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Pharmacogenomics
Author: Joe Veltmann Jr. Ph.D. FAAIM DCCN
Address: GENESIS Center for Integrative Medicine
1488 South St. Francis Drive. Suite A
Santa Fe, New Mexico 87505
In a previous issue of JAAIM-Online, it was suggested that Integrative Medicine, in contrast to conventional medicine, is a personalized health care system because its practitioners:
- are focused on the health and vitality of the person versus attacking the disease;
- practice preventive medicine;
- are patient centered such that patients are evaluated on the physical, emotional, mental and spiritual levels;
- listen to their patients empathically;
- view chronic disease as multi-factorial condition versus the single agent, single treatment and single proof of efficacy used by allopathic medicine; and
- may use nutrigenomics, which individualizes diets, supplement plans, exercise, lifestyle choices and environmental concerns based on a person’s genetic predispositions to certain chronic diseases (1)
By adding pharmacogenomics to this list, the IM practitioner can customize and personalize prescription and non-prescription medications, thereby minimizing the risk for adverse drug reactions, drug-drug interactions and potential dangerous drug-botanical interactions in patients.
Pharmacogenomics is the study of genetic variability and its relationship to an individual’s response to pharmaceutical drugs, non-prescription drugs and over-the- counter medications (2). By examining the variations in a person’s DNA sequence, the IM practitioner can use the right drug for the right person at the right time, reducing the risk of serious adverse drug reactions.
Adverse drug reactions (ADR) are the fourth leading cause of death in the United States (4). The costs of ADR in terms of human life, emotional and mental anguish and finances are staggering. In 2000, hospital ADR amounted to 106,000 deaths and cost 12 billion dollars while deaths associated with outpatient ADR were 199,000 and cost 77 billion dollars (4). Of the more than 3.34 billion prescriptions billed in 2002, an alarming one-in-four patients suffered observable side effect ranging from rash and fatigue to life-threatening reactions (5). That is more than 800,000 thousand people! Because of the aging population, problem is only going to get worse according to an editorial that accompanied this study (6). The worst record of ADR belongs to the SSRIs (selective serotonin reuptake inhibitors), NSAIDs (non-steroidal anti-inflammatory drugs) and calcium-channel blockers. (7)). It is not surprising that ADR are the single largest source of malpractice payouts (4).
Ironically, only 60 % of the prescriptions written produce the desired therapeutic benefits in patients. The remaining 40 % produce a negative response or actually harm the patient (2). There are two possible explanations for this statistic.
- Drugs are usually tested using a fairly healthy people, who are not taking other medications (8).
When the drug enters the marketplace, however, it is often prescribed to an individual, who has a lot of health problems, typically taking more than one medication, including over-the-counter drugs, and perhaps even taking herbal or botanical supplements. The importance of knowing how botanicals or dietary constituents affect drug metabolism will be discussed later in this paper.
- The second reason is genetic variability associated with the cytochrome P450 (CYP) enzyme systems, which is part of Phase 1 detoxification (8, 9,10 ).
The body has evolved an elaborate system called Phase 1 and Phase 2 detoxification to biotransform exogenous and endogenous substances that may be potentially toxic to cells, organs and tissues. The sophistication of this system can be traced to man’s early attempts to differentiate what plants, herbs and other food sources were toxic (10). In Phase 1 detoxification, medications, steroids, and other compounds are biotransformed by oxidation, hydrolysis or reduction into more polar, water-soluble compounds. In Phase 2 detoxification, the metabolic products generated in Phase 1 are conjugated by glucuronidation, sulphation, acetylation, glutathione transferase or methylation and quickly excreted from the body, minimizing any potential toxic effects (12).
The CYP family of heme containing monooxygenase enzymes comprises the most important group in Phase 1 detoxification and is made up of about 100 enzymes in humans found in the liver, kidney and small intestine (11).
