Sunday, December 28, 2008

Interspecific Scaling of Dosages for Nutrients or Physiological Substances

I was converting some of these dosages, communicated in journal articles as "mg per kg rat chow" or "mg per 100 g diet" of rats and mice, and I guess I just think there are some issues with the application of pharmacological principles to research in nutrition journals. I know that you want the animals to ingest whatever it is you're studying, given that intravenous or intraperitoneal injections produce different distributions of the substance than oral administration does. But it seems to me that dosages and concentrations could be brought into the 21st century, so to speak. Frequently, intracellular concentrations are not given in journal articles, such as for intracellular total folates, but are given as nanomoles/gram wet weight of tissue. Some researchers do conversions that can approximate intracellular concentrations in molarity (moles per liter of intracellular fluid) from those types of units, and I did those conversions for some of the articles in my folic acid paper. I didn't include them, even though researchers often have to include approximations like that in journal articles. But it took about an hour to do for one part of one paper, and it just seems to me....

I don't want to complain, given that I have the entire world of scientific knowledge at my fingertips. And I'm aware of the equations for rats and mice and other animals, converting mg/kg diet into mg/kg body weight. I'm also aware that a dosage for a rat or a mouse tends to be divided by 10, given that rodents have higher metabolic rates and higher surface-area-to-volume ratios than humans and different ratios of organs to body weights. But in the folic acid paper, I didn't do the one-tenth scaling (that's the least sophisticated and most crude rule of thumb for interspecific, or between-species, scaling). This was partly because some of the articles comparing dosages between rodents and humans didn't do the scaling, and I also wanted to show that the scaling doesn't seem to work very well. Anyway, I'll try to post some of these basic "mg per kg rat chow" calculations for some of the articles. I think maybe the scaling calculations should be applied more loosely, because the scaling factor that someone obviously applied to the case of folic acid, 40 or 50 years ago, seems to be about 5 times what it should be. There are other issues with it, but I won't go into that.

This isn't really about inconvenience for me but about the ongoing issues with long-term trials in these areas. Researchers generally make choices on dosages that are totally arbitrary, etc. I would go through some of the recently-publicized "megatrials" in these areas, but there are so many issues with the trials.

Here's a link to some of the basic data for "rat chow" or "mouse chow" conversions: (http://www.who.int/entity/ipcs/food/jecfa/en/tox_guidelines.pdf). It's a document from the World Health Organization because it's tedious and difficult to find references on these topics. These conversion factors, on the second-to-last page, agree approximately with the ones I applied in the "folic acid paper." But I read through parts of some articles on "allometric," between-species (interspecific) scaling of pharmacokinetic parameters, in the current literature, and this is still a big area of controversy. The problems related to the scaling of pharmacokinetic data for xenobiotics (drugs) haven't been resolved, by any means, and drugs are arguably much more neatly metabolized than nutrients like folic acid. Drugs given orally tend to not be extensively metabolized outside of the liver or kidneys, and there's a limited number of variables. The situation is more complicated, I think, for nutrients, given that physiological substances can be taken up and metabolized by most cells in the body. I'll try to make sense of some of those types of articles in relation to things like magnesium, for example. The intracellular magnesium concentrations, in red blood cells, do not correlate well with either therapeutic effects, such as fasting blood sugar or whatever other variable, or with the change in serum magnesium, etc.

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