American Association for Cancer Research

Clinical Trials and Special Patient Populations

How our bodies handle drugs differently

Now, let’s talk about the variability in the way our bodies handle drugs. There are a lot of different factors in the way our bodies respond to drugs. We know some of it is related to gender, and then there is age. Age is not just chronological age, but rather, a surrogate for poor organ function. Normally, a 70-year-old’s kidneys don’t function like a 20-year-old’s. As we grow older, our organs are not functioning as well, so we don’t excrete drugs as quickly and sometimes there are a lot of side effects. Environmental exposures are another factor influencing how our bodies handle drugs. Smoking is one of these. Then there’s also genetic variability.

Physicians have always known that the same dose of one drug may work in some people and not others, or cause severe side effects in some patients while others tolerate the drug very well. This has never been well understood, but right now we have some insights.

Single Nucleotide Polymorphisms

The body’s genetic code, DNA, is composed of chemicals that—when grouped together—are the signals for our bodies to make amino acids, which, in turn, make proteins. There are four main chemicals—A, T, G and C—which stand for adenine, thymine, guanine and cytosine. These four chemicals, which are called nucleotide bases, are combined in different ways to code for all of the amino acids that make up proteins. Usually, when you have three of these chemicals together, they lead to your body making an amino acid. As an example, you can have a situation where most people will have CCA, which could be the code for the amino acid proline. But in some people, for reasons we don’t understand, if you go to that position in a DNA strand and look at the code, instead of CCA, they have a different chemical instead of A. They have G.

This switch from A to G is called a single nucleotide polymorphism. All that it means is that you switched one nucleotide. In this case, CCG also happens to make proline, just like CCA does. The scientist calls it a degenerate code, which means that you have different combinations that will make the same amino acid. If one mistake always resulted in the wrong amino acid—so the protein it was part of didn’t work—we’d probably not have survived as a species. So the process has back-up systems: People might have this polymorphism but they are making the same amino acid, so they have the same protein; it doesn’t make any difference.

But in another situation, say you have the code AGC and this person’s body has changed the A to a G. AGC codes for an amino acid called serine, but GGC means the body makes glycine. Aha! There’s a different amino acid, so now you make a different protein. Sometimes, the body sees that there’s a mistake here and it destroys the protein. If this protein is an enzyme that breaks down a drug, then it means that if we give you that drug, you don’t have enough enzyme to break it down and you’re going to have a lot of side effects.

We now know that because of this phenomenon where a single nucleotide polymorphism makes a different protein, there can be differences in individuals. Many drugs are transported into cells by proteins called transporters. In addition, drug targets—such as epidermal growth factor receptor—are all proteins. The enzymes that break down drugs are also proteins. People can inherit variations, or polymorphisms, in a number of these proteins, but we are not at the point where we can test everybody for these variations. So sometimes you have to take the quick and dirty way, which is identifying the fact that a protein variation is more common in a particular group of people. You might have a protein variation that is common in 20 percent of Caucasians but that you rarely see in African-Americans, or vice versa. For now, this method of identifying specific protein variations in different ethnic groups is very important for some treatments, including some cancer treatments.

Codeine FinalI’ll give you one example. Codeine that we take for pain is actually methylmorphine.

Morphine Final When you change the OCH3 in codeine's structure to an OH group, you get morphine. Codeine by itself is not very active, until after it’s converted to morphine in the body. There are inherited variations in the activity of the protein that converts codeine to morphine. We know that a fair number of African-Americans have low levels of the enzyme that convents codeine into morphine. If you give these individuals codeine, it’s ineffective. When I was a resident at Howard University, we assumed that codeine was ineffective in these folks because they were probably drug addicts. Well, it isn’t drug addiction; it’s inherited variations in how their bodies handle codeine.

We know this polymorphism thing may explain a big part of why drugs work in some people and don’t work in others, and it might explain side effects also. But we don’t have the whole explanation.