Each CYP is classified by a family, subfamily, and isoform-gene number (9). For example, CYP2D6 stands for family 2, subfamily D and gene 6. Seventeen different CYP families have been described in man (4) Nearly 56 % of all drugs in use today are primarily cleared from the body by the CYP enzyme system (4). Most drug metabolism is largely mediated by CPY3A4 (approximately 50 %) and CYP2D6 (approximately 30 %). CYP1A2, 2C9/10, 2C19 and 2E1 account for approximately equal percentages of the remaining 20 % (8, 11, 13).
For CYP2C9 there are three possible variations: the wild type (CYP2C9*1), which has no genetic variation and two additional alleles, CYP2C9*2 and *3. In both mutated alleles a point mutation leads to a substitution of an amino acid in the protein rendering them less than 12 % and 5 % efficient as the wild type enzyme, respectively. In CYP2C9*2 an arginine at position 144 is converted to a cysteine whereas in CYP2C9*3 an isoleucine at position 359 is converted to a leucine (14) Polymorphisms or genetic variation in the DNA of an individual influence the enzymatic activity of the CYP system.
The variability associated with Phase 1 detoxification among health people has been reported to be 1000 fold (15). Therefore, what one person’s food is another person’s poison. The activity of CYP can also vary along racial and geographical lines (4). A large percentage, for example, of Caucasians are genetically deficient in CYP2D6 (5-10 % of the population), whereas perhaps 20% of Asians are genetically deficient in CYP2C19 (8) Testing is currently available to detect genetic polymorphisms for the following CYP enzymes:
CYP1A1, CYP1B1, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 (16)
CYP enzymes are not only under the control of genetic polymorphisms but also can be inhibited or induced by
- drugs (antibiotics, anticonvulsants, antidepressants, antifungals, antipsychotics, H2 blockers);
- dietary constituents (alcohol, caffeine, tobacco, charcoal broiled foods, cruciferous vegetables, grapefruit juice);
- botanical compounds ( St. John’s wort, green tea);
- and endogenous substances such as steroid hormones (4).
An abbreviated list of drugs, which pass through CYP3A4, drugs and/or botanicals that inhibit or induce this enzyme, is given in Table 1. Similar arrays (substrates, inhibitors, and inducers) have been constructed for many of the other CYP enzymes and are essential references especially when dealing with potential drug-drug or drug-botanical interactions. Arrays for CYP1A1, CYP1B1, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are available from the author (j.r.veltmann@att.net).
Several examples from the literature and from the author’s clinical practice are given to illustrate how pharmacogenomics can be used in a clinical setting.
- Patients with venous and arterial thromboembolic disorders are often treated with an anticoagulant coumarin derivative, warfarin. Even though there have been considerable improvements in oral anticoagulant therapy, it is still difficult to predict the optimal dose for warfarin therapy. The effective daily dose ranges from 0.5 mg to 60 mg. This variability is associated with genetic polymorphism for CYP2C9. For a group of patients with a daily warfarin dose of 1.5 mg or less, 81% had one or more of the variant alleles present compared to 40 % in the control group; individuals, who were genetically predisposed (high-responders to warfarin) had bleeding complications 4 times more often than did the control group who were stabilized on larger doses of the drug (17). Identifying CYP2C9 polymorphisms in advance of warfarin therapy can decrease the risk of bleeding complications in patients and can help the health care professional opt for another coumarin derivative not detoxified by CYP2C9 in high risk patients.
- Genetic mapping revealed that a woman has genetic polymorphism in CYP3A4, meaning that the activity of this enzyme to detoxify drugs via this route is compromised. Her primary care physician, who is unaware of her genetic predisposition, prescribes prednisone, a substrate for CYP3A4, as an anti-inflammatory for Inflammatory Bowel Disease. The woman shares her genetic map with her physician and he orders another anti-inflammatory not detoxified by CYP3A4, avoiding a possible ADR.
- Organ-transplant patients require cyclosporine, a very expensive drug, to suppress the immune system. Consuming grapefruit juice (naringenen) everyday, which inhibits the activity of CYP1A1 and CYP1A2—the detoxification pathway for cyclosporine—allows for lower dose of the drug without compromising its pharmacological action on the immune system (15).
