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Pharmacokinetic Genes[edit]

A pharmacokinetic gene is a gene that codes for proteins that are involved in the absorption, distribution, metabolism, or excretion (ADME) of a drug.[1] Pharmacokinetic genes encode a diverse array of proteins such as transporters, ion channels, cytochrome P450, and structural proteins. Pharmacokinetic genes can alter the bioavailability of a drug by regulating the concentration of drug in the blood and tissues.

The Effect of Pharmacokinetic Genes on ADME[edit]

  • Absorption: The route of administration determines the availability of the drug within the body. Absorption usually occurs within the gastrointestinal tract for drugs that are ingested and within the lungs for drugs that are administered via inhalation. Using an intravenous route of administration results in no absorption of the drug because the drug is injected directly into the blood stream.[2] Variation in absorption-based pharmacokinetic genes can affect gastrointestinal cell transporter and channel structure and activity, which can affect the absorption of a drug.
  • Distribution: The action of the cardiovascular system is the primary mechanism by which a drug is distributed throughout the body. Distribution of the drug may face difficulty at specific sites within the body such as the hematoencephalic barrier.[3] Variation in distribution-based pharmacokinetic genes can alter the integrity of the hematoencephalic barrier allowing more or less distribution to the brain.
  • Metabolism: The majority of drugs are enzymatically broken down by the action of the hepatic cytochrome P450 family of redox enzymes. Cytochrome P450 enzyme activity on drug substrate can change the pharmacology of a drug. Some of the changes that can occur are activation of a prodrug or production of a pharmacologically inert metabolite.[4] Variation in metabolism-based pharmacokinetic genes can alter the activity of cytochrome P450 enzymes, which will affect the pharmacology of a drug, the rate of elimination amongst other things.
  • Excretion (Elimination) : The body rids of the drug primarily through the mechanism of excretion in the urine and/or in solid waste. Variation in elimination-based pharmacokinetic genes can affect the activity of the nephron and nephrological proteins that pertain to the excretion of drug metabolites in the urine.

Genetic Variation in Pharmacokinetic Genes[edit]

Variation in the nucleotide sequence of a pharmacokinetic gene can alter the structure and chemistry of the encoded protein product. Single nucleotide polymorphisms may or may not have an affect on pharmacokinetic genes depending on the position of the mutation in the gene. In addition to mutations in a pharmacokinetic gene itself, nucleotide variation in non-protein coding regulatory regions can also affect the expression of a pharmacokinetic gene. [5]


Atorvastatin (Lipitor) is a statin-based small molecule drug that is administered to lower cholesterol levels. Atorvastatin targets mainly the liver and hepatic enzymes. It is a competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. In the mevalonate pathway, HMG-CoA reductase functions as the rate-determining enzyme for cholesterol production as it catalyzes the reduction of HMG-CoA to mevalonate.[6]

Three single-nucleotide polymorphisms have been associated with affecting Atorvastatin activity. These SNPs are associated with the HMG-CoA gene (HMGCR), the kinesin-like protein (KIF6), and the multidrug resistance protein-1 (ABCB1). At the 14863 SNP loci of the HMGCR gene the common allele, A, is changed to the mutant allele T. This SNP in the HMGCR gene will cause a decrease in HMG-CoA’s response to statin drugs such as Atorvastatin.[7] At the 2250 SNP loci of the KIF6 gene a missense mutation is occurring such that the common allele, T, is changed to the mutant allele, C. This SNP in the KIF6 gene will cause an increased response of kinesin-like protein to Atorvastatin.[8] At the 208920 SNP loci of the ABCB1 gene, the common allele, A, is changed to the mutant allele, T. This SNP in the ABCB1 gene causes a large decrease in low-density lipoprotein and a slight increase in high-density lipoprotein cholesterol in females.[9]

Controversies[edit]

Some alleles that vary in frequency between specific populations have been shown to be associated with differential responses to specific drugs. The beta blocker Atenolol is an anti-hypertensive medication that is shown to more significantly lower the blood pressure of Caucasian patients than African American patients in the United States. This observation suggests that Caucasian and African American populations have different alleles governing oleic acid biochemistry, which react differentially with Atenolol.[10] Similarly, hypersensitivity to the antiretroviral drug abacavir is strongly associated with a single-nucleotide polymorphism that varies in frequency between populations.[11]

