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Pain Management, CYP450 2D6/2C19 Genotype

Pain Management, CYP450 2D6/2C19 Genotype

Test Summary

Pain Management, CYP450 2D6/2C19 Genotype, Qualitative

  

Clinical Use

  • Assess likelihood of reduced or enhanced response to pain medications metabolized by CYP2D6 or CYP2C19 enzymes

  • Guide treatment strategy for patients being considered for, or receiving, these medications

Clinical Background

Opioids are widely used for the management of moderate to severe pain; however, the efficacy of specific opioids can vary dramatically among individuals. Such variation can be attributed to alterations in opioid metabolism, which can cause the drug or metabolite to leave the body too rapidly or remain in the body too long. In the first scenario, the drug may not reach a therapeutic level, while in the second, the patient may experience a heightened clinical effect or toxicity.1,2 These variations may make dosage optimization a significant challenge for clinicians.

The cytochrome P450 (CYP450) enzymes are a super-family of enzymes located in the liver and mucosal surface of the intestinal tract. They play important roles in the biosynthesis and metabolism of endogenous and exogenous compounds.3 Of the more than 50 CYP450 enzymes identified in humans, 7 metabolize >90% of the clinically most important drugs.3,4 For example, CYP2D6 is involved in the metabolism of 25% to 30% of all prescribed drugs, while CYP2C19 is involved in metabolizing 15%.5,6

Allelic variations in the CYP2D6 and CYP2C19 genes result in markedly increased or decreased drug metabolism, leading to wide variations in clinical effect.7,8 For example, codeine is metabolized by CYP2D6 to the biologically more active drug, morphine.9 Certain variations in the CYP2D6 gene can result in ultra-rapid metabolism of codeine and a markedly exaggerated clinical response, while other variations can result in poor codeine metabolism, little conversion to morphine, and a blunted therapeutic response. Conversely, methadone is an active drug, but is later inactivated by CYP2C19.9 Genetic variations in CYP2C19 that cause ultra-rapid methadone metabolism may require a larger methadone dose to reach a given therapeutic effect, while variations causing poor metabolism may require a lower dosage to reach the same effect. It is estimated that 1% to 3% of Caucasians and 13% to 23% of Asians have the CYP2C19*2 or *3 variant that results in poor metabolizer status.10

Recent studies have indicated that genetic testing for variations in CYP2D6 and CYP2C19 may result in improved pain management, a decrease in episodes of drug toxicity, and fewer adverse drug interactions.2,7,8 This assay tests for common variants of CYP2D6 and CYP2C19 that can result in increased or decreased metabolism of opioid analgesics and other common drugs.

Individuals Suitable for Testing

  • Individuals being considered for, or receiving, pain drugs metabolized by CYP2D6 or CYP2C19

Method

  • Multiplex polymerase chain reaction

  • Microarray hybridization of a total of 28 CYP2D6 and CYP2C19 variants

  • Results reported:

   Phenotype (eg, ultra-rapid, extensive [normal], or poor metabolizer) predicted based on CYP2D6 and

CYP2C19 gene analysis

   Dosing suggestions, based on predicted phenotype, for 8 common drugs: codeine, oxycodone,

hydrocodone, tramadol, methadone, carisoprodol, meperidine, amitriptyline

Reference Range

Extensive (normal) metabolizer phenotype

Interpretive Information

Presence of 2 normal functioning alleles predicts an extensive (normal) metabolizer phenotype; standard dosing can be used. The optimum dose for other phenotypes depend on whether the drug is inactive (ie, prodrug) or is active as ingested (see Table). Dosing for drugs not listed in the table may be determined by reviewing the pharmacokinetic profile in resources such as the Physician’s Desk Reference or Internet resources such as the professional version of Drugs.com.

Because drug metabolism is highly complex, an individual’s response to a specific drug and dosage can be affected by a myriad of factors including underlying disease, overall clinical condition, other medications, foods, and mental status. Choice of medication and dose should not be made based solely on these test results.

Additional assistance in interpretation of results is available from our Genetic Counselors by calling 1-866-GENE-INFO (1-866-436-3463).

Table. Drug Characteristics and Dosing Considerations
Drug Prodrug Enzyme Ultra-rapid Metabolizera Intermediate Metabolizerb Poor Metabolizerc
Codeine Yes CYP2D6 Decrease dose Increase dose Alternate drug
Oxycodone Yes CYP2D6 Decrease dose Increase dose Alternate drug
Hydrocodone Yes CYP2D6 Decrease dose Increase dose Alternate drug
Tramadol Yes CYP2D6 Decrease dose Increase dose Alternate drug
Methadone No CYP2C19 Increase dose NA Decrease dose
Carisoprodol Yes CYP2C19 Decrease dose NA Alternate drug
Meperidine Yes CYP2C19 Decrease dose NA Increase dose or alternate drug
Amitriptyline Yes CYP2D6 and
CYP2C19
Decrease dose NA Increase dose or alternate drug

NA, not applicable.
a Presence of 1 copy of an ultra-rapid metabolizer allele predicts an ultra-rapid metabolizer phenotype.
b Presence of 1 copy of a CYP2D6 poor metabolizer allele predicts an intermediate metabolizer phenotype.
c Presence of 2 copies of a poor metabolizer allele predicts a poor metabolizer phenotype.

References

  1. Tucker G. Advances in understanding drug metabolism and its contribution to variability in patients’ response. Ther Drug Monitor. 2000;22:110-113.

  2. Jannetto PJ, Bratanow NC. Pain management in the 21st century: utilization of pharmacogenomics and therapeutic drug monitoring. Expert Opin Drug Metab Toxicol. 2011;7:745-752.

  3. Shapiro LE, Shear NH. Drug interactions: Proteins, pumps, and P-450s. J Am Acad Dermatol. 2002;47:467-484.

  4. Lewis DF. 57 varieties: The human cytochromes P450. Pharmacogenomics. 2004;5:305-318.

  5. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 2009;48:761-804.

  6. Blaisdell J, Mohrenweiser H, Jackson J, et al. Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics. 2002;12:703-711.

  7. De Gregori M, Allegri M, De Gregori S, et al. How and why to screen for CYP2D6 interindividual variability in patients under pharmacological treatments. Curr Drug Metab. 2010;11:276-282.

  8. Rollason V, Samer C, Piguet V, et al. Pharmacogenetics of analgesics: toward the individualization of prescription. Pharmacogenomics. 2008;9:905-933.

  9. Trescot AM, Datta S, Lee M, et al. Opioid pharmacology. Pain Physician. 2008;11:S133-S153.

  10. Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84:613-624.
     

This test was developed and its performance characteristics have been determined by Quest Diagnostics. Performance characteristics refer to the analytical performance of the test.

 Content reviewed 04/2013

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