Disulfiram Pathway published in Pharmacogenetics and Genomics

Substance abuse disorders are a significant public health cost [PMID: 34453125]. Prescribers have limited choices for pharmaceutical therapies with only three FDA-approved choices for alcohol use disorder and zero for cocaine use disorder. Disulfiram is an FDA-approved treatment for alcohol use disorder which is also used for cocaine use disorder. There are some preliminary studies on the PGx of disulfiram but little replication.

PharmGKB together with Dr Aneysis De Las Mercedes Gonzalez (Stanford University School of Medicine), have published PharmGKB summary: disulfiram pathway in Pharmacogenetics and Genomics, 2023 Sep 21. doi: 10.1097/FPC.0000000000000509. Online ahead of print. PMID: 37728645. It summarizes the candidate genes involved in disulfiram PGx in pharmacokinetics and action in dopaminergic, seratonergic and noradrenergic neurons and highlights the knowledge gaps.

As always interactive versions of the diagrams with underlying linked evidence, are available on PharmGKB:

Disulfiram Pathway, Pharmacokinetics,

Disulfiram Pathway, Pharmacodynamics (Cocaine and Ethanol PK), 

Disulfiram Pathway, Pharmacodynamics (Dopaminergic neuron), 

Disulfiram Pathway, Pharmacodynamics (Serotonergic neuron), 

Sympathetic Nerve Pathway (Neuroeffector Junction)

PharmGKB and Reactome collaborate on two pathways

PharmGKB has collaborated with Reactome for two new pharmacokinetics pathways, Ribavirin, and Prednisone and Prednisolone available via both formats:

Ribavirin Pathway, Pharmacokinetics 

on Reactome 

on PharmGKB

Prednisone and Prednisolone Pathway, Pharmacokinetics 

on Reactome

on PharmGKB

 

Study of vitamin K pathways presents potential new warfarin candidates

Almost two decades after the cloning of VKORC1 and association with warfarin dose, a new pathway of vitamin K cycling has been published. Mishima et al [PMID:35922516] report on the Ferroptosis suppressor protein 1 (FSP1), coded for by the AIFM2 gene, and its mechanism of maintaining vitamin K in the hydroquinone form. While not interacting directly with warfarin, AIFM2 may play a role in vitamin K-related branches in the warfarin PD pathway that warrant investigation for PGx. 

A review of several ferroptosis related proteins (Vabulas, 2021) discusses some variants of AIFM2. The review mentions a functional study of E156A in the FAD cofactor binding domain that found it impaired anti-ferroptotic activity. This variant is not found in dbSNP. A different amino acid change, E156D (rs1272224219C>A), has not been observed in the ALFA populations that dbSNP reports on, while yet another amino acid change, E156V (rs760393626T>A), is extremely rare (found in 1/121216 alleles). The review lists 2 other potential AIFM2 candidates for functional investigation which are more frequently observed: M135T (mapped by PharmGKB to rs10999147A>G) and D288N (mapped to rs2271694C>T).

(Edited 9/20/22) The Warfarin Pathway, Pharmacodynamics has been updated to include the new candidate gene.

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PharmGKB Acyclovir/Ganciclovir Pathway Published

The PharmGKB Acyclovir/Ganciclovir Pathway has recently been published in the journal Pharmacogenetics and Genomics.

Acyclovir (ACV) and ganciclovir (GCV) are commonly prescribed antivirals to treat infections caused by herpes viruses, varicella-zoster virus or cytomegalovirus (eg. cold sores, shingles and chicken pox, etc.). The pathway, co-developed by Maud Maillard along with other members of the Yang Lab in St. Jude, as well as members of the PharmGKB team, outlines the metabolism, transport, and mechanism of action of ACV and GCV with a view to decipher the existing interpatient variability, and highlights pharmacogenomics implications by the variants of the NUDT15 and ABCC4 genes on ACV and GCV efficacy.  Further work is needed to validate these findings and discover other candidates, with the aim of optimizing antiviral therapy.

 

View the interactive pathway on PharmGKB:
Acyclovir/Ganciclovir Pathway, Pharmacokinetics/Pharmacodynamics

 

Read our new publication:

PharmGKB summary: acyclovir/ganciclovir pathway
Maud Maillard, Li Gong, Rina Nishii, Jun J Yang, Michelle Whirl-Carrillo, Teri E Klein
Pharmacogenet Genomics. 2022 Jul 1;32(5):201-208. Epub 2022 May 30.

PMID: 35665708

View all pathways on PharmGKB.

Update to individual statin pathways to support release of new CPIC guidelines for statins

To coincide with the release of the updated CPIC guidelines for SLCO1B1, ABCG2 and CYP2C9 and statin-associated musculoskeletal symptoms, we have updated the statin pharmacokinetic (PK) pathways. We now have one PK pathway for each individual drug in the guideline and have added details of the specific metabolites as well as the candidate genes and references. 

Atorvastatin Pathway, Pharmacokinetics

Fluvastatin Pathway, Pharmacokinetics

Lovastatin Pathway, Pharmacokinetics

Pitavastatin Pathway, Pharmacokinetics

Pravastatin Pathway, Pharmacokinetics

Rosuvastatin Pathway, Pharmacokinetics

Simvastatin Pathway, Pharmacokinetics

Note: If you have visited pathways recently you may need to refresh your browser or empty cookies to see the updated versions. Plus the history log at the bottom of the pathway lets you know if you are seeing the most updated version. 

PharmGKB Heparin-Induced Thrombocytopenia Pathway published

A PharmGKB pathway of heparin-induced thrombocytopenia (HIT) has been published in Pharmacogenetics and Genomics.

