[Fwd: Emerging Enzyme test can predict drug side effects]

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Liver Success

Emerging Enzyme Test Can Predict Drug Side Effects

By Barrett Mann

Special to The Washington Post

Tuesday, April 18, 2006; Page HE01

Adverse drug reactions -- what most of us call side effects -- can range

from annoying (headaches) to debilitating (diarrhea, vomiting) to

deadly. And certain drugs -- especially psychiatric and cardiac ones --

are more apt to cause severe reactions. If only doctors had a way to

predict who's most susceptible.

In many cases, they do, just by conducting a blood test or cheek swab

before writing a prescription.

Researchers in the growing field of pharmacogenetics -- the study of how

people's genetic make-up affects their response to medicines -- say

doctors can screen for genetic variations that often prevent liver

enzymes from processing certain drugs properly. When that occurs, a dose

may not register at all -- or it may produce a toxic reaction. Cost for

the one-time screening? Between $200 and $1,400.

Mrazek, chairman of psychiatry and psychology at the Mayo Clinic

in Rochester, Minn., says he does such testing " very regularly, "

especially with children (who are particularly vulnerable to drug side

effects) and patients with a personal or family history of adverse drug

reactions. Many other doctors in his field are unfamiliar with the tests

or don't use them.

To understand how these tests work, it helps to know something about the

role of both the liver and genes in drug metabolism.

The liver is responsible for regulating most chemical levels in the

blood. When you swallow a pill, the medication typically travels via the

bloodstream from your stomach to your liver. There, one or more types of

liver enzyme process the drug, breaking it down into forms that are

easier for the rest of the body to use. Some of the drug travels on

through your bloodstream; the rest is tagged as poisonous and filtered out.

The most important liver enzymes in drug metabolism are the ones in the

" cytochrome P450 " (CYP) family. They process 25 percent of all drugs,

including those that cause the most adverse reactions --

antidepressants, anti-psychotics, painkillers, beta blockers (which slow

the heart rate and lower blood pressure) and drugs used to treat

attention-deficit hyperactivity disorder (ADHD).

Say you take a drug that is mostly processed by the enzyme CYP 2D6. If

your liver produces too much of this enzyme, it could over-process the

drug and flush it right out of your body, and you'd get no therapeutic

effect. If, on the other hand, your liver produces too little of the 2D6

enzyme or none at all, the drug wouldn't be sufficiently broken down.

Instead, it would build up in your bloodstream. You could overdose on

what, for most people, would be a normal dose.

The Role of DNA

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Just as eye color and hair color are determined by our genes, so are

liver enzymes. And some vary more than others. There are more than 50

variations in the 2D6 gene. And the enzyme it governs is involved in

metabolizing about 70 different drugs, including the antidepressants

Paxil and Prozac and the ADHD drug Strattera, explains Mrazek. Even the

popular antihistamine Claritin is metabolized by 2D6.

Like other genes, those that code for liver enzymes can vary by race and

even your ancestors' geographic origin. Most people have two good copies

of the 2D6 gene, so they produce a normal amount of the related liver

enzyme. But an estimated 7 percent of Caucasians have two bad copies of

the gene -- or no copies at all. These " poor metabolizers " don't produce

any of the enzyme.

Sometimes, what you don't know can kill you. A 2000 case report in the

Journal of Child and Adolescent Psychopharmacology tells of a 9-year-old

boy with Tourette's syndrome, ADHD and obsessive-compulsive disorder who

was treated with a combination of Ritalin, clonidine and Prozac. After

10 months on the drug regimen, he suffered seizures, then a heart

attack; he later died. When an autopsy revealed toxic levels of Prozac

in the child's blood and brain tissue, authorities first thought his

adoptive parents had poisoned him. They were cleared when tests showed

the boy was a 2D6 poor metabolizer.

Thirty percent of people who can trace their roots to North Africa and

20 percent of those whose families came from the Middle East have a

different problem with 2D6: They are born with three or more copies of

the gene. These " ultra-rapid metabolizers " produce too many 2D6 enzymes,

which speed certain drugs out of the body. African Americans are more

likely to be ultra-rapid metabolizers than whites, says Mrazek. Only 2

percent of Caucasians fall in this category.

Liver Success

Then there are the " intermediate metabolizers " -- those who have one

good and one bad copy of a particular gene -- say, the one for the 2D6

enzyme. Because they produce roughly half the 2D6 liver enzymes that a

normal person does, explains Mrazek, they could get the same amount of a

2D6-metabolized drug into their bloodstream by taking half the normal

dose. One estimate is that as many as 35 percent of Caucasians are

intermediate metabolizers of 2D6.

The intermediate metabolizers are a particularly tricky group, say some

experts. They might feel positive results from a drug at first, but get

sick over time as it slowly builds up in their bloodstream. But because

they've been on the drug for weeks or months, they might not recognize

their symptoms as an adverse reaction to it.

