About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« More on Drug Prices | Main | And Always Keep Ahold of Nurse, For Fear of Finding Something Worse »

July 23, 2002

Rats, For Fear of Worse

Email This Entry

Posted by Derek

I've had some mail asking a good (and Frequently Asked) question: how good are the alternatives to animal testing? How close are we to not dosing animals to get toxicology information?

My short answer to the second question is, simultaneously, "A lot closer than we used to be" and "Not very close, for all that." The root of the problem is complexity. Toxicological properties are, to use the trendy word, emergent. You need the whole living system to be sure that you're seeing all there is to see.

You could try to mix and connect cell cultures, where the compound, after being exposed to one type of cell, then flowed off to another, and the original cells got a chance, if they'd been changed, to affect other different cell types. . .and so on. But by the time you got all the connections worked out, you'd have built an animal.

An example of a emergent tox problem is the recent withdrawal by Novo Nordisk of a clinical candidate that they were developing with the Indian company, Dr. Reddy's. Bladder cancer was the problem, seen in long-term dosing. But it's mostly a problem in rats - mice showed enough to notice, but it was the rat data that really set off the sirens.

There aren't a lot of good in vitro methods to predict carcinogenic potential. It's for sure that this compound had been through screens like the well-known Ames test for mutagenicity, for example. If it hadn't passed, it's unlikely that they would have carried the compound as far as they did. (I'll be writing more on the Ames test at a later date.)

Bladder cancer's a bit unusual. Playing the percentages, you'd have to guess that the problem isn't the compound itself, but some metabolite produced in the body which concentrates in the urine. And the rodent differences might suggest that rats produce more of this metabolite than mice do (or, alternatively, that they produce the same one, but that rat bladders are more sensitive to it.) Something like this would be the way to bet.

How much are you willing to bet, though? Are you willing to give people bladder cancer, or even put them at risk for it? (And are you willing to invite some many liability suits to land on you that you'll think it's snowing?) Your chances of getting through (and the chances of your customers!) depend on what the mechanism of the tox might be, and whether it operates in humans, as opposed to rats.

Novo and Dr. Reddy's are certainly going to take their time to thoroughly investigate what the problem might be, and whether it can be fixed. There was really no way to anticipate it without animal testing, though, since we don't have an in vitro system that mimics the bladder. Even if we did, they might have run their compound through it and gotten a green light, if the problem is in fact some later metabolic product. There's no substitute for the whole animal.

Comments (0) + TrackBacks (0) | Category: Animal Testing | Toxicology



Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry