Cytochrome P450 2C19 Genotyping

Web Seminar: Pharmacogenetics in the Practice of Medicine

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Download Plavix CYP2C19 Information

CYP2C19 (cytochrome P450 2C19) acts on 5-10% of drugs in current clinical use. About 2-6% of individuals of European origin (Caucasians), 15-20% of Japanese, and 10-20% of Africans have a slow acting, poor metabolizer form of this enzyme. However there is wide variability among populations. For example, the percent of Polynesians who are poor metabolizers ranges from 38-79% depending on location. CYP2C19 is an important drug-metabolizing enzyme that catalyzes the biotransformation of many other clinically useful drugs including antidepressants, barbiturates, proton pump inhibitors, antimalarial and antitumor drugs.
Genelex offers improved detection rates using an extended Cytochrome P-450 2C19 DNA test. This test identifies 7 small nucleotide variants in PCR-multiplex format, providing increased sensitivity and quality performance. This CYP2C19 detection panel is the most extensive on the market and covers seven known poor metabolizer phenotypes. Analytical specificity and sensitivity for detection of these mutations are >99%.

Specimen Types

Please call Client Services at 800-523-3080 to obtain specimen kits.

• Buccal Swabs: 4 sterile Buccal Swabs
• Blood: 5-10 cc whole blood lavender-top EDTA or Yellow-top ACD-A tubes.

• Turnaround Time: 6 days

CPT Codes

CYP2C19 Mutation DNA Analysis (provided for your guidance only)
1 X 83891, 2 X 83892, 1 X 83900, 3 X 83901, 7 X 83914, 1 X 83909, 1 X 83912, 1 X 83912-26

Clinical Significance

Phenotype prevalence is 2-6% PM Caucasian, 13-19% PM Asians, 10-20% PM African; 24-36% IM; Drugs metabolized by this enzyme approximately 5-10%.

Cytochrome P450 2C19 (CYP2C19) is a highly polymorphic liver enzyme of the cytochrome P450 super family involved with the metabolism and elimination of many commonly prescribed drugs. Genetic polymorphisms in CYP2C19 are common and can affect therapeutic response to drugs. The enzyme activity is expressed at highly variable levels. Three phenotypes are identified: poor metabolizers (PM), intermediate metabolizers (IM) and normal metabolizers (NM).

Detecting genetic variations in drug-metabolizing enzymes is useful for identifying individuals who may experience adverse drug reactions with conventional doses of certain medications. Individuals who possess CYP2C19 poor metabolizer variants may exhibit different pharmacokinetics (drug levels) than normal individuals. As a result, such individuals may require non-conventional doses of medications that require CYP2C19 activity for biotranformation. Conversely, medications that do not require CYP2C19 biotranformation may be preferentially selected for patients with potentially impaired CYP2C19 metabolic capacity to avoid adverse drug reactions.

The seven CYP2C19 allelic variants detected in this genotyping test provide greater than 98% coverage of the variant alleles found for this gene. The active allele (wild type) of the CYP2C19 gene is designated CYP2C19*1. Homozygous wild-type individuals have a normal metabolizer phenotype (NM). The most common poor metabolizer phenotypes have been identified as CYP2C19*2 and CYP2C19*3. CYP2C19*2 (G681A) and CYP2C19*3 (G636A) each differ from the active CYP2C19*1 by a single nucleotide substitution, which leads to impaired enzyme activity. The allele frequency of CYP2C19*2 has been reported to be as high as 75-85% in Asians and approximately 15% in Europeans and African Americans. The allele frequency of CYP2C19*3 has been reported to be as high as 6-10% in Asians and is rare in Europeans and African Americans. Other alleles associated with reduced metabolism include CYP2C19 *4, *5, *6, *7 and *8, but these are less frequent in the general population. CYP2C19*4 accounts for approximately 3% of Caucasian poor metabolizers.

Laboratory Test Interpretation

Genelex offers improved detection rates using an extended Cytochrome P-450 2C19 DNA mutation panel. This test identifies 7 small nucleotide variants in PCR-multiplex format, providing increased sensitivity and quality performance.

Cytochrome P-240 2C19 Mutations Detected
CYP2C19 allele	Nucleotide change	Effect on Enzyme Metabolism
*1	None (wildtype)	Normal
*2	681G>A	Inactive
*3	636G>A	Inactive
*4	1A>G	Inactive
*5	1297C>T	Inactive
*6	395G>A	Inactive
*7	IVS5+2T>A	Inactive
*8	358T>C	Inactive

For additional information see the CYP2C19 allele nomenclature database at http://www.cypalleles.ki.se/cyp2c19.htm

Testing places individuals in one of three categories:

• Normal metabolizers  (NM) represent the norm for metabolic capacity. In general normal metabolizers can be administered drugs which are substrates of the CYP2C19 enzyme following standard dosing practices. Genotypes consistent with the normal metabolizer phenotype include two active CYP2C19 alleles.
  
