Cytochrome P-450 CYP2C19: Difference between revisions

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In [[biology]], the '''cytochrome P-450 CYP2D19''' is an [[isoenzyme]] of [[cytochrome P-450]].<ref>{{OMIM|124020}}</ref> 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2C19 [[isoenzyme]].<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |month=November |pmid=11710893 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11710893 |issn=}}</ref><ref name="pmid12571261">{{cite journal |author=Weinshilboum R |title=Inheritance and drug response |journal=N. Engl. J. Med. |volume=348 |issue=6 |pages=529–37 |year=2003 |month=February |pmid=12571261 |doi=10.1056/NEJMra020021 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12571261&promo=ONFLNS19 |issn=}}</ref> More recently, a study suggests that 30% of patients may have a reduced-function allele with the reduced function allele being more common in asians and africans and less common in anglos and hispanics.<ref name="pmid19106084">{{cite journal |author=Mega JL, Close SL, Wiviott SD, ''et al'' |title=Cytochrome P-450 Polymorphisms and Response to Clopidogrel |journal=N. Engl. J. Med. |volume= |issue= |pages= |year=2008 |month=December |pmid=19106084 |doi=10.1056/NEJMoa0809171 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106084&promo=ONFLNS19 |issn=}}</ref>
In [[biology]], the '''cytochrome P-450 CYP2D19''' is an [[isoenzyme]] of [[cytochrome P-450]].<ref>{{OMIM|124020}}</ref> 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2C19 [[isoenzyme]].<ref name="pmid11710893">{{cite journal |author=Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W |title=Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review |journal=JAMA |volume=286 |issue=18 |pages=2270–9 |year=2001 |month=November |pmid=11710893 |doi= |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11710893 |issn=}}</ref><ref name="pmid12571261">{{cite journal |author=Weinshilboum R |title=Inheritance and drug response |journal=N. Engl. J. Med. |volume=348 |issue=6 |pages=529–37 |year=2003 |month=February |pmid=12571261 |doi=10.1056/NEJMra020021 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12571261&promo=ONFLNS19 |issn=}}</ref> More recently, a study suggests that 30% of patients may have a reduced-function allele with the reduced function allele being more common in asians and africans and less common in anglos and hispanics.<ref name="pmid19106084">{{cite journal |author=Mega JL, Close SL, Wiviott SD, ''et al'' |title=Cytochrome P-450 Polymorphisms and Response to Clopidogrel |journal=N. Engl. J. Med. |volume= |issue= |pages= |year=2008 |month=December |pmid=19106084 |doi=10.1056/NEJMoa0809171 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106084&promo=ONFLNS19 |issn=}}</ref>


CYP2C19 polymorphism affects response to [[clopidogrel]].  CYP2C19 loss-of-function alleles are associated with more cardiovascular events.<ref name="pmid19106083">{{cite journal |author=Simon T, Verstuyft C, Mary-Krause M, ''et al.'' |title=Genetic determinants of response to clopidogrel and cardiovascular events |journal=N. Engl. J. Med. |volume=360 |issue=4 |pages=363–75 |year=2009 |month=January |pmid=19106083 |doi=10.1056/NEJMoa0808227 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106083&promo=ONFLNS19 |issn=}}</ref> Concomitant [[proton pump inhibitor]]s, which are also metabolized by CYP2C19, may<ref name="pmid19258584">{{cite journal |author=Ho PM, Maddox TM, Wang L, ''et al.'' |title=Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome |journal=JAMA |volume=301 |issue=9 |pages=937–44 |year=2009 |month=March |pmid=19258584 |doi=10.1001/jama.2009.261 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=19258584 |issn=}}</ref><ref name="pmid20978260">{{cite journal| author=Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K et al.| title=Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. | journal=JAMA | year= 2010 | volume= 304 | issue= 16 | pages= 1821-30 | pmid=20978260 | doi=10.1001/jama.2010.1543 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20978260  }} </ref> (especially inhibitors other than [[pantoprazole]]<ref name="pmid19176635">Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180(7):713-8. Epub 2009 Jan 28. PMID 19176635</ref>) or may not<ref name="pmid19106083">{{cite journal |author=Simon T, Verstuyft C, Mary-Krause M, ''et al.'' |title=Genetic determinants of response to clopidogrel and cardiovascular events |journal=N. Engl. J. Med. |volume=360 |issue=4 |pages=363–75 |year=2009 |month=January |pmid=19106083 |doi=10.1056/NEJMoa0808227 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106083&promo=ONFLNS19 |issn=}}</ref><ref name="pmid20979470">{{cite journal| author=Paré G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J et al.| title=Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 18 | pages= 1704-14 | pmid=20979470 | doi=10.1056/NEJMoa1008410 | pmc= | url= }} </ref><ref name="pmid20855802">{{cite journal| author=Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ et al.| title=Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. | journal=Ann Intern Med | year= 2010 | volume= 153 | issue= 6 | pages= 378-86 | pmid=20855802 | doi=10.1059/0003-4819-153-6-201009210-00005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20855802  }} </ref> increase adverse cardiac events.
CYP2C19 polymorphism may affect response to [[clopidogrel]].  A [[systematic review]] of association studies concluded CYP2C19 "genetic association studies does not indicate a substantial or consistent influence of CYP2C19 gene polymorphisms on the clinical efficacy of clopidogrel."<ref>{{Cite journal | doi = 10.1136/bmj.d4588 | issn = 0959-8138 | volume = 343 | issue = aug04 1 | pages = d4588-d4588 | last = Bauer | first = T. | coauthors = H. J. Bouman, J. W. van Werkum, N. F. Ford, J. M. ten Berg, D. Taubert | title = Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis
| journal = BMJ | accessdate = 2011-08-11 | date = 2011-08 | url = http://www.bmj.com/cgi/doi/10.1136/bmj.d4588 }}</ref> Prior studies were conflicting whether loss-of-function alleles are associated with more cardiovascular events. Concomitant [[proton pump inhibitor]]s, which are also metabolized by CYP2C19, may<ref name="pmid19106083">{{cite journal |author=Simon T, Verstuyft C, Mary-Krause M, ''et al.'' |title=Genetic determinants of response to clopidogrel and cardiovascular events |journal=N. Engl. J. Med. |volume=360 |issue=4 |pages=363–75 |year=2009 |month=January |pmid=19106083 |doi=10.1056/NEJMoa0808227 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106083&promo=ONFLNS19 |issn=}}</ref><ref name="pmid19258584">{{cite journal |author=Ho PM, Maddox TM, Wang L, ''et al.'' |title=Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome |journal=JAMA |volume=301 |issue=9 |pages=937–44 |year=2009 |month=March |pmid=19258584 |doi=10.1001/jama.2009.261 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=19258584 |issn=}}</ref><ref name="pmid20978260">{{cite journal| author=Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K et al.| title=Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. | journal=JAMA | year= 2010 | volume= 304 | issue= 16 | pages= 1821-30 | pmid=20978260 | doi=10.1001/jama.2010.1543 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20978260  }} </ref> (especially inhibitors other than [[pantoprazole]]<ref name="pmid19176635">Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180(7):713-8. Epub 2009 Jan 28. PMID 19176635</ref>) or may not<ref name="pmid19106083">{{cite journal |author=Simon T, Verstuyft C, Mary-Krause M, ''et al.'' |title=Genetic determinants of response to clopidogrel and cardiovascular events |journal=N. Engl. J. Med. |volume=360 |issue=4 |pages=363–75 |year=2009 |month=January |pmid=19106083 |doi=10.1056/NEJMoa0808227 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19106083&promo=ONFLNS19 |issn=}}</ref><ref name="pmid20979470">{{cite journal| author=Paré G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J et al.| title=Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 18 | pages= 1704-14 | pmid=20979470 | doi=10.1056/NEJMoa1008410 | pmc= | url= }} </ref><ref name="pmid20855802">{{cite journal| author=Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ et al.| title=Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. | journal=Ann Intern Med | year= 2010 | volume= 153 | issue= 6 | pages= 378-86 | pmid=20855802 | doi=10.1059/0003-4819-153-6-201009210-00005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20855802  }} </ref> increase adverse cardiac events.


