On reading through some research on the effects of certain drugs I often come across staggeringly high dosages such as in this paper:

Römer, B., Pfeiffer, N., Lewicka, S., Ben-Abdallah, N., Vogt, M. A., Deuschle, M., ... & Gass, P. (2010). Finasteride treatment inhibits adult hippocampal neurogenesis in male mice. Pharmacopsychiatry, 43(05), 174-178.

The paper says:

After 2 weeks of acclimatization all mice received at an age of 12 weeks an identical treatment with either finasteride (100 mg/kg) or 2-hydroxypropyl-ß-cyclodex- trin as vehicle [32]. A single daily injection was administered subcutaneously during 7 consecutive days.

To give context, a standard dosage of Finasteride for androgenic alopecia is 1mg per day orally and 5mg for benign prostatic hyperplasia. The dosage listed in the paper would be equivalent to me taking 7200mg per day via injection. I see this sometimes in drug research and I imagine this is done to force an effect and see what that effect is. Are they inferring that the effect scales linearly and that the standard dose has 1/7200th the effect?

What is the reasoning behind this approach?


1 Answer 1


Mice are simply different from humans; they have different metabolism, different lifespan, different body size.

Generally, for a first order approximation, one might scale simply by body weight to account for body size, expressing dose in units of "drug/body weight". Among humans, that can work fairly well, though fails in several cases:

  • Kids, and especially young children/infants, whose metabolism differs a lot from adults

  • By sex, since body fat percentages differ on average between men and women

  • For the obese, especially for drugs that partition differently in different tissues.

It fails for mice, too; most typically the dose per weight to get the same level of effect in mice is much higher than for humans.

An alternative is to adjust based on body surface area, though that isn't something easy to measure, so typically we still express and adjust doses among members of the same species by weight. However, you can use a rough estimate to come up with some constant cross-species conversion factors. Nair and Jacob, 2016 recommend a 12.3X higher dose per weight to adjust for surface area differences between mice and humans (they have a whole table for other species, too).

Ultimately, the appropriateness of any adjustment depends on precisely what drug you're talking about and how exactly that drug is metabolized. Drugs may also have different affinities for target receptors in different species, which may lead to additional conversion factors. These things can only be worked out with specific study.

There can also be experimental reasons. When doing a study for safety, it may be preferable to study doses much higher in animals than expected for use in humans, both because the sample sizes in an animal study are going to be far smaller than the population sizes exposed to a pharmaceutical drug that is approved, and because the tolerance for risk in humans is far lower than the tolerance for risk in the animal study. If you give a drug at 10x or 100x the effective dose and it doesn't cause problems, you can be far more confident going into clinical trials that there isn't a lurking disaster (of course, bad safety results still happen). You may also plan to give the drug to people for years on end; a mouse can't live nearly that long, so a higher dose over a shorter time might help build an understanding of the safety profile, or at least an approximation. It of course isn't quite as simple as giving a drug at 100X the dose for 1/100th the time, but moving in that direction may be preferable to testing a drug in a mouse for only a week that is used in humans for years.

Additionally, when screening drugs for some effect, it may be easier to test a lot of drugs at high doses in small samples, find which ones do something like what you're targeting, and then experiment further with the dose.

One more point that applies to the specific example you gave is that bioavailability can vary depending on how a drug is administered. Generally, IV is the most direct route with the highest bioavailability. For mice, intraperitoneal injections are also used that typically have high bioavailability, since IV injections can be a bit complicated. Oral bioavailability is typically lower, since the drug may be modified to inactive form in the digestive tract, especially in the acidic stomach environment, or through liver metabolism before reaching systemic circulation. Subcutaneous typically has the least bioavailability and slowest systemic uptake. Of course, for drugs that are intended to be modified, the effects of different administration routes can be opposite (for example, a drug that is more potent after liver metabolism, or a drug that reacts with stomach acid to its active form).

Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of basic and clinical pharmacy, 7(2), 27.


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