Why Allegra may not work as well for you: genetics of ABCB1 proteins

Ever wonder why a certain medication may work great for a friend and do nothing for you?  One reason could be your genes.

Let’s take fexofenadine (Allegra) for example.  You have watery eyes and a drippy nose during spring allergy season and pop an Allegra.  There is a lot that goes on in your body before that medication brings about allergy relief.  It has to dissolve, be absorbed, get transported to the cells where it is going to act — and it has to stay inside of those target cells.

Staying inside the cells instead of the medicine being transported back out again is where genetics comes in to play.

Some medications and other toxins are transported back out of cells by an ATP-binding cassette transporter protein encoded by the ABCB1 gene.  In the epithelial cells that line your intestines, the ABCB1 proteins are involved in pumping substances back into the intestinal lumen.  So imagine if you take an Allegra, it dissolves, gets absorbed, and then part of that gets pumped back into the intestines to be eliminated. Genetic variants in ABCB1 affect how much stays in the cells vs getting eliminated (through intestines, bile, urine).

In general, it seems like a good thing for the body to get rid of a substance that it thinks might be toxic. While an allergy medication not working quite as well is not that big of a deal, the real problem comes in when trying to keep chemotherapy drugs inside of cancer cells in order to act upon them.  This gene has been studied in depth for cancer treatment drugs.

ABCB1 gene (multidrug resistance protein, p-glycoprotein):
The genetic variant known as rs1045642 or C3435T has been extensively studied in regards to response to quite a few different drugs.  Those who have the AA genotype (23andMe orientation) have less of an efflux of certain drugs — meaning that less of the drug is transported back out of the cell by the ABCB1 transporter. [study]  Less of a drug transported out of the cell usually indicates a higher effectiveness of the drug on that individual.  The variant, AA, is fairly common with about 25% of Caucasians carrying it (less frequent in Asian populations).

Check your 23andMe results for rs1045642(v.4 only):
AA: reduced drug efflux (out of cell), thus better response to fexofenadine, may need lower dosages of some drugs in comparison to those with GG
AG: somewhat reduced efflux
GG: normal efflux (out of the cell) for drugs and toxins, may need higher dosages of some drugs compared to those with AA

Here are more examples of studies on the variation in drug effects based on ABCB1 variants:

  • Lower response to fexofenadine (Allegra) for GG and significantly higher response for those with AA  [study][study]
  • In a study of escitalopram (Lexapro) dosage, AG and GG carriers needed about a 2-fold greater dosage to gain remission from depression. [study]
  • Plasma THC levels were almost 50% less in AA, AG genotypes vs. GG when sampled in those with heavy cannabis use. This would show that those with AA and AG are keeping more THC inside their cells.   [study]  Another study showed that those with the GG genotype were more likely to become dependent on cannabis. [study]
  • Those with the A allele are at a higher risk for lupus. [study]

Diet and Supplements:

There are a lot of studies being done on inhibitors of ABCB1 in an effort to maximize the effectiveness of certain chemotherapy drugs.  I imagine that someday soon we will have personalization of chemo dosages based on ABCB1 genetic variants, but that is way beyond the scope of this article.

One natural inhibitor of ABCB1 which acts by binding to the receptor is piperine, a substance found in black pepper.[study]  Studies have shown that piperine does increase the effectiveness of fexofenadine (Allegra) by about 2-fold. [study] [study]

Another natural substance that modulates the ABCB1 protein is curcumin, which is found in turmeric.[studyCurcumin supplements are often combined together with piperine.

More to read:

There are many studies on cancer-related drugs, methadone dose, Lipitor responsePlavix dose, pesticide exposure, various antidepressants, and  more.  I encourage you to go to www.pubmed.gov and search for “rs1045642” to read through the 100+ studies on this genetic variant.  Keep in mind when you are reading the studies that the minus orientation is used for this variant, so you will need to mentally switch T with A and C with G to match the plus orientation given on 23andMe data.

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