Since achieving the goals of the “mission impossible” Human Genome Project in 2003, biomedical sciences entered the new era of genetically informed use of pharmaceuticals. The Project helped in our understanding of how genes affect an individual’s response to drugs.
Although it was known for decades that the response to drugs depends on genetic background of each individual, the knowledge of key mechanisms involved in these processes was mostly missing. Genetics finally provided a definite understanding of pharmacokinetics, the branch of science studying what the body does to the drugs. This article will look at how drug response may vary between individuals, and how genetics play an important role in the drug response in patients with Parkinson’s disease.
Why drug responses vary
In general, there are three main reasons why response to a particular drug may vary from one individual to another. These factors are:
- The responsiveness of the site of drug action
- The drug concentration (reflected by its plasma level)
- The type or sub-type of the disease itself.
Nonetheless, in most cases, the drug plasma concentration plays the central role. Most of the drugs taken orally undergo metabolism once they enter the body. In this process, the drug will be changed into its active or metabolite form. The rate of metabolism differs between individuals, resulting in different drug plasma concentrations. The drug metabolism process is carried out by various enzymes depending on the nature of the drug. The levels and activity of these enzymes are also different between individuals. This is a critical factor in determining or predicting the response to a drug.
The activity and expression level of enzymes involved in drug metabolism is determined by genes. Even single mutations, or single nucleotide polymorphisms (SNPs) in genes’ DNA sequence can cause a huge difference to the individual metabolism of a particular drug. Mutations in genes’ regulatory sequences can also seriously influence the levels of key enzymes.
Parkinson’s disease & drug responses
Parkinson’s disease is an age-related, debilitating neurodegenerative disorder that mainly affects the motor system. People with this disease experience shaking, rigidity, slowness of movement, and difficulties with walking. Parkinson’s disease is marked by a loss of dopamine-producing neurons in the brain.
Today, one of the treatments to improve the condition of patients involves the use of drugs that mimic or increase levels of dopamine. However, using drugs to regain the normal level of dopamine can be complex, as the level of this neuromediator should not go too high (when it produces undesirable side effects), nor remain too low (when no effect is observed).
It is well established that drugs against Parkinson’s disease have different efficiency between patients. Recent research has revealed genetic determinant of this difference. The findings might inform better drug prescription and allow physicians to tailor targeted therapy for individuals suffering from this neurodegenerative condition.
The pharmacogenetics of the drug levodopa
Levodopa is a common medication for Parkinson’s disease and has been considered a gold standard since the 1960s. The drug is a direct metabolic precursor of dopamine in the body and thus can increase dopamine levels. However, 35-40% of patients develop side effects such as dyskinesia and motor fluctuation after 4-6 years of using it.
A number of studies have revealed various mutations and SNPs in genes related to levodopa metabolism, responsible for these side effects. A recent research study published earlier this year demonstrated that SV2C gene variants may modulate the amount of levodopa and suggests that the dose of levodopa should be reduced in people with this gene variant to prevent possible side effects.
Another study published three years ago showed that the effect of levodopa treatment on motor skills varies between individuals. The treatment in patient with low dopamine transmission gives better motor learning outcomes compared to the same treatment in patients with high dopamine transmission. The authors of the study stated that DRD2 gene polymorphism contributes to these varying outcomes.
Fortunately, the mutations or SNPs in the genes are not always a bad news. Recent research published this year demonstrates that two SNPs in the DRD2 gene brings good outcomes in patients treated with rasagiline monotherapy. Rasagiline is a selective, irreversible inhibitor of monoamine oxidase B and has been approved by the FDA as a symptomatic treatment for Parkinson’s disease. This research is the first study to be conducted in patients with early-onset Parkinson’s disease.
Methods for identification of patients who might experience side effects from using the dopamine agonists are also being explored. Recent findings from a group of Australian researchers provide preliminary evidence that dopamine gene profiling may be useful for identifying people at risk of developing side effects from dopamine agonists, the drug called ropinirole in particular. This study also explored the usefulness of an individualized treatment approach.
Unfortunately, the therapeutic options for patients suffering from Parkinson’s disease are very limited at the present time. Personalised genetic profiling may advise the optimal strategy for using this limited arsenal of therapeutic tools in each individual case. This approach will minimize the potential side effects and optimize drug efficiency.
New drugs for Parkinson’s are being developed, and there are several very interesting candidates in the pipeline. But it may still take many years to find something more efficient than we have now. In the meantime, it will be useful to dedicate more research to the issue of genetically determined drug response in relation to Parkinson’s disease. This will likely enable physicians to adjust treatments for individual patients and thus provide them with significant health benefits in the short term.
References
Altmann, V., Schumacher-Schuh, A., Rieck, M., Callegari-Jacques, S., Rieder, C., & Hutz, M. (2016). Influence of genetic, biological and pharmacological factors on levodopa dose in Parkinson’s disease Pharmacogenomics, 17 (5), 481-488 DOI: 10.2217/pgs.15.183
Connolly, B., & Lang, A. (2014). Pharmacological Treatment of Parkinson Disease JAMA, 311 (16) DOI: 10.1001/jama.2014.3654
MacDonald, H., Stinear, C., Ren, A., Coxon, J., Kao, J., Macdonald, L., Snow, B., Cramer, S., & Byblow, W. (2016). Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole Journal of Cognitive Neuroscience, 28 (7), 909-919 DOI: 10.1162/jocn_a_00946
Masellis, M., Collinson, S., Freeman, N., Tampakeras, M., Levy, J., Tchelet, A., Eyal, E., Berkovich, E., Eliaz, R., Abler, V., Grossman, I., Fitzer-Attas, C., Tiwari, A., Hayden, M., Kennedy, J., Lang, A., Knight, J., & , . (2016). Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson’s disease: a pharmacogenetic study Brain, 139 (7), 2050-2062 DOI: 10.1093/brain/aww109
Pearson-Fuhrhop, K., Minton, B., Acevedo, D., Shahbaba, B., & Cramer, S. (2013). Genetic Variation in the Human Brain Dopamine System Influences Motor Learning and Its Modulation by L-Dopa PLoS ONE, 8 (4) DOI: 10.1371/journal.pone.0061197
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