  
• Intermediate metabolizers (IM) may require lower than average drug dose for optimal therapeutic response to medications with the exception of prodrugs. For the majority of drugs consider decreased dosage. For prodrugs, like Plavix, that require activation by CYP2C19, an alternative treatment or increased dose should be considered. Genotypes consistent with the intermediate metabolizer phenotype are those with one active and one inactive CYP2C19 allele.
  
  
• Poor metabolizers (PM) are at increased risk of drug-induced side effects due to diminished drug elimination or for prodrugs, like Plavix, lack of therapeutic effect resulting from failure to generate the active form of the drug. Alternative treatment should be considered. Genotypes consistent with the poor metabolizer phenotype are those with no active CYP2C19 alleles.
  
  

Co-administration of other drugs. Genotype results should be interpreted in context of the individual clinical situation. In all cases monitor for co-administration of CYP2C19 inhibitors which may convert patients to poor metabolizer status. Potential adverse outcomes included overdose toxicity or treatment failure particularly for prodrugs. For more information see GeneMedRx drug-drug and drug-gene interaction software and Cytochrome P450 Metabolism Inhibitor/Inducer Tables. Access GeneMedRx via the patient access code provided at www.GeneMedRx.com/DNAlogin.

Dosage Recommendations

A complicating factor in correlating CYP2C19 genotype with phenotype is that most drugs may reduce CYP2C19 catalytic activity but prodrugs increase CYP2C19 activity. It is important to interpret the results of testing in the context of other co administered drugs.

CYP2C19 activity also is dependent upon hepatic and renal function status, as well as age. Patients also may develop toxicity if hepatic or renal function is decreased. Consider the results of testing and dose adjustments in the context of renal and hepatic function and age.

Prodrugs: Plavix

For prodrugs, such as Plavix, that require activation by CYP2C19, consider:

• Normal Metabolizer (NM) (homozygous normal) No change.
  
  
• Intermediate Metabolizer (IM) (heterozygous one functional allele, one deficient allele). An alternative treatment or increased dose should be considered. For Plavix: Consider doubling maintenance dose, e.g. 1200 mg loading and 150 mg maintenance; monitor for decrease in platelet function. Maintenance dosage of up to 300mg/day might be required to achieve adequate platelet inhibition.
  
  
• Poor Metabolizer (PM) (homozygous non-functional alleles) Consider alternative therapy.

For drugs that are not prodrugs, consider:

• Intermediate Metabolizers (IM)
  Start IM’s at lowest efficacious dose, avoid multiple drug therapy that inhibits or is processed through the same pathway.
  
  
• Poor Metabolizers (PM)
  Reduce dose to 20-60% of standard dosage.
  
  

Therapeutic drug monitoring in PM and IM subjects is highly recommended. Again standard measures of efficacyFor specific dosages see charts and tables are adapted from Julia Kirchheiner, et al Molecular Psychiatry Feature Review, 9 442-473 (2004), "Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response," a meta analysis of published research from 1970-2003 on the relevance of pharmacogenetic effects of CYP2D6 and CYP2C19 on 36 antidepressants and 38 antipsychotics.

TEST Methodology and Limitations

DNA extraction / Polymerase Chain Reaction (PCR) / Bead Hybridization.

This assay detects all common and many rare cytochrome P 450 2C19 (CYP2C19) variants with known clinical significance. Laboratory specimens were analyzed using PCR based technologies that detect 8 nucleotide variants. The performance of this assay was validated by Genelex Corporation. As with all laboratory testing there is a possibility of error. Genelex Corporation is certified by the Clinical Laboratory Improvement Amendments (CLIA No. 50D0980559) and as Washington State Medical Test Site No. MTS-3919, qualified to perform high complexity clinical testing.

DNA testing will not detect all the known mutations that result in decreased or inactive CYP2C19. Absence of a detectable gene mutation or polymorphism does not rule out the possibility that a patient has an intermediate or poor metabolizer phenotype. This test does not detect polymorphisms other than those listed. Other polymorphisms in the primer binding regions can affect the testing, and ultimately, the genotyping assessments made. Rare diagnostic errors may occur due to primer site mutations. Mutations in other genes associated with drug metabolism will not be detected. Drug metabolism may be affected by non-genetic factors. DNA testing does not replace the need for clinical and therapeutic drug monitoring.