This brings up the concept of race-based medicine, which is a very controversial subject. [12] . It is a scientific fact that similar population such as ethnicities or races have similar genetics, thus, similar races may have similar patterns of SNPs. A drug’s effectiveness is dependent upon an individual’s genome and any SNPs that lie within the genes or in the regulatory genes that are associated with a drug’s response. Therefore, it seems logical to develop and prescribe specific drugs to certain populations due solely to similarities in their genomic makeup; yet, society has condemned this idea and has labeled it as racist.

For example, the FDA approval of the drug BiDil with a label specifying African-Americans with congestive heart failure, produced a storm of controversy over race-based medicine and fears of genetic stereotyping, even though the label for BiDil did not specify any genetic variants but was based on racial self-identification. [13]

See also[edit]

References[edit]

  1. ^ Dudley, Joel (2013). Exploring personal genomics. Oxford: Oxford University Press. ISBN 9780199644483.
  2. ^ Thomas, Gareth (2007). Medicinal chemistry (2nd ed., Extensively rev. and updated. ed.). Chichester: John Wiley. ISBN 9780470025970.
  3. ^ Thomas, Gareth (2007). Medicinal chemistry (2nd ed., Extensively rev. and updated. ed.). Chichester: John Wiley. ISBN 9780470025970.
  4. ^ Thomas, Gareth (2007). Medicinal chemistry (2nd ed., Extensively rev. and updated. ed.). Chichester: John Wiley. ISBN 9780470025970.
  5. ^ Dudley, Joel (2013). Exploring personal genomics. Oxford: Oxford University Press. ISBN 9780199644483.
  6. ^ Trevor, edited by Bertram G. Katzung ; associate editors, Susan B. Masters, Anthony J. (2009). Basic & clinical pharmacology (11th ed.). New York: McGraw-Hill Medical. ISBN 9780071604055. {{cite book}}: |first= has generic name (help)CS1 maint: multiple names: authors list (link)
  7. ^ Chasman, D (2004). "Pharmacogenetic study of statin therapy and cholesterol reduction". JAMA. 291 (23): 2821–2827. doi:10.1001/jama.291.23.2821. PMID 15199031. Retrieved 1 May 2014.
  8. ^ Iakoubova, C (2008). "Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials". Journal of the American College of Cardiology. 51 (4). J Am Coll Cardiol: 435–443. doi:10.1016/j.jacc.2007.05.057. PMID 18222353. Retrieved 1 May 2014.
  9. ^ Kajinami, K (2004). "Polymorphisms in the multidrug resistance-1 (MDR1) gene influence the response to atorvastatin treatment in a gender-specific manner". The American Journal of Cardiology. 93 (8). J Am Cardiol: 1046–1050. doi:10.1016/j.amjcard.2004.01.014. PMID 15081455. Retrieved 1 May 2014.
  10. ^ Wikoff, William (2013). "Pharmacometabolomics Reveals Racial Differences in Response to Atenolol Treatment". PLOS ONE. 8 (3): e57639. doi:10.1371/journal.pone.0057639. PMC 3594230. PMID 23536766.
  11. ^ Rotimi, Charles (2010). "Ancestry and Disease in the Age of Genomic Medicine". New England Journal of Medicine. 363 (16). NEJM: 1551–1558. doi:10.1056/NEJMra0911564. PMID 20942671. Retrieved 1 May 2014.
  12. ^ Krimsky, edited by Sheldon (2011). Race and the genetic revolution : science, myth, and culture. New York: Columbia University Press. ISBN 978-0231156974. {{cite book}}: |first= has generic name (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  13. ^ Krimsky, eSheldon (2011). Race and the genetic revolution : science, myth, and culture. New York: Columbia University Press. ISBN 978-0231156974. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

Further reading[edit]

External links[edit]

Journals:

Category:Genomics Category:Pharmacology Category:Pharmacy

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