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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: derekb.lowe@gmail.com Twitter: Dereklowe

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April 27, 2012

How Do Drugs Get Into Cells? A Vicious 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 (37) + TrackBacks (0) | Category: Drug Assays | Pharma 101 | Pharmacokinetics


COMMENTS

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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5. Cellbio on April 27, 2012 10:54 AM writes...

I have not read the papers, so maybe this is discussed, but isn't it simplifying the situation to think about the issue as "getting into a cell"? Isn't it more useful to think about partitioning to distinct compartments, including membranes, with a distribution at any one time driven by physical properties of the compound, concentration in the "loading compartment" (media in cell culture), transport/efflux kinetics, biological half-life of the compartments (eg membrane turnover) and subsequent partitioning to the compartment of the target as free drug?

If one breaks down drug behavior in circulation, is it not clear that this sub-compartment partitioning is in play and drives favorable PK? Why would this not also be invoked for biological surfaces, including membranes and ECM?

In one query of compound behavior, it was evident that some compounds partitioning to target was driven by concentration in the media, as media exchange caused an immediate drop in target inhibition, while another persisted in activity. On/off rates on the target were the same, and careful analysis of media and cell compartments revealed the compound rapidly distributed to cell compartments. This compound made it to humans, but failed in dose escalation due to adverse events. PK showed the compound was "gone", but the cell work, done later, showed that it was probably accumulating post-dosing and creating a long lived bio-burden we did not understand.

Then, for the fun of 'pure speculation', I'll add, following CW's theme, that membrane flux and exchange of chemical matter by membranous structures almost certainly preceded life and likely persists today. When I read about exosomes and cell transfer of membranes and molecules I wonder if there might be more promiscuous exchange of material than a rational design would imagine. Maybe exosomes account for some attributes of ADME.

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6. barry on April 27, 2012 11:09 AM writes...

now that the human genome is published, the number of transporters is limited. In time, we will characterize them all. I'm betting that we'll find that only very few of them are important to drug transport. And the ones that are important are mostly responsible for transporting molecules (notoriously antibiotics and neuraminidase inhibitors) that violate Lipinski's Rules.

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7. Spike on April 27, 2012 11:46 AM writes...

Are we trying to make things too black and white here? Derek states "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). But is that the end of the story? What about endocytosis (not sure if Derek is equating endocytosis to a pore or not). Fatty acids bound to albumin can be taken up by endocytosis. Why can't drugs? Also, there are receptor-mediated mechanisms for uptake in albumin. Perhaps we have been thinking too narrowly about how drugs get into cells - could it be that we should be thinking about mechanisms of how protein-bound drugs get into cells and not simplify things by saying that only free drug can get into cells by passive diffusion or by active transport?

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8. ronathan richardson on April 27, 2012 12:28 PM writes...

I think that if most drugs depended on transporters to get in, then (for anti-cancer or anti-microbials) we would see more resistance mutations in such transporters. Those mutations seem to be quite rare, though I'm not sure we've looked for them well enough...

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9. alf on April 27, 2012 12:31 PM writes...

I suspect that both sides are "correct", as is usually the case in most scientific debates. The idea of what a membrane-bound carrier looks like is probably too narrow in the mind of most medicinal chemists. Lipid-protein-drug interactions are complex and biological membranes have a lot of protein. On the other hand molecules do have general property requirements to bind to membrane, cross hydrophobic core, and then enter the intracellular aqueous environment (aka passive diffusion). Unlikely that both extreme positions are completely "correct".

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10. Tim McDaniel on April 27, 2012 2:00 PM writes...

Aw, I thought "viscious" was a clever pun!

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11. Ed on April 27, 2012 2:16 PM writes...

Barry (#6) - you are assuming that epigenetic factors won't come into play, along with all the complexities that would introduce. Things such as MUC1 ( off the top of my head) -where there are multiple glycosylations possible, will no doubt severely muddy the waters.

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12. Rick Wobbe on April 27, 2012 2:50 PM writes...