Shirley , an African American from Orange Park, Fla., desperately

wishes she'd known she was an intermediate metabolizer for both the 2D6

and the 2C19 genes. When the former parole officer suffered from severe

depression in 2002, doctors first prescribed Zoloft (metabolized by the

2C19 and 2D6 enzymes, among others). The entry-level dose was okay, but

when it was raised, she experienced gastrointestinal problems, hair

loss, night sweats, fever and heart palpitations. She switched to Paxil

(metabolized by 2D6) and then Wellbutrin (metabolized by 2D6 and three

other enzymes), but bad side effects continued.

In April 2004, after nearly two years of antidepressant treatment,

's doctors took her off the drugs when her blood tests showed

elevated liver enzymes. Doctors first assumed she'd contracted a viral

form of hepatitis, she recalls, but tests came back negative. The

diagnosis: drug-induced autoimmune hepatitis, with permanent liver

damage. Testing by Genelex, a DNA lab in Seattle -- at a cost of $800,

paid by 's insurer -- identified her enzyme problem. says

she's been told her life expectancy is eight to 10 years.

So Why Not Test?

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Mrazek is convinced of the value of genetic testing for enzyme problems.

" Before I would put any child " on a drug metabolized by the 2D6 enzyme,

he says, " I would want to know that they have at least one good copy of

the 2D6 gene. . . . I've been very surprised by some very senior

psychiatrists saying, 'I don't need this; I've been prescribing Prozac

for years.' Young clinicians are very quick to say, 'Gee, here's a tool

that can potentially prevent a tragic event.' "

But Washington psychiatrist Lynn Cozza, an assistant professor at

the Uniformed Services University of the Health Sciences, regards the

testing as an unnecessary expense for most patients. An alert doctor,

she says, should be able to recognize drug metabolism problems

clinically. For example, she can ask patients, " Have you ever had any

problems taking Robitussin? Does it make you queasy or jittery or

sleepy? " Since Robitussin is metabolized by 2D6, a " yes " could be a red

flag.

Cozza also notes that many factors besides DNA can affect liver enzyme

production, including age, weight, diet, other drugs and smoking. Brain

receptors may also affect how the body reacts to different drugs.

Then there's the question of cost. Genelex will test for a problem on

one gene for $250; a battery of four tests (for genes 2D6, 2C19, 2C9 and

1A2) costs $800.

Until last year, only a few labs, like Genelex and the Mayo Clinic

(whose fees are similar to Genelex's), offered this genotyping. But last

year Roche Diagnostics introduced a new technology, approved by the Food

and Drug Administration (FDA), that allows less specialized labs to test

for genetic defects on 2D6 and 2C19. Now the labs need to convince more

doctors to order the tests. Pam Sherry, a spokeswoman for Roche's

LabCorp, quoted a " ballpark retail " price of $1,360 -- but said insurers

that have contracts with LabCorp will probably pay less.

But many policies -- including ones from Aetna, CareFirst BlueCross

BlueShield and Cigna HealthCare -- won't pay at all, because the

insurers consider use of the testing in clinical practice " experimental

and investigational. " UnitedHealthcare doesn't have a written policy on

cytochrome P450 testing yet, says spokesman s, but the

company's plans -- including M.D.-IPA and Optimum Choice -- may approve

the testing on a case-by-case basis, if it's prescribed and used

properly. Federal workers are guaranteed coverage for medically

necessary testing, said Office of Personnel Management spokesman

Orenstein, because Federal Employees Health Benefit Plan contracts

stipulate that FDA-approved tests may not be considered investigational.

But do you really want your health insurance plan to pay for the

testing? Cozza posed an interesting question: If your insurer learned

that you had a CYP defect . . . could it decide to require preapproval

for every prescription any doctor writes for you?

No insurance plans are paying for routine genotyping yet. But the field

of pharmacogenetics is young. " My prediction, " said Mrazek, " is that,

down the line, pediatricians will do this testing during a child's

infancy. " But first the labs know they have some convincing to do. ·

Drugs With Special Side Effect Risks

Tuesday, April 18, 2006; Page HE08

According to the Web site of Genelex, a DNA lab, the following common

drugs are metabolized by enzymes in the cytochrome P450 family. This

means that some people with certain genetic variations may be vulnerable

to getting too much or too little of these drugs' active ingredients in

their bloodstreams.

CYP 2D6

Painkillers: codeine, OxyContin, Percocet, Ultram, Ultracet, Vicodin

Antidepressants: Effexor, Elavil, imipramine, Paxil, Prozac

Antipsychotics: Haldol, Risperdal

Cardiovascular: Coreg, Inderal, Lopressor, Timoptic, Toprol

ADHD treatment: Adderal, Concerta, Strattera

Miscellaneous: Claritin, dextromethorphan (active ingredient in most

cough suppressants), Flomax

· CYP 2C19

Painkillers: methadon

[Guest guest]

Doris,

Thank you SO MUCH for posting this... I think this may be a problem in my

family, and I had never heard it before.

Caroline

[Guest guest]

Does Dr Goldberg test for this gene or do genetic testing?

Kristie