July 18, 2005: Why must clinicians know about pharmacogenomics?

Clinicians must understand pharmacogenomics as it explains the variability in response to drugs.  It also offers potential explanations regarding individual susceptibility to addiction. 

Pharmacogenomics identifies the structural polymorphisms in genes that cause variable (interindividual) response to drugs. A gene is considered functionally polymorphic when stable variants exist in a population with a given level of frequency. Polymorphism of receptors and cytochrome enzymes offer one explanation for the varying interindividual susceptibility to drug dependence and addiction. (1) 

P450 cytochromes are microsomal drug metabolizing enzymes that are important in endogenous biosynthesis and oxidative drug metabolism. These mono-oxygenases are mostly located in liver tissue, but can also be found in the intestine.  At a subcellular level, they are anchored to endoplasmic reticulum.  Accepted nomenclatures identifies these cytochromes as CYP; Arabic numeral designating family (1 to 4); a letter designating subfamily (A to F); and another Arabic numeral designating isoenzyme (1 to 20). (1)(2)

CYP2D6 catalyzes hydroxylation or demethylation of more than 20 % of drugs and has more than 80 distinct allelic variants (polymorphism).  The phenotype (allelic variants) determines the rate of drug metabolism. A person with homozygous alleles containing inactivating mutations at CYP2D6 are poor drug metabolizers, those with one or 2 functional alleles exhibit intermediate or extensive metabolism, and those with duplicated genes experience ultrarapid metabolism. (1) (3) (4) (5)

Polymorphism explains the mood-altering properties of three popularly prescribed drugs-codeine, tramadol, and dextromethorophan. (4)(5)

Polymorphism and Codeine
Analgesic effects of codeine are the result of O-demethylation (via CYP2D6) into plasma morphine. The O-demethylated metabolites have a greater affinity for the µ receptor than any other metabolites. Usually, 10 % of the total amount of codeine is converted into morphine, but this varies depending on the patient’s phenotype.  The analgesic efficacy of codeine is dependent on the number of functional alleles for CYP2D6 which convert the codeine to morphine. If a person has two functional alleles, ultrarapid metabolism may result in increased concentration of morphine and symptoms of opiate toxicity may be seen.  Codeine is an ineffective analgesic in individuals homozygous for nonfunctional CYP2D6 alleles because so little codeine is metabolized to morphine. If individual phenotypes were known, one could predict those for whom codeine is an effective analgesic and those whom would experience opiate toxicity with typical doses. (3)(4)(5)(6)
Polymorphism and Tramadol
Tramadol is structurally similar to codeine. The analgesic and euphoric effects of  Tramadol are the result of the O-demethylation via CYP2D6 to a metabolite designated (M1). Other metabolites are inactive. Both Tramadol and M1 are μ opiate receptor agonists.  Compared to poor metabolizers, extensive metabolizers have increased concentration of  M1 leading to greater stimulation of the µ receptor and therefore greater analgesia and euphoria.(6) (7)

Polymorphism and Dextromethorphan (DM)
DM is the methylated dextrorotatory analog of levorphanol and does not possess the full range of CNS effects common to opioid agonists.  

The active metabolite, dextrorphan, is produced by  O-demethylation catalyzed by CYP2D6.   Dextrorphan has anticonvulsant, sedative, and antitussive properties and an affinity for the PCP site on the NMDA receptor. (8)

Poor metabolizers produce negligible dextrorphan, report more negative subjective effects and demonstrate a greater decrease in psychomotor performance than rapid metabolizers. (8) Rapid metabolizers may have a greater potential for abuse of DM.

Addiction and pharmacogenomics
As the causes of addiction are so multifactorial, it is difficult to determine the significance of polymorphism in determining addiction. Genetically determined inactivity of CYP2D6 decreases the analgesic and euphoric effects of codeine (decreased morphine) and tramadol (decreased M1) and the euphoric effects of dextromethorphan (decreased dextrorphan).  One could theorize that extensive metabolizers who metabolize drugs to greater concentration of metabolites with euphoric effects are at greater risk of becoming addicted. (6)

(1) Tribut O, Lessard Y, Reymann J, Allain H, Bentue-Ferrer D. Pharmacogenomics. Med Sci Monit 2002; 8(7); RA152-63

(2) Wilkinson Grant.  Drug Metabolism and Variability among Patients in Drug Response. N Engl J Med 2005; 352: 2211-2221

(3)  Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 Metabolism. N Engl J Med 2004; 351: 2827-2831

(4)  Kathiramalainathan K, Kaplan H, Romach MK, et al. Inhibition of cytochrome P450 2D6 modifies cocaine abuse liability. J Clin Psychopharmacol 2000; 20(4): 435-444

(5) Caraco Y. Genes and the Response to Drugs.  N Engl J Med 2004;(352)27;2867-69

(6) Lotsch J, Starke C, Liefhold J, geisslinger G.  Genetic Predictors of the Clinical Response to Opioid Analgesics.  Clin Pharmacokinet 2004; 43(14);983-1013

(7) Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43(13): 879-923

(8)  Zawertailo L, Kaplan H, Busto, et al. Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study. J Clin Psychopharmacol 1998; 18(4): 332-337

As always, if there are any questions, please call the Tennessee Poison Center at 1-800-222-1222 or 936-0760.

I am interested in any questions you would like answered in the Question of the Week.  Please email me with any suggestions at Donna.Seger@Vanderbilt.edu.

Donna Seger, MD
Medical Director
Tennessee Poison Center