- In 1991, a man prescribed the popular ulcer drug, cimetidine (Tagamet) suffered liver failure, requiring a liver transplant due to a drug-pesticide interaction. Tagamet inhibits the activity of CYP2C19, which biotransforms some medications but more importantly detoxifies environmental chemicals such as pesticides and insecticides. Exposure to a biocide (he sprayed his lawn with an insecticide) along with Tagamet increased this man’s susceptibility to pesticide poisoning resulting in liver failure (18).
- Drug-botanical interaction: Imatinib (Gleeve or Clivec) is used to treat cancer. Imatinib is metabolized by CYP3A4. Drugs that induce this enzyme reduce the plasma concentration of imatinib, resulting in a lowered efficacy of imatinib. St. John’s wort (Hypericum perforatum) induces CYP3A4, altering imatinib pharmacokinetics (metabolism, absorption and excretion) by an average of 30 %, which would render imatinib treatment ineffective. Cancer patients may self-medicate with St. John’s wort to alleviate mild to moderate depression. Patients who are taking imatinib should not use St. John’s wort and in the event that they did, the dose of imatinib needs to be increased to compensate for it is increased clearance or reduction in efficacy (19). Similar reductions in pharmacokinetics were observed with St. John’s wort and two immunosuppressive agents, cyclosporine and tacrolimus (20).
- The ethnic background of an individual can increase the probability that he/she will be a poor metabolizer of drugs. Individuals with reduced activity of CYP2D6 due to a genetic polymorphism cannot convert the drug codeine to its active metabolite and therefore will receive little therapeutic benefit from taking codeine. In addition, these individuals will be unable to metabolize many of the psychotropic drugs, especially phenothiazines and may experience toxicity when taking usual doses of these drugs (9). The incidence of individuals classified as poor metabolizers for CYP2D6 is about 8 % for Caucasians, 4 % for African Americans and less than 1 % for Asians (21).
- A man has no genetic polymorphism for CYP1A1, but is given two medications by separate physicians, one of which is a substrate for CYP1A1 the other an inducer of this enzymatic pathway. Outcome: the second drug upregulates the biotransformation of the first drug making the first drug ineffective (8).
Summary
Pharmacogenomics matches drugs to an individual’s specific genetic make-up, thereby reducing the “trial and error” in health care, increasing treatment successes and reduces ADR. By understanding the pharmacogenomics of drugs, an IM practitioner can make informed treatment decisions which drugs will most likely be efficacious, minimize the risk of a serious drug-drug and drug-botanical interactions. When more than one drug is prescribed, the IM practitioner will know which drug(s) will induce or inhibit a specific CYP enzyme and can deduce whether the addition of a second drug is likely to cause a clinically meaningful change in the clearance of the first drug. If so, the health care professional can do one of several things. He/she can adjust the dose of the affected drug to compensate for its altered clearance or choose not to prescribe the inducer/inhibitor but rather use a drug with the same therapeutic benefit, which does not impact the metabolism of the initial drug.
References:
- Veltmann JR. Integrative Medicine as Personalized Medicine. JAAIM-Online (2005) http://www.aaimedicine.com/jaaim/june05/veltmann-impm.php?printable
- Flockhart, DA and Tanus-Santos, JE. Implications of Cytochrome P450 Interactions when Prescribing Medication for Hypertension. Arch Intern Med162: 405-12 (2002).
- Lazarou, J, Pomerenz, BH, and Corey, PN. Incidence of Adverse Drug Reactions in Hospitalized Patients: a Meta Analysis of Prospective Studies. JAMA 279:1200-05(1998).
- Adverse Drug Reaction Chart (2002) from http://www.genovations.com
- Gandhi, TK, Weingart SN, Borus J, Seger AC, Peterson J, Burdick E, Seger DL, Shu K, Federico F, Leape LL, and Bates DW. Patient Safety: Adverse Drug Events in Ambulatory Care. N Engl J Med 348:16:1556-64 (2003).
