Mycophenolic acid Pathway, Pharmacokinetics/Pharmacodynamics

We updated the Mycophenolic acid Pathway in collaboration with Kinjal Sanghavi and Dr. Vishal Lamba from the University of Minnesota.

Mycophenolic Acid (MPA) is an immunosuppressive agent and is indicated as prophylactic agent in patients receiving allogeneic renal, cardiac or hepatic transplants. 

This PharmGKB pathway describes the steps and metabolites involved in the pharmacokinetic of mycophenolate mofetil, the prodrug of MPA. 

The target of MPA is the inosine monophosphate dehydrogenase, which is an important rate limiting enzyme involved in purine synthesis. The pharmacodynamic section highlights several mechanisms of action of MPA.

Genetic variants within genes involved in MPA uptake and metabolism, and in its targets have been reported to affect MPA response in patients undergoing transplantation. For more information read the entire pathway description of the Mycophenolic acid Pathway at PharmGKB.

View all pathways at PharmGKB.

GWAS in PGx: Pharmacogenomics Special Issue

This month's Future Medicine Pharmacogenomics Journal focuses on genome-wide association studies (GWAS) in PGx. Articles include highlights from the latest PGx GWAS, and topics covering data analysis techniques, rare variants, and direct-to-consumer PGx testing.

Pharmacogenomics, March 2013, Volume 14, Number 4 

Special Focus Issue: Genome-wide association studies in pharmacogenomics.

Spanish Association of Hospital Pharmacists: Excellence Course in PGx

The current issue of the European Journal of Hospital Pharmacy has a report from our collaborators at Leiden University Medical Center regarding the Excellence Course in PGx organized by the Spanish Association of Hospital Pharmacists.

The course was established to educate pharmacists on the concepts and clinical applications of PGx, and the technology and resources available to help them implement PGx in their hospital pharmacy. The course featured a webinar demonstration of PharmGKB by one of our Scientific Curators highlighting the clinically-relevant PGx information found on our website as a useful resource.

View clinically-relevant PGx information on PharmGKB:

• Genotype-based Dosing Guidelines 
• PharmGKB Clinical Annotations
• Drug labels with PGx information
• Genetics tests relevant to PGx

Read the Short Report:

Centres of Excellence Course in Pharmacogenetics, 25–28 June 2012. Cristina Lucía Dávila-Fajardo, Jesse J Swen, Tahar van der Straaten, Henk-Jan Guchelaar. Eur J Hosp Pharm 2013;20:132.

PharmGKB at AMIA Summit on Translational Bioinformatics

The American Medical Informatics Association (AMIA) Joint Summits on Translational Science is being held in San Francisco this week.

Russ Altman is a keynote speaker at the conference, presenting a review of the past year in Translational Bioinformatics on Wednesday 20th March. Check out Michelle Whirl Carrillo's poster on Natural Language Processing (NLP) developments at PharmGKB. Also in attendance at the conference is Darla Hewett, our NLP/Ai developer and guru, and one of our Scientific Curators Daniel Klein.  

CPIC publishes guidelines for tricyclic antidepressants and CYPs

Guidelines regarding the use of pharmacogenomic tests in dosing for tricyclic antidepressants have been published in Clinical Pharmacology and Therapeutics.  The guideline focuses on amitriptyline and nortriptyline dosing for individuals with CYP2D6 and CYP2C19 haplotypes being treated for depression. Since most studies have examined the effects of CYP2D6 and CYP2C19 haplotypes independently the guideline tables consider these separately. A combined table is provided with the caution that further studies are needed to develop moderate or strong dosing recommendations for tricyclics when considering combined CYP2D6/CYP2C19 phenotypes.

The guideline recommends avoiding amitriptyline use in CYP2D6 and CYP2C19 poor metabolizers and ultrarapid metabolizers, and to consider dose modifications in those with intermediate metabolizer status. 

Other tricyclics for which there is less published clinical data, but which have pharmacokinetic data and follow a similar pattern of metabolism by CYPs are also discussed and the evidence listed in the supplement. These include -->clomipramine, desipramine, doxepin, imipramine and trimipramine.

The relevant papers used to compile the evidence are annotated in PharmGKB under the PGx tabs for each drug, and gene-centered PharmGKB pathways are available for clomipramine, doxepin and imipramine/desipramine (and amitriptyline/nortriptyline pharmacokinetic pathway is coming soon). 

