Wednesday, May 2, 2012

Prescription Strengths Based on a Patient's Genetic Background

When watching an episode of House in which a patient attacks Dr. House for prescribing a certain blood pressure medication in accordance to his race, I wondered how this concept could be true. The patient thought this profiled prescribing was racist and refused to take the "black" drug, so House just told him he was prescribing the "white" drug, but nonetheless gave him the “black” one.  I had heard of this concept before and it seemed somewhat interesting to me that an entire group of people could be substantially more or less sensitive to a certain medication. Is the difference in efficacy really that considerable, and what exactly is the difference at play here that causes different sensitivities? Does this spur from differences in the physiology that is actually causing the ailment being treated, or is it a difference in the way the body responds to the chemical therapy? If it is a difference in chemical reactivity in the body, how does this work on a molecular level? I sought to find what was happening differently in the body from ingestion to excretion that would cause a difference in the drug’s action in the body. I wanted to know what it is that is different in the body between people and what is the same, to hopefully have a better understanding of not just differing biological chemistries, but of drug pharmacology as well.
           As someone who will be going into the field of pharmacy, having worked in a pharmacy and hearing many people talk of how certain drugs have worked for them, I was a little skeptical about how different the effectiveness could be on such a large scale. I found a study that compared the differences in effectiveness of propranolol (a beta receptor blocker that reduces the ability of adrenaline to affect heart activity) and hydrochlorothiazide (a diuretic that brings down blood pressure by reducing blood volume). As shown in this chart (see figure 1), the decrease in systolic blood pressure due to propanolol was  roughly double for whites (marked as W) than for blacks (marked as B). Also, decrease in systolic blood pressure due to hydrochlorothiazide was 5.2 mmHg more for blacks. So there is definitely a difference in response between races in this case, as is also shown in the more graphical representation in figures 2 and 3. 

Figure 2.
Figure 3.
       Even though there did seem to be a difference in drug response based on racial makeup, this data does not rule out any possible confounders in these results. This data does not actually link genetic difference to this outcome; it just shows the difference in drug response in an observational manner. So in looking at other research, I was able to find definitive evidence for genetic links to drug sensitivities (see figure 4). This revealed how mutations in gene coding changed the therapeutic effect of the drug. So even though confounders could have been present in the previous study, we can now see the link between genetics and drug response. Here we can now see that the nature side of human biology can change how well a medication works within the body, but mutations only really show differences from one person to the next, not an entire ethnic or racial group. So what is it exactly that causes differences for an entire group of people, not just a difference from one person to the next?
Figure 4.
So with a little more digging, the culprit of these differences seems to come from the actual metabolism of the drug itself, and that pharmacology differences for each individual drug is not the reason that entire ethnicities have certain drug sensitivities. The Cytochrome family of hepatic enzymes has a number of isoforms that specialize at metabolizing certain drugs. Allelic variations in certain isoforms of CYP enzymes are very common within different races and ethnicities. Families of CYP enzymes can differ by just a few amino acids, as shown in figure 5. It is clear there are many variations of cysteine and leucine expression within racial groups. This information was found in the article “Molecular Basis of Ethnic Differences in Drug Disposition and Response” by Hong-Guang Xie et al. This article also explains that the distribution of these variants leads to certain types of people poorly metabolizing certain medications. This was the answer I was looking for. Finally I had found an actual definitive explanation for what was actually different within ethnic groups that would cause consistent sensitivity. The difference in chemical metabolism is what causes these differences in sensitivity. Now that I had put my finger on the actual topic that was at fault for this issue, I had to understand what the CYP enzymes do that would change how well a medication was used in the body.

Figure 5.
Figure 6.

Figure 7.

