Tuesday, December 30, 2008

Sample Calculation That Scales a Rat Dosage to a Human Dosage

I've done more of these crude scalings for articles on topics other than folic acid, and I'll try to put those up soon. But I wanted to apply this to a great article showing some dose-response data for folic acid in an animal model of breast cancer (http://carcin.oxfordjournals.org/cgi/content/full/26/9/1603). I'll try to get some equations for the ng/g tissue into intracellular molarity up on here, because that's useful to be able to do. I keep having difficulty finding the equations I've used in the past.

But the researchers, the authors of that article, used either 0, 2 mg/kg diet, or 8 mg/kg diet in rats. If one scales these dosages, using the 2,000 ug/kg diet dose for a rat, one gets 100 ug/kg bw for a rat. When I apply the 4.71 scaling factor, for scaling a rat dosage to a dosage for a 70-kg human (I'll try to put up a generic scaling equation, because I'm wondering how much the magnitude of the scaling factor would differ for someone who weighed 55 or 60 kg, for example), then 100 ug/kg bw for a rat would scale to 21.3 ug/kg/day for a human. This would translate into a dose of 1.49 mg of folic acid/day. Their 8 mg/kg diet dose in rats would be 5.96 mg/day of folic acid in a human. Even that higher dose did not elevate the intracellular folate levels in the cells in the mammary tissue of the rats. I did the calculation awhile back, and it's like below 1 uM. The intracellular total folate level is "assumed" to be 20 uM in human cells, but, as I've said before, that's unlikely to be the case. Their DNA methylation data also shows that the elevation in intracellular total folate was not large enough to really have much of an effect on the epithelial or other cells in the mammary tissues. That's a really important type of result that's relevant to humans, and the only way to see the full message of that article is to do the crude scaling calculations.

I'll try to read more about the bioavailability differences between folic acid and L-methylfolate, but the AUC and Cmax values in response to a dose of L-methylfolate, past a certain critical level, are several times those for an equimolar dose of folic acid. So one issue is probably the bioavailability and tissue distribution, with folic acid.

I know one could use a different number to scale the dosages, but even the traditional, standardized, non-species-specific factor of ten allows one to interpret the article in a meaningful way.

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