3 ms·

I'm surprised the article didn't mention anything about pharmacogenetics. For example, drug-metabolizing enzyme polymorphisms can often lead to a 10+ fold diffe

I'm surprised the article didn't mention anything about pharmacogenetics. For example, drug-metabolizing enzyme polymorphisms can often lead to a 10+ fold difference in Cmax (or name the parameter) between a poor and an ultrarapid metabolizer of some enzyme.

klevertree 3y ago
Author here. Enzyme polymorphisms are tricky and would require a whole different blog post. Some drugs they matter a lot for, some drugs they do not. I actually have not found any drugs with 10-fold variability that could be ascribed solely (or even mainly) to polymorphisms, although it doesn't seem impossible.
- opportune 3y ago
  https://www.ncbi.nlm.nih.gov/books/NBK84174/ https://www.ncbi.nlm.nih.gov/books/NBK84174/ Here’s an article I found in 30s of searching (granted, I already knew Warfarin was hugely affected by CYP2D6) stating that equivalent maintenance doses of Warfarin can vary by a factor of >10 (from 0.5mg to 7mg) based on the CYP2D6 phenotype of the patient.
- atombender 3y ago
  Don't know about 10x, but having the MTHFR mutation genotype 667TT reduces folate activation [1] by 70-80%, which is a problem with drugs that require folate supplementation, like methotrexate. [1] https://www.snpedia.com/index.php/Rs1801133 https://www.snpedia.com/index.php/Rs1801133
303uru 3y ago
What drug has a 10 fold difference in Cmax, as a pharmacist I can’t think of anything even close to that.
- NicotineFiend 3y ago
  Many tricyclic antidepressants metabolized by CYP2D6 would be here, if you put the nonmetabolizers up against the rapid metabolizer, https://en.wikipedia.org/wiki/Doxepin https://en.wikipedia.org/wiki/Doxepin for example.
- klevertree 3y ago
  Cyclosporine and tacrolimus, if you look at the range in any of their pk trials you'll easily see 10 fold variability.
- opportune 3y ago
  Warfarin is one of the most well known scientifically, but as a practitioner you may not know this because hospitals and insurers are scared to acknowledge the ongoing rate of preventable bad outcomes caused by not accounting for variances in metabolism. That is to say, if we were to actually start assessing patients’ ability to metabolize warfarin we’d have to confront the fact that a huge number of bad clinical outcomes in the recent past stemmed from not doing this.
  - carbocation 3y ago
    > hospitals and insurers are scared to acknowledge the ongoing rate of preventable bad outcomes caused by not accounting for variances in metabolism. Healthcare systems are so aware of and open about warfarin's risks that they have warfarin clinics set up to repeatedly measure patients' prothrombin times so that they can adjust dosing empirically. Further, they also provide nutritional guidance to patients taking warfarin to help them reduce diet-influenced variance in warfarin metabolism.
    - deleted 3y ago
      [deleted]
- scheme271 3y ago
  What about codeine with ultra-rapid metabolizers (e.g. the significant population in Saudi Arabia), it might not be a 10x difference but normal dosages can result in overdose or death in people that are ultra-rapid metabolizers or even in their babies if they are nursing mothers.
- ikiris 3y ago
  you're a bit behind on your CE time. There are lots with that high of variability.

klevertree 3y ago

Author here. Enzyme polymorphisms are tricky and would require a whole different blog post. Some drugs they matter a lot for, some drugs they do not. I actually have not found any drugs with 10-fold variability that could be ascribed solely (or even mainly) to polymorphisms, although it doesn't seem impossible.

opportune 3y ago
https://www.ncbi.nlm.nih.gov/books/NBK84174/ https://www.ncbi.nlm.nih.gov/books/NBK84174/ Here’s an article I found in 30s of searching (granted, I already knew Warfarin was hugely affected by CYP2D6) stating that equivalent maintenance doses of Warfarin can vary by a factor of >10 (from 0.5mg to 7mg) based on the CYP2D6 phenotype of the patient.
atombender 3y ago
Don't know about 10x, but having the MTHFR mutation genotype 667TT reduces folate activation [1] by 70-80%, which is a problem with drugs that require folate supplementation, like methotrexate. [1] https://www.snpedia.com/index.php/Rs1801133 https://www.snpedia.com/index.php/Rs1801133

303uru 3y ago

What drug has a 10 fold difference in Cmax, as a pharmacist I can’t think of anything even close to that.

NicotineFiend 3y ago
Many tricyclic antidepressants metabolized by CYP2D6 would be here, if you put the nonmetabolizers up against the rapid metabolizer, https://en.wikipedia.org/wiki/Doxepin https://en.wikipedia.org/wiki/Doxepin for example.
klevertree 3y ago
Cyclosporine and tacrolimus, if you look at the range in any of their pk trials you'll easily see 10 fold variability.
opportune 3y ago
Warfarin is one of the most well known scientifically, but as a practitioner you may not know this because hospitals and insurers are scared to acknowledge the ongoing rate of preventable bad outcomes caused by not accounting for variances in metabolism. That is to say, if we were to actually start assessing patients’ ability to metabolize warfarin we’d have to confront the fact that a huge number of bad clinical outcomes in the recent past stemmed from not doing this.
- carbocation 3y ago
  > hospitals and insurers are scared to acknowledge the ongoing rate of preventable bad outcomes caused by not accounting for variances in metabolism. Healthcare systems are so aware of and open about warfarin's risks that they have warfarin clinics set up to repeatedly measure patients' prothrombin times so that they can adjust dosing empirically. Further, they also provide nutritional guidance to patients taking warfarin to help them reduce diet-influenced variance in warfarin metabolism.
  - deleted 3y ago
    [deleted]
scheme271 3y ago
What about codeine with ultra-rapid metabolizers (e.g. the significant population in Saudi Arabia), it might not be a 10x difference but normal dosages can result in overdose or death in people that are ultra-rapid metabolizers or even in their babies if they are nursing mothers.
ikiris 3y ago
you're a bit behind on your CE time. There are lots with that high of variability.