Heparin is a commonly used anticoagulant. The pathway, written by Elise Miller along with other members of the Karnes lab at the University of Arizona as well as members of the PharmGKB team, outlines the atypical immune response which can occur in some patients receiving heparin. HIT can have a mortality rate of up to 30% and shares some similarities with COVID-19 while patients with COVID-19 have been found to be at an increased risk of HIT. Pharmacogenomics research has identified some candidate biomarkers, particularly in immune system receptors, which may affect a patient’s risk of experiencing HIT, however further work is needed to validate these and discover other candidates.

 

An interactive version of the pathway can be found on the PharmGKB website.

New pathways on PharmGKB

The following pathways have been recently released on PharmGKB:

Acenocoumarol Pharmacokinetics

Phenprocoumon Pharmacokinetics

Piroxicam Pharmacokinetics

Siponimod Pharmacokinetics/Pharmacodynamics

Aminoglycoside Ototoxicity, Adverse Drug Reaction

These pathways cover gene-drug pairs which have been assigned level A or B by CPIC.A full list of PharmGKB pathways can be found at https://www.pharmgkb.org/pathways

Two new pathways released: Allopurinol Pharmacokinetics and Pimozide Pharmacokinetics.

Allopurinol is a purine analogue used in the treatment of gout. This drug has a level A CPIC Guideline for allopurinol and HLA-B. The new pathway shows the candidate genes and metabolites involved in Allopurinol Pharmacokinetics.

Pimozide is a typical antipsychotic FDA approved for treatment of Tourette’s disorder. The FDA drug label has a testing recommendation for CYP2D6 poor metabolizers and the gene-drug pair is level A/B on the CPIC list and noted for future guideline development. The new pathway was developed by recent work from Chapron et al [PMID: 32847865], and shows candidate genes and metabolites involved in Pimozide Pharmacokinetics in a stylized liver cell.

New PharmGKB pathway for Cannabidiol Pharmacokinetics

PharmGKB released a new pharmacokinetics pathway for Cannabidiol, a phytocannabionoid found in the Cannabis sativa plant approved to treat two rare forms of epilepsy. 

The pathway was produced by graduate student Kris Oreschak from the University of Colorado Denver Anschutz Medical Campus with guidance from scientific curator Dr Caroline F. Thorn. While there are currently no published studies documenting the pharmacogenomics of cannabidiol, many pharmacogenes are involved in its metabolism presenting future opportunities to look at variable responses. 

View all pathways at PharmGKB

Lamotrigine pathway published in Pharmacogenetics and Genomics

The PharmGKB lamotrigine pathway has been recently published in the journal Pharmacogenetics and Genomics.

The publication, written by Taraswi Mitra-Ghosh, now at Auburn University, and Samuel Callisto of the Univeristy of Minnesota along with collaborators, including former PharmGKB Scientific Curator Julia Barbarino, reviews both the pharmacokinetics and pharmacodynamics of lamotrigine. Lamotrigine is an antiseizure drug which has also been approved for the treatment of bipolar disorder. It is extensively metabolized in the liver primarily by UGT enzymes. Although the exact pharmacodynamic effects of lamotrigine remain unclear, it is thought that it may act as an antagonist of voltage-gated sodium channels and voltage-gated calcium channels.

Adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients treated with lamotrigine. A number of alleles at the HLA locus which have been linked to lamotrigine-related adverse events are also reviewed in this paper.

The pathway, including a clickable image, is also freely available on the PharmGKB website.

PharmGKB papers in the February 2020 issue of Pharmacogenetics and Genomics

The February 2020 issue of Pharmacogenetics and Genomics has a PharmGKB double feature, with the publication of our sertraline pathway and our VIP summary for CACNA1S.

The sertraline pharmacokinetic pathway, written by Scientific Curator Dr. Rachel Huddart and collaborators, is featured on the cover of the journal. Sertraline is a selective serotonin reuptake inhibitor (SSRI), which is used in the treatment of some psychiatric disorders, such as major depressive disorder. Metabolism of sertraline in the liver by CYP2C19 forms the basis of clinical guidelines from CPIC and the DPWG.

CACNA1S is a subunit of the dihydropyridine receptor and is expressed in skeletal muscle, where it plays a role in muscle contraction. Variants in CACNA1S have been linked to a number of myopathies as well as malignant hyperthermia, which can occur in some patients when exposed to inhaled anesthetics. The recent CPIC guideline forinhaled anesthetics includes recommendations based on CACNA1S variants. Our VIP summary, written by Senior Scientific Curator Dr. Katrin Sangkuhl with Dr.Robert Dirksen of the University of Rochester and former PharmGKB curator Maria Alvarellos, outlines the role of CACNA1S in both normal muscle function and in disease genetics. Key variants which have been associated with malignant hyperthermia are discussed in detail.

Both the sertraline pathway and CACNA1S VIP summary can be accessed on the PharmGKB website.

PharmGKB ondansetron and tropisetron pathways published in Pharmacogenetics and Genomics

The PharmGKB pathways for ondansetron and tropisetron have been published in the June 2019 issue of Pharmacogenetics and Genomics. Ondansetron and tropisetron are serotonin receptor antagonists which are prescribed for their antiemetic activity. After an overview of the pharmacokinetics and pharmacodynamics of each drug, the publication discusses the current pharmacogenetic evidence available, some of which has informed the CPIC guidelines for ondansetron and tropisetron.

You can access interactive versions of the Ondansetron Pathway, Pharmacokinetics/Pharmacodynamics and the Tropisetron Pathway,Pharmacokinetics/Pharmacodynamics at the PharmGKB website.