uniprot Name
DNA topoisomerase 1
Molecular Weight
90725.19 Da
References
  1. Xu Z, Guo D, Jiang Z, Tong R, Jiang P, Bai L, Chen L, Zhu Y, Guo C, Shi J, Yu D: Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019 Dec 1;183:111682. doi: 10.1016/j.ejmech.2019.111682. Epub 2019 Sep 6. [Article]
  2. Wolska-Washer A, Robak T: Safety and Tolerability of Antibody-Drug Conjugates in Cancer. Drug Saf. 2019 Feb;42(2):295-314. doi: 10.1007/s40264-018-0775-7. [Article]
  3. Pernas S, Tolaney SM: HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019 Mar 19;11:1758835919833519. doi: 10.1177/1758835919833519. eCollection 2019. [Article]
  4. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]
Details3. Cathepsin B
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Thiol protease which is believed to participate in intracellular degradation and turnover of proteins (PubMed:12220505). Cleaves matrix extracellular phosphoglycoprotein MEPE (PubMed:12220505). Involved in the solubilization of cross-linked TG/thyroglobulin in the thyroid follicle lumen (By similarity). Has also been implicated in tumor invasion and metastasis (PubMed:3972105)
Specific Function
Collagen binding
Gene Name
CTSB
Uniprot ID
P07858
Uniprot Name
Cathepsin B
Molecular Weight
37821.35 Da
References
  1. Xu Z, Guo D, Jiang Z, Tong R, Jiang P, Bai L, Chen L, Zhu Y, Guo C, Shi J, Yu D: Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019 Dec 1;183:111682. doi: 10.1016/j.ejmech.2019.111682. Epub 2019 Sep 6. [Article]
  2. Rinnerthaler G, Gampenrieder SP, Greil R: HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer. Int J Mol Sci. 2019 Mar 5;20(5). pii: ijms20051115. doi: 10.3390/ijms20051115. [Article]
Details4. Procathepsin L
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Thiol protease important for the overall degradation of proteins in lysosomes (Probable). Plays a critical for normal cellular functions such as general protein turnover, antigen processing and bone remodeling. Involved in the solubilization of cross-linked TG/thyroglobulin and in the subsequent release of thyroid hormone thyroxine (T4) by limited proteolysis of TG/thyroglobulin in the thyroid follicle lumen (By similarity). In neuroendocrine chromaffin cells secretory vesicles, catalyzes the prohormone proenkephalin processing to the active enkephalin peptide neurotransmitter (By similarity). In thymus, regulates CD4(+) T cell positive selection by generating the major histocompatibility complex class II (MHCII) bound peptide ligands presented by cortical thymic epithelial cells. Also mediates invariant chain processing in cortical thymic epithelial cells (By similarity). Major elastin-degrading enzyme at neutral pH. Accumulates as a mature and active enzyme in the extracellular space of antigen presenting cells (APCs) to regulate degradation of the extracellular matrix in the course of inflammation (By similarity). Secreted form generates endostatin from COL18A1 (PubMed:10716919). Critical for cardiac morphology and function. Plays an important role in hair follicle morphogenesis and cycling, as well as epidermal differentiation (By similarity). Required for maximal stimulation of steroidogenesis by TIMP1 (By similarity)
Specific Function
Collagen binding
Gene Name
CTSL
Uniprot ID
P07711
Uniprot Name
Procathepsin L
Molecular Weight
37563.97 Da
References
  1. Xu Z, Guo D, Jiang Z, Tong R, Jiang P, Bai L, Chen L, Zhu Y, Guo C, Shi J, Yu D: Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019 Dec 1;183:111682. doi: 10.1016/j.ejmech.2019.111682. Epub 2019 Sep 6. [Article]
  2. Rinnerthaler G, Gampenrieder SP, Greil R: HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer. Int J Mol Sci. 2019 Mar 5;20(5). pii: ijms20051115. doi: 10.3390/ijms20051115. [Article]
Details5. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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
  1. Xu Z, Guo D, Jiang Z, Tong R, Jiang P, Bai L, Chen L, Zhu Y, Guo C, Shi J, Yu D: Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019 Dec 1;183:111682. doi: 10.1016/j.ejmech.2019.111682. Epub 2019 Sep 6. [Article]
  2. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]

Transporters

Details1. ATP-dependent translocase ABCB1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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
  1. Nagai Y, Oitate M, Shiozawa H, Ando O: Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys. Xenobiotica. 2019 Sep;49(9):1086-1096. doi: 10.1080/00498254.2018.1531158. Epub 2019 Jan 4. [Article]
  2. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]
Details2. Solute carrier organic anion transporter family member 1B1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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
  1. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]
Details3. Solute carrier organic anion transporter family member 1B3
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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
  1. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]
Details4. Multidrug and toxin extrusion protein 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Multidrug efflux pump that functions as a H(+)/organic cation antiporter. Mediates the efflux of cationic compounds, such as the model cations, tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP+), the platinum-based drug oxaliplatin or weak bases that are positively charged at physiological pH, cimetidine, the platinum-based drugs cisplatin and oxaliplatin or the antidiabetic drug metformin. Mediates the efflux of endogenous compounds such as, creatinine, thiamine and estrone-3-sulfate. Plays a physiological role in the excretion of drugs, toxins and endogenous metabolites through the kidney
Specific Function
Antiporter activity
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]
Details5. Multidrug resistance-associated protein 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Mediates export of organic anions and drugs from the cytoplasm (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export (PubMed:9281595). Hydrolyzes ATP with low efficiency (PubMed:16230346). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthezing cells (By similarity). Mediates ATP-dependent, GSH-independent cyclic GMP-AMP (cGAMP) export (PubMed:36070769). Thus, by limiting intracellular cGAMP concentrations negatively regulates the cGAS-STING pathway (PubMed:36070769)
Specific Function
Abc-type glutathione s-conjugate transporter activity
Gene Name
ABCC1
Uniprot ID
P33527
Uniprot Name
Multidrug resistance-associated protein 1
Molecular Weight
171589.5 Da
References
  1. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]
Details6. Broad substrate specificity ATP-binding cassette transporter ABCG2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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
  1. FDA Approved Drug Products: Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use [Link]

Drug created at May 20, 2019 14:38 / Updated at May 11, 2024 02:51