Cytochrome P450 2C19 Genotyping

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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 800-523-6487 to obtain specimen kits.

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

• Turnaround Time: 10 -14 days turnaround (4 day turnaround for STATS)

CPT Codes

CYP2C19 Mutation DNA Analysis (provided for your guidance only)
83891, 83892, 83901 x2, 83896 x14, 83912

Clinical Significance

Phenotype prevalence is 2-6% PM Caucasian, 15-20% PM Japanese, 10-20% PM African;
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 extensive metabolizers (EM, "normal").
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 an extensive metabolizer phenotype (EM). 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.

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.imm.ki.se/CYPalleles/cyp2C19.htm

Testing places individuals in one of three categories:

• Extensive metabolizers (EM) represent the norm for metabolic capacity. Genotypes consistent with the EM phenotype include two active CYP2C19 alleles. In general, extensive metabolizers can be administered drugs that are substrates of the CYP2C19 enzyme following standard dosing practices.
• Intermediate metabolizers (IM) may require lower than average drug dosages for optimal therapeutic response. Genotypes consistent with the IM phenotype are those with one active CYP2C19 allele.
• Poor metabolizers (PM) are at increased risk of drug-induced side effects due to diminished drug elimination or lack of therapeutic effect resulting from failure to generate the active form of the drug. Genotypes consistent with the PM phenotype are those with no active CYP2C19 alleles. These individuals have a deficiency in drug metabolism.

Direct 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 a rare 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.

Dosage Recommendations

A complicating factor in correlating CYP2C19 genotype with phenotype is that many drugs may reduce or increase CYP2C19 catalytic activity. Consequently, an individual may require a dosing decrease greater than predicted based upon genotype alone. 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. the results of testing and dose adjustments in the context of renal and hepatic function and age.

• PM
  Reduce dose to 20-60% of standard dosage.
  
  
• IM
  Start IM's at lowest efficacious dose, avoid multiple drug therapy that inhibits or activated through the same pathway.
  
  
• Therapeutic drug monitoring in PM and IM subjects is highly recommended. Again standard measures of efficacy

For specific dosages see charts and tables 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.

Methodology

DNA extraction/Polymerase Chain Reaction (PCR)/ Enzyme inactivation /Allele-specific primer extension / Hybridization using immobilized nucleic acid probes/ Fluorescent detection.
Laboratory specimens were analyzed using the Tag-ItTM Mutation Detection System for P450-2C19 which detects 7 nucleotide variants in a multiplex polymerase chain reaction and allele-specific primer extension format.

Drug Metabolism Guide

This list is not all inclusive and is for your guidance only.

Substrates Metabolized through Cytochrome P-450 2C19

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

acenocoumarol	desmethyldiazepam	omeprazole	thioridazine
amitriptyline	desogestrel	pantoprazole	trimipramine
bufuralol	dextromethorphan	perphenazine
cilostazol	diazepam	phenytoin
citalopram	doxepin	progesterone
cloazapine	fluoxetine	propranolol
clominpramine	imipramine	rabeprazole
cyclophosphamide	lansoprazole	ranitidine
dapsone	methadone	sertraline
deprenyl	nelfinavir	tamoxifen

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.

amiodarone	fluconazole	ketoconazole	paroxetine
amprenavir	fluvastatin	loratidine	probenicid
cimetidine	fluvoxamine	lovastatin	valproic acid
delavirdine	isoniazid	nicardipine	zafirlukast

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.

dexamethasone

rifampin

References

1. 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

2. 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

3. 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.

4. 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.

5. Blaisdell J, Mohrenweiser H, Jackson J, Ferguson S, Coulter S, Chanas B, Xi T, Ghanayem B, Goldstein JA.. Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics. 2002 Dec;12(9):703-11.

6. Brockmoller J et.al. Pharmacogenetic diagnosis of cytochrome P450 polymorphisms in clinical drug development and in drug treatment. Pharmacogenetics. 2000:1:125-51.

7. 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

8. Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Daly AK, Goldstein JA. An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics. 1998 Apr;8(2):129-35

9. Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P, Ghanayem BI, Blaisdell J. 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

10. Cozza KL, Armstrong SC, Oesterheld JR (2003) Drug Interaction principles for Medical Practice. American Psychiatric Publishing Inc

11. Linder MW and Valdes RJr. Pharmacogenetics in the Practice of Laboratory Medicine. Molecular Diagnosis. 1999;4:365-79. Mol Pharmacol. 1994 Oct;46(4):594-8

12. De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol. 1994 Oct;46(4):594-8

 

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