To find out more:

Please click here to see excerpts from the guideline and access downloads of the article and supplement . 

Please click here for a complete list of CPIC publications.

Interactive Dosing Guidelines now on PharmGKB

PharmGKB now has interactive PGx dosing guidelines...simply pick the genotype or diplotype of the gene from a dropdown menu and the CPIC recommended dosing guidelines for that specific allele combination will appear.

These are available for all published CPIC guidelines.

Simple instructions:
1. On PharmGKB, go to the drug or gene page of interest, or select from the PGx drug dosing guidelines list. If available, CPIC dosing guidelines appear in the Clinical PGx tab of gene and drug pages (see picture below).
2. "Look up your guideline" by selecting the genotype or diplotype of your choice from the dropdown menus of alleles.  
3. The CPIC recommendations for that particular genotype-drug pair will appear. 
4. Change the genotype or diplotype by using the dropdown menus - the recommendations will change accordingly.  

Example: Azathioprine CPIC dosing guidelines for the *2/*3A TPMT diplotype

Data from Web Searches Could Help Identify Drug Side Effects and Drug-Drug Interactions

Researchers at Stanford and Columbia Universities teamed up with Microsoft to show that information from internet searches could potentially be used to identify novel drug-drug interactions and aid surveillance of drug safety.

In 2011, Tatonetti et al utilized adverse drug event reporting system of the FDA to identify novel drug-drug interactions. One potential novel drug-drug interaction discovered using this method was between the commonly prescribed drugs paroxetine and pravastatin. When prescribed together they were associated with hyperglycemia, and this finding was confirmed in subsequent mouse models and when examining patient electronic medical records.

The latest study continues from this previous work. The hypothesis was that users experiencing side effects from a drug will carry out internet searches for terms related to the drugs they are taking and their symptoms, and that this information could be used to identify potential drug side effects and novel drug-drug interactions. Logs of browser searches (including Google, Bing, Yahoo) from consenting web users were mined to identify users who had searched for hyperglycemia-related symptoms and terms. (These logs pre-dated the aforementioned publications regarding paroxetine and pravastatin drug interaction). 82 million drug, symptom and condition queries were analyzed. They found that users searching for both paroxetine and pravastatin in a 12-month window also searched for hyperglycemia-related symptoms more often than those who searched for just one of these drugs. The study shows that logs of web searches could contribute to pharmacovigilance.

Read more:
Web-scale pharmacovigilance: listening to signals from the crowd
Ryen W White, Nicholas P Tatonetti, Nigam H Shah, Russ B Altman, Eric Horvitz
J Am Med Inform Assoc doi:10.1136/amiajnl-2012-001482
  
Learn about the pharmacogenetics of pravastatin and paroxetine

Considerations for automated functional comparisons

Congratulations on a great paper from Sean Mooney's lab and colleagues at the National Center for Biomedical Ontology at Stanford. It shows that when performing high throughput analysis of omics datasets such as microarrays, proteomics etc, combining manually curated GO terms with additional terms found by text mining is more effective than using GO alone. As a curator this doesn't surprise me - we do a great job, but with the volume of work out there we will never catch everything. Often when manually curating a paper there might be a concept that doesn't map exactly to the ontology in use, or sometimes there are situations where it can map to many terms and a curator may be constrained from picking them all by limitations of their curation tool. It is not always possible for a human curator to examine all the ontologies out there to find the best annotation in a given circumstance. And curators are scientists too, so it is essential for us to to be able to incorporate free text especially when it doesn't seem to follow the rules exactly. Methods and tools that account for these limitations by employing a mixed approach therefore seem like a good idea - and over 2000 people have accessed the article in the past 2 weeks, so its getting some attention!

PharmGKB at the ASCPT 2013 Annual Meeting

The American Society for Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting is being held this week in Indianapolis.  

Michelle Whirl-Carrillo, Assistant Director of PharmGKB, will be presenting a talk entitled "PharmGKB: From Pharmacogenomics Knowledge to Clinical Interpretation and Implementation" in the "Putting Pharmacogenetics into Practice" symposium on March 9th. She is representing Teri Klein, Director of PharmGKB, who is out on medical leave. This symposium features international speakers within the field of PGx, from Leiden University Medical Center, University of Chicago, St Jude's Children's Research Hospital and Stanford University.

Russ Altman, PI of PharmGKB, will assume the role of President of ASCPT at the meeting. He will also chair several sessions throughout the conference.