 The Cytochrome P450 is the set of liver enzymes that are the first pass metabolism mechanism for foreign chemicals in the body. The CYP enzymes metabolize organic chemicals by converting them from being hydrophobic to hydrophilic. Because the body does not play well with hydrophobic molecules as we are mostly made up of water, converting these chemicals to be more hydrophilic allows them to absorb systemically to be used throughout the body. As seen in figures 6 and 7, the substrate (drug) will enter the CYP complex--which is sitting in the membrane of a cell--at an active site and is oxidized to a more hydrophilic product that exits through the egress site. (citation will be on caption of image) A specific example of a cytochrome drug oxidation can be seen with the metabolism of Warfarin, a Vitamin-K derivative anti-coagulant (source here). As seen in the marvinsketch in figure 8, R-Warfarin metabolizes to 6- and 8-hydroxywarfarin by CYP1A2 and to 10-hydroxywarfarin by CYP3A4 and these then oxidize to warfarin alcohol, which is the final metabolite of the drug. Warfarin Alcohol is the molecule that actually interacts in the body,  and can do so as it is a more biologically friendly molecule than the pre-metabolized warfarin. The variances of the CYP enzymes involved throughout different ethnicities lead to the requirement of different warfarin dosing for different individuals in order to receive the same desired coagulation in the blood as other individuals.

Figure 8. Mouseover sends to MarvinSketch.
After finding the Xie article, the explanation of the vast differences in the CYP enzymes from one race to the next, I understood how the type of person is very crucial when dosing and selecting a drug. This introduction into pharmacogenomics opened my eyes to the minute differences in the human body that cause drug effects to be non-ubiquitous. Prescribers of drugs currently choose their medication and dose it using maybe the age and weight of the patient, but with more advancement in the field of pharmacogenomics, through the family history of drug efficacies of a patient, the writings on their prescription pads might soon be influenced more heavily on this knowledge.  Now I only wonder what actually causes the differences in these CYP levels in ethnicities and races. Over thousands of years of enclosure in a certain area, do these types of people gain their hepatic fingerprints from their diets? And if this is so, will the progression toward a unified global society cause these differences in drug metabolisms to decrease? As a world that has slowly moved from many defined races and ethnicities divided by the areas they live in, to a melting pot of people, we are slowly blurring the lines that differ us as genetic groups. It seems that as this continues, these variants that we see could possibly become something of the past. This is something that I believe will be interesting to see as human kind changes and advances into the future.

Berka, Karel, et al. "Membrane Position of Ibuprofen Agrees with Suggested Access Path Entrance to 
     Cytochrome P450 2C9 Active Site." The Journal of Physical Chemistry 115.41 (2011): 11248–11255. 
     American Chemical Society. Web. 3 May 2012. < 

Johnson, Julie A. "Ethnic Differences in Cardiovascular Drug Response Potential Contribution of 
     Pharmacogenetics." Circulation (2008): 1383-1393. American Heart Association. Web. 3 May 2012. 

     Annual Review of Pharmacology and Toxicology 41 (Apr. 2001): 815-850. Annual Reviews. Web. 3 
     May 2012. <>. 

Evans, William E, and Julie A Johnson. "PHARMACOGENOMICS: The Inherited Basis for Interindividual 
     Differences in Drug Response." Annual Review of Genomics and Human Genetics 2 (Sept. 2001): 
     9-39. Annual Reviews. Web. 3 May 2012. < 

Williams, Pamela A, et al. "Crystal structure of human cytochrome P450 2C9 with bound warfarin." 
     Letters to Nature (July 2003): 464-468. Nature. Web. 3 May 2012. 

1 comment:

  1. I thought the topic was really fascinating because this is a topic I've actually never heard of. I know that evidently people react different to certain medications due to their metabolisms but I never thought it would be at such a large scale. I think the author chose a perfect topic that would not only interest themselves due to their future path in the pharmaceutical industry, but also a topic that would interest any college student in the science field.

    The one thing I kept wondering throughout the article was exactly how these differences arose. What about the evolution of humans could have led to such metabolic differences? Really great job with the article, though I would have hoped to see more studies included because I was skeptical with some of the conclusions that were made since they weren't fully supported by further study.