A headline on ScienceDaily (May 10, 2010) reads:
The article describes the research of Wang et al. (Wang, Guo, Wrighton, Cooke and Sadee) who published their finding in The Pharmacogenomics Journal. Wang et al studied liver tissue from humans and found that a very small genetic mutation could influence the dose required for up to half of all drugs. ScienceDaily:
Each gene contains two alternative forms -- called alleles -- that are identical in most people. However, in this case, the researchers found that the activity level, or expression, of one allele differs from its partner allele in a single gene. That small difference is called a single nucleotide polymorphism, or SNP (pronounced snip). This SNP affects the gene's protein-producing process, in turn lowering the level of an enzyme known as CYP3A4. The faster a drug is processed, or metabolized, by this enzyme in the liver, the more quickly it is eliminated from that tissue and the body as a whole. When this enzyme level is lowered by the presence of this SNP, people are likely to require smaller doses of medicines that the enzyme metabolizes. But this also means that higher doses of these same drugs can be dangerous to people with the mutation if those levels become toxic. (Ohio State University 2010)
Physicians and scientists have long known that individual patients respond differently to drugs and that one reason for this is genetics. The fields of pharmacogenetics and personalized medicine are based on this. This study sheds more light on why individuals vary.
It also supports, once again, the notion that relying on rodents or monkeys to predict human response to drugs is not viable. There are many more differences between species than one tiny mutation.
"Right now, because there are no biomarkers available to predict CYP3A4 activity, trial and error determines whether cholesterol goes down with the prescribed dose," Wang said. "You never know who has what enzyme level, so you never really know what dose to give an individual if you don't have a biomarker." The biomarker also could be applied to early clinical trials of new drugs, Wang said, by identifying research participants ahead of time who will not respond well to new formulations. (Ohio State University 2010)
Human-based research like this will decrease the cost of developing new drugs because individual populations can be identified early thus neither underdosing nor overdosing will not occur. Overdosing could lead to side effects that would shelve the drug while underdosing would make the drug appear ineffective. Losing drugs because of these two factors currently increases the cost of medications. Not to mention it keeps good drugs off the market.
Very small differences at the genetic level can mean very significant differences in drug response. This is one reason why different humans respond differently to the same drugs. Testing on animals is not going to solve this problem. The sooner the scientific community as a whole acknowledges that animals are not predictive for human response to drugs and disease, the sooner society can have personalized medicine.
Ohio State University. 2010. Tiny mutation might help indicate proper dosage for half of all drugs. ScienceDaily, May 11 2010 [cited May 11 2010]. Available from http://www.sciencedaily.com /releases/2010/05/100510161334.htm.
Wang, D., Y. Guo, S. A. Wrighton, G. E. Cooke, and W. Sadee. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J.