- Tierney W. Adverse Outpatient Drug Events-A Problem and an Opportunity. N Engl J Med 348:16:1587-89 (2003).
- Null, G, Dean C, Feldman M and Rasio D. Death by Medicine-3. (2003) http://www.garynull.com/documents/iatrogenic/deathbymedicine/DeathbyMedicine3.htm
- Preskorn, SH and Harvey AT. Cytochrome P450 Enzymes and Psychopharmacology. (2000) http://www.acnp.org/g4/GN401000086/CH085.html.
- Brown, CH. Overview of Drug Interactions Modulated by Cytochrome P450. (2000) http://www.uspharmacist.com/oldformat.asp?url=newlook/files/Feat/drugineractions.crm&pub_id=8&article_id=704
- Ingelman-Sundberg M, Oscarson M and Mclellan RA. Polymorphic Human Cytochrome P450 Enzymes: an Opportunity for Individualized Drug Treatment. TIPS 20: 342-49 (1999).
- Glue P and Clement RP. Cytochrome P450 Enzymes and Drug Metabolism-Basic Concepts and Methods of Assessment. Cell Mol Neur 19: 309-24 (1999)
- Bertz RJ and Granneman GR. Use of in vitro and in vivo Data to Estimate the Likelihood of Metabolic Pharmacokinetic interactions. Clin Pharmacokinet 32: 210-58 (1997).
- Coutts RT and Urichuk LJ. Polymorphic Cytochromes P450 and Drugs Used in Psychiatry. Cell Mol Neur 19: 325-54 (1999).
- Bland, J. Functional Medicine Update. 25 (7) July 2005.
- http://www.genovations.com
- de Morais, SMF, Wilkinson GR and Blaisdell J. The Major Genetic Defect Responsible for the Polymorphism of S-Mephenytoin Metabolism in Humans. JBC 269: 15419-22.
- http://www.majidaili.com/canary_page_3.htm
- Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, and Egorin MJ. Effect of St. John’s Wort on Imatinib Mesylate Pharmacokinetics. Clin Pharmacol Ther 76: 323-29 (2005).
- Hebert MF, Park JM, Chen YI, Akhtar S and Larson AM. Effects of St. John’s wort (Hypericum perforatum) on Tacrolimus Pharmacokinetics in Healthy volunteers. J Clin Pharmacol 44: 89-94 (2004).
- Ereshefsky L, Drug-drug Interactions involving antidepressants: Focus on Venlafaxine. J. Clin Psychopharmacol 16 (Suppl 2): 37S-50S; discussion 50S-53S (1996).
Table 1. Partial list of substrates (those compounds that are detoxified by this enzyme), inhibitors (compounds that reduce this enzyme’s activity) and inducers (compounds that increase this enzyme’s activity) for CYP3A4.
Substrates
Pharmaeuticals
Antidepressants |
Inhibitor
Pharmaeuticals |
Inducers
Pharmaceuticals |
Amitryiptyline (Elavil)
|
Cimetidine
|
Omeprazole (Prilosec) |
| Clomipramine (Anafranil) |
Ciprofloxacin (Cipro) |
Phenytoin (Dilantin) |
| Imipramine (Trofranil) |
Erythromycin |
Phenobarbital |
| |
Fluvoxamine (Luvox) |
Rifampin |
| Acetaminophen (NAPQ)) |
Pyrene |
|
| Caffeine |
Ticlopidine |
Aromatic Hydrocarbons |
| Clozapine (Clozaril) |
|
Cigarette smoke |
| Coumarin activation |
Botanicals |
Charbroiled foods |
| Estradiol, Estrone (4-OH) |
Ginseng (possible) |
|
| Heterocyclic amines |
Grapefruit juice (naringenin) |
|
| Naproxen |
|
|
| Propanolol (Inderal) |
|
|
| Tacrine (Cognex) |
|
|
| Testosterone |
|
|
| Theophylline |
|
|
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