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Pain Management, CYP450 3A4/3A5 Genotype, Qualitative

Pain Management, CYP450 3A4/3A5 Genotype, Qualitative

Test Summary

Pain Management, CYP450 3A4/3A5 Genotype, Qualitative

  

Clinical Use

  • Assess likelihood of an altered clinical response to medications metabolized by CYP3A4 or CYP3A5 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, the CYP3A enzymes metabolize over 40% of the drugs currently approved by the United States Food and Drug Administration.5 Of the CYP3A enzymes, CYP3A4 and CYP3A5 are the ones most abundantly expressed in the liver, and thus the most important in drug metabolism. It is estimated that approximately 90% of interindividual differences in hepatic CYP3A activity are the result of genetic variation.6

Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation in CYP3A genes. Marked genetic variations have been observed in different ethnic groups. For example, CYP3A4*1B allele frequencies are 4% in Europeans and 82% in Africans, whereas the CYP3A4*2 allele was absent in both populations.7

Allelic variations of CYP3A4 and CYP3A5 have been associated with decreased enzyme activity, potentially leading to increased drug levels and toxicity.8 For example, fentanyl is normally converted to the inactive form, ie, norfentanyl, by CYP3A4-mediated N-dealkylation.9 But in the presence of a CYP3A4 variant, less fentanyl would be inactivated, and a lower dosage could be used.

Recent studies have suggested that genetic testing for variations in CYP450 genes associated with drug metabolism may result in improved pain management, a decrease in episodes of drug toxicity, and fewer adverse drug interactions.2 This assay tests for common variants of CYP3A4 and CYP3A5 that can result in decreased metabolism of certain opioid analgesics (eg, buprenorphine, fentanyl, hydrocodone, meperidine, methadone) and other common drugs (eg, clonazepam).

Individuals Suitable for Testing

  • Individuals being considered for, or receiving, drugs metabolized by CYP3A4 or CYP3A5

Method

  • Multiplex polymerase chain reaction and single nucleotide primer extension

  This assay detects 7 common variants of CYP3A: CYP3A4*1B, *2, *3, *11, *12, and *17; and

CYP3A5*3

  • Analytical sensitivity and specificity: >99%

  • Results reported: variant(s) detected and interpretive comment

Reference Range

No CYP3A4 or CYP3A5 variants detected

Interpretive Information

The absence of variant alleles in both genes suggests a normal metabolizer phenotype, and standard dosing can be used. Variant alleles of CYP3A4 and CYP3A5 have been associated with decreased enzyme activity. Thus, the presence of variant alleles may result in decreased drug metabolism.

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.

This assay cannot detect deletions; duplications; or smaller genetic alterations, such as point mutations, that affect the amino acid coding sequence, regulatory sequences, or mRNA splicing in the CYP3A4 and CYP3A5 genes.

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

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. Zanger UM, Turpeinen M, Klein K, et al. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008;392:1093-1108.

  6. Ozdemir V, Kalowa W, Tang BK, et al. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics. 2000;10:373-388.

  7. Garsa AA, McLeod HL, Marsh S. CYP3A4 and CYP3A5 genotyping by pyrosequencing. BMC Med Genet. 2005;6:19. doi: 10.1186/1471-2350-6-19.

  8. Lee SJ, Goldstein JA. Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics. 2005;6(4):357-371.

  9. 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 02/2013
 

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