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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

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April 27, 2012

How Do Drugs Get Into Cells? A Viscious Debate.

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Posted by Derek

So how do drug molecules (and others) get into cells, anyway? There are two broad answers: they just sort of slide in through the membranes on their own (passive diffusion), or they're taken up by pores and proteins built for bringing things in (active transport). I've always been taught (and believed) that both processes can be operating in most situations. If the properties of your drug molecule stray too far out of the usual range, for example, your cell activity tends to drop, presumably because it's no longer diffusing past the cell membranes. There are other situations where you can prove that you're hitching a ride on active transport proteins, by administering a known inhibitor of one of these systems to cells and watching your compound suddenly become inactive, or by simply overloading and saturating the transporter.

There's another opinion, though, that's been advanced by Paul Dobson and Douglas Kell at Manchester, and co-workers. Their take is that carrier-mediated transport is the norm, and that passive diffusion is hardly important at all. This has been received with varying degrees of belief. Some people seem to find it a compelling idea, while others regard it as eccentric at best. The case was made a few years ago in Nature Reviews Drug Discovery, and again more recently in Drug Discovery Today:

All cells necessarily contain tens, if not hundreds, of carriers for nutrients and intermediary metabolites, and the human genome codes for more than 1000 carriers of various kinds. Here, we illustrate using a typical literature example the widespread but erroneous nature of the assumption that the ‘background’ or ‘passive’ permeability to drugs occurs in the absence of carriers. Comparison of the rate of drug transport in natural versus artificial membranes shows discrepancies in absolute magnitudes of 100-fold or more, with the carrier-containing cells showing the greater permeability. Expression profiling data show exactly which carriers are expressed in which tissues. The recognition that drugs necessarily require carriers for uptake into cells provides many opportunities for improving the effectiveness of the drug discovery process.

That's one of those death-or-glory statements: if it's right, a lot of us have been thinking about these things the wrong way, and missing out on some very important things about drug discovery as well. But is it? There's a rebuttal paper out in Drug Discovery Today that makes the case for the defense. It's by a long list of pharmacokinetics and pharmacology folks from industry and academia, and has the air of "Let's get this sorted out once and for all" about it:

Evidence supporting the action of passive diffusion and carrier-mediated (CM) transport in drug bioavailability and disposition is discussed to refute the recently proposed theory that drug transport is CM-only and that new transporters will be discovered that possess transport characteristics ascribed to passive diffusion. Misconceptions and faulty speculations are addressed to provide reliable guidance on choosing appropriate tools for drug design and optimization.

Fighting words! More of those occur in the body of the manuscript, phrases like "scientifically unsound", "potentially misleading", and "based on speculation rather than experimental evidence". Here's a rundown of the arguments, but if you don't read the paper, you'll miss the background noise of teeth being ground together.

Kell and Dobson et al. believe that cell membrane have more protein in them, and less lipid, than is commonly thought, which helps make their case for lots of protein transport/not a lot of lipid diffusion. But this paper says that their figures are incorrect and have been misinterpreted. Another K-D assertion is that artificial lipid membranes tend to have many transient aqueous pores in them, which make them look more permeable than they really are. This paper goes to some length to refute this, citing a good deal of prior art with examples of things which should have then crossed such membranes (but don't), and also find fault with the literature that K-D used to back up their own proposal.

This latest paper then goes on to show many examples of non-saturatable passive diffusion, as opposed to active transport, which can always be overloaded. Another big argument is over the agreement between different cell layer models of permeability. Two of the big ones are Caco-2 cells and MDCK cells, but (as all working medicinal chemists know) the permeability values between these two don't always agree, either with each other or with the situation in living systems. Kell and Dobson adduce this as showing the differences between the various transporters in these assays, but this rebuttal points out that there are a lot of experimental differences between literature Caco-2 and MDCK assays that can kick the numbers around. Their take is that the two assays actually agree pretty well, all things considered, and that if transporters were the end of the story that the numbers would be still farther apart.

The blood-brain barrier is a big point of contention between these two camps. This latest paper cites a large pile of literature showing that sheer physical properties (molecular weight, logP) account for most successful approaches to getting compounds into the brain, consistent with passive diffusion, while examples of using active transport are much more scarce. That leads into one of the biggest K-D points, which seems to be one of the ones that drives the existing pharmacokinetics community wildest: the assertion that thousands of transport proteins remain poorly characterized, and that these will come to be seen as the dominant players compared to passive mechanisms. The counterargument is that most of these, as far as we can tell to date, are selective for much smaller and more water-soluble substances than typical drug molecules (all the way from metal ions to things like glycerol and urea), and are unlikely to be important for most pharmaceuticals.

Relying on as-yet-uncharacterized transporters to save one's argument is a habit that really gets on the nerves of the Kell-Dobson critics as well - this paper calls it "pure speculation without scientific basis or evidence", which is about as nasty as we get in the technical literature. I invite interested readers to read both sides of the argument and make up their own minds. As for me, I fall about 80% toward the critics' side. I think that there are probably important transporters that are messing with our drug concentrations and that we haven't yet appreciated, but I just can't imagine that that's the whole story, nor that there's no such thing as passive diffusion. Thoughts?

Comments (4) + TrackBacks (0) | Category: Drug Assays | Pharma 101 | Pharmacokinetics


1. Gerog-Martin Krapper on April 27, 2012 9:34 AM writes...

I took a quick look at this about a year ago and have linked the url for that post to this comment. If influx is as common as the authors believe then wouldn't we expect to see influx in Caco-2 and MDCK assays as frequently as we see efflux?

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2. Anonymous on April 27, 2012 9:46 AM writes...

I'm sitting at about 90% with the critics. There's just too much literature supporting passive transport.

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3. David P on April 27, 2012 9:49 AM writes...

Viscous or vicious? Or both?

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4. Curious Wavefunction on April 27, 2012 9:51 AM writes...

Occam's Razor would dictate that in the absence of evidence to the contrary, one should assume passive diffusion. Passive diffusion is a simple physical phenomenon. It undoubtedly operated during the formation of the first primitive protocells. Active transport proteins did not exist then and appeared much later in relatively advanced organisms. Given these facts, passive diffusion should be assumed as the default mechanism for molecular transport unless refuted by evidence implicating transporter proteins. I certainly wouldn't assume most transport processes to be actively mediated.

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