Drug Metabolism Guide

This list is not all inclusive and is for your guidance only. A more comprehensive Cytochrome list of substrates, inhibitors, and inducers can be found here.

Substrates Metabolized through Cytochrome P-450 2C19

Substrates refers to drugs that are either activated or deactivated by the pathway.

Note=italics indicated minor pathway

amitriptyline	{esomeprazole}	nelfinavir	sertraline
carisoprodol	{fluoxetine}	omeprazole	Soma
citalopram	flunitrazapam	{pantoprazole}	trimipramine
clomipramine	imipramine	phenytoin	Vfend
clopidogrel	lansoprazole	Plavix	voriconazole
cyclophosphophamide (p)	Malarone	proguanil (p)
diazepam	mephenytoin	Propranolol
escitalopram	moclobemide	R-warfarin

Inhibitors of Cytochrome P-450 2C19

Inhibitors refers to drugs that reduce the ability of the pathway to process drugs.
Co-administration will decrease the rate of metabolism of drugs through the metabolic pathway listed, increasing the possibility of toxicity.

chloramphenicol	fluoxetine	omeprazole	ticlopidine
delavirdine	fluvoxamine	oral contraceptives	topiramate
efavirenz	isoniazid	oxcarbazepine	voriconazole
felbamate	lansoprazole	Prilosec
fluconazole	modafinil	Provigil

Inducers of Cytochrome P-450 2C19

Inducers refers to drugs that increase the activity of a pathway.
Co-administration increases the rate of excretion for drugs metabolized through the pathway indicated, reducing the drug's effectiveness.

ginko biloba                               rifampin                        St John’s Wort

References

1. Mega J.L et al. Cytochrome P-450 Polymorphisms and Response to Clopidogrel. N Engl J Med 2009; 360:354-362
2. Tabassome S. et al Genetic Determinants of Response to Clopidogrel and Cardiovascular Events  N Engl J Med 2009;360:363-75
3. Patrick Gladding, Pharmacogenetic Testing for Clopidogrel Using the Rapid INFINITI Analyzer, A Dose-Escalation Study, JACC: Cardiovascular Interventions 2009; VOL. 2 , No. 11: 1095-1101

4. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002;41(12):913-58.

5. Kirchheiner J et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Molecular Psychiatry 2004;9:442-473.
6. Cozza KL, Armstrong SC, Oesterheld JR (2003) Drug Interaction principles for Medical Practice. American Psychiatric Publishing Inc
7. Seeringer A, Kirchheiner J. Pharmacogenetics-guided dose modifications of antidepressants. Clin Lab Med. 2008 Dec;28(4):619-26.
8. Kirchheiner J, Brosen K, Dahl ML, et al.:  CYP2D6 and CYPSC19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psych Scand 2001 Sept;104(3):173-192
9. Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM, Evans DA. Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 1997, 7: 59-64
10. Brockmoller J et.al. Pharmacogenetic diagnosis of cytochrome P450 polymorphisms in clinical drug development and in drug treatment. Pharmacogenetics. 2000:1:125-51.
11. Blaisdell J, et al. Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics. 2002 Dec;12(9):703-11
12. Ibeanu GC,  et al. Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther. 1998 Sep;286(3):1490-5.
13. Ibeanu GC, et al. An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics. 1998 Apr;8(2):129-35.
14. Fukushima-Uesaka H,  et al.  Genetic variations and haplotypes of CYP2C19 in a Japanese population. Drug Metab Pharmacokinet. 2005 Aug;20(4):300-7.
15. Helsby NA. Pheno- or genotype for the CYP2C19 drug metabolism polymorphism: the influence of disease. Proc West Pharmacol Soc. 2008;51:5-10.
16. De Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA, The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem. 1994 Jun 3;269(22):15419-22
17. Ferguson RJ, De Morais SM, Benhamou S, Bouchardy C, Blaisdell J, Ibeanu G, Wilkinson GR, Sarich TC, Wright JM, Dayer P, Goldstein JA. A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin. J Pharmacol Exp Ther. 1998 Jan;284(1):356-61.
18. Xiao ZS, Goldstein JA, Xie HG, Blaisdell J, Wang W, Jiang CH, Yan FX, He N, Huang SL, Xu ZH, Zhou HH. Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele. J Pharmacol Exp Ther. 1997 Apr;281(1):604-9.

 

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