In one negative analysis, adding PPIs to clopidogrel as associated with increased adverse events, but not more so than adding PPIs to patients not taking clopidogrel.<ref name="pmid20855802">{{cite journal| author=Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ et al.| title=Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. | journal=Ann Intern Med | year= 2010 | volume= 153 | issue= 6 | pages= 378-86 | pmid=20855802 | doi=10.1059/0003-4819-153-6-201009210-00005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20855802  }} </ref>
In one negative analysis, adding PPIs to clopidogrel as associated with increased adverse events, but not more so than adding PPIs to patients not taking clopidogrel.<ref name="pmid20855802">{{cite journal| author=Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ et al.| title=Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. | journal=Ann Intern Med | year= 2010 | volume= 153 | issue= 6 | pages= 378-86 | pmid=20855802 | doi=10.1059/0003-4819-153-6-201009210-00005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20855802  }} </ref>

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In biology, the cytochrome P-450 CYP2D19 is an isoenzyme of cytochrome P-450.[1] 2-6% of anglos and 15-25% of asians are poor metabolizers of drugs that use the CYP2C19 isoenzyme.[2][3] More recently, a study suggests that 30% of patients may have a reduced-function allele with the reduced function allele being more common in asians and africans and less common in anglos and hispanics.[4]

CYP2C19 polymorphism may affect response to clopidogrel. A systematic review of association studies concluded CYP2C19 "genetic association studies does not indicate a substantial or consistent influence of CYP2C19 gene polymorphisms on the clinical efficacy of clopidogrel."[5] Prior studies were conflicting whether loss-of-function alleles are associated with more cardiovascular events. Concomitant proton pump inhibitors, which are also metabolized by CYP2C19, may[6][7][8] (especially inhibitors other than pantoprazole[9]) or may not[6][10][11] increase adverse cardiac events.

In one negative analysis, adding PPIs to clopidogrel as associated with increased adverse events, but not more so than adding PPIs to patients not taking clopidogrel.[11]

External links

References

  1. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 124020. World Wide Web URL: http://omim.org/.
  2. ↑ Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (November 2001). "Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review". JAMA 286 (18): 2270–9. PMID 11710893. [e]
  3. ↑ Weinshilboum R (February 2003). "Inheritance and drug response". N. Engl. J. Med. 348 (6): 529–37. DOI:10.1056/NEJMra020021. PMID 12571261. Research Blogging.
  4. ↑ Mega JL, Close SL, Wiviott SD, et al (December 2008). "Cytochrome P-450 Polymorphisms and Response to Clopidogrel". N. Engl. J. Med.. DOI:10.1056/NEJMoa0809171. PMID 19106084. Research Blogging.
  5. ↑ Bauer, T.; H. J. Bouman, J. W. van Werkum, N. F. Ford, J. M. ten Berg, D. Taubert (2011-08). "Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis". BMJ 343 (aug04 1): d4588-d4588. DOI:10.1136/bmj.d4588. ISSN 0959-8138. Retrieved on 2011-08-11. Research Blogging.
  6. ↑ 6.0 6.1 Simon T, Verstuyft C, Mary-Krause M, et al. (January 2009). "Genetic determinants of response to clopidogrel and cardiovascular events". N. Engl. J. Med. 360 (4): 363–75. DOI:10.1056/NEJMoa0808227. PMID 19106083. Research Blogging. Cite error: Invalid <ref> tag; name "pmid19106083" defined multiple times with different content
  7. ↑ Ho PM, Maddox TM, Wang L, et al. (March 2009). "Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome". JAMA 301 (9): 937–44. DOI:10.1001/jama.2009.261. PMID 19258584. Research Blogging.
  8. ↑ Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K et al. (2010). "Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.". JAMA 304 (16): 1821-30. DOI:10.1001/jama.2010.1543. PMID 20978260. Research Blogging.
  9. ↑ Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180(7):713-8. Epub 2009 Jan 28. PMID 19176635
  10. ↑ Paré G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J et al. (2010). "Effects of CYP2C19 genotype on outcomes of clopidogrel treatment.". N Engl J Med 363 (18): 1704-14. DOI:10.1056/NEJMoa1008410. PMID 20979470. Research Blogging.
  11. ↑ 11.0 11.1 Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ et al. (2010). "Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study.". Ann Intern Med 153 (6): 378-86. DOI:10.1059/0003-4819-153-6-201009210-00005. PMID 20855802. Research Blogging.
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