Without further definition of what exactly we're talking about here, everyone is right! Or everyone is wrong! Caco-2 and MDCK cells are like E. coli for pharmacokinetics; they represent a highly specialized set of cells that model (usually relatively well) two things, "get things into the cells of an intestinal or kidney epithelium" and "get things out of the cells of an intestinal or kidney epithelium (usually at the other end)", via a limited number of fairly well-characterized, specific mechanisms. Using them to generalize about how things "get into cells" in general is about as appropriate as using the amygdala to describe how the brain does theoretical physics. So which are we talking about, how epithelial cells transport drugs from lumens (e.g. the intestine) into the blood, or how the gazillions of other cell types might take up drugs from the surrounding medium? I assume that by "cells" we're talking about human cells, not bacterial, fungal, worm, or parasite, otherwise the story gets even more complicated.

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13. PT on April 27, 2012 3:32 PM writes...

If its indeed the case that carrier mediated transport dominates different organelles should end up with different concentrations of drugs as they have different sets of transporter proteins. This could be tested using fluorophores.

Also if CM hypothesis is correct inhibiting protein synthesis without affecting degradation should alter cell permeability more then if the dominant mechanism is passive diffusion. Same goes for depleting cell ATP.

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14. deuxciel on April 27, 2012 4:01 PM writes...

10. "New Repulsive Electromagnetic Energy Extraction Principles" on Youtube


.
. ! .

One often hears of Yin & Yang, rarely the reverse. They remain equals nonetheless and clearly function as a unified operation.

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15. Spiny Norman on April 27, 2012 8:29 PM writes...

Alf @9, I prefer to think of it as both sides being incorrect. But that's just how I roll.

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16. mad on April 28, 2012 5:49 AM writes...

I go with the side with the actual data...

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17. Puff the Mutant Dragon on April 28, 2012 12:03 PM writes...

I tend to agree that "speculation" is an accurate way to characterize the K-D paper.

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18. clueless on April 29, 2012 6:28 AM writes...

I have been always on K-D side.

Most of small molecule drugs do get into cells by passive diffusion, of which mechanism is a non-specific and concentration dependent. And some drug are known to be taken in by transporters or pores of which the actual mechanisms have been identified and been taken advantage of. We believe that because we have generated the results based on those assays we screened for.

But there are (or might be) other under-explored opportunities (mechanisms) that one could also use to send those "difficult" molecules, such as molecule weight larger than 1000 or highly charged compounds, into cells.

Since our mind is set on passive diffusion, we always check permeability at high concentrations. We should ask these questions: by doing that, have we actually missed the other specific and less specific mechanisms that are saturable and could deliver drugs at low concetration into cells? and do we really need high concentration drugs to act on cellular targets? if not, isn't it a better way to reduce potential drug toxicity?

Since more than decade ago, drug discovery has been built on high throughput screenings, which are highly efficient but over-simplified. Not enough research resources are devoted into further understand what are going on in a real world (cells). The show-me-data mentality actually might have killed many chances to do speculative experiments to discover fundamentals that could have huge impact on drug discovery process.

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19. simplequestion on April 30, 2012 5:08 AM writes...

If passive diffusion is the rule, how do we manage to formulate drugs liposomes? give the size and the gradient, I would expect those liposomes to empty themselves ASAP...

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20. Morten G on April 30, 2012 5:50 AM writes...

What's the evolutionary rationale for broad specificity influx transporters? Plenty of reasons for efflux pumps but I can't really see any for influx. Especially since there are thousands of transporter proteins. If there were only a few then that would be a good argument for broad specificity but with many you would expect high specificity.

I hope they aren't wasting any grad students time on this.

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21. Hap on April 30, 2012 4:26 PM writes...

Does anyone have the reference to the rebuttal paper?

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22. Jonadab on April 30, 2012 7:04 PM writes...

Well, we know there *are* molecules that diffuse through passively. Water is probably the best and most famous example, but I'll take the wager at any odds that it's not the *only* thing that gets through passively.

However, it's also obviously likely that the membranes must stop *some* kinds of things from getting through much, if at all. Otherwise, what's the point of having membranes?

I think the only real question is how many drugs can squeeze into the former category -- or, stated another way, how many of them are simply too large or too chemically wrong or whatever to get through the membrane passively.

I can't say as I'd be very surprised if it turned out that the majority of drug molecules needed some level of active transport to get in at high enough doses to be effective.

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23. Allchemistry on May 1, 2012 4:20 AM writes...

@22

The very rapid movement of water through the membranes of many cells is facilitated by aquaporins. It is not due to simple passive diffusion over the lipid bilayer.

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24. Keep Calm and Synthesise On on May 1, 2012 6:01 AM writes...

All through my chemistry education, I've been taught one model, only at a later date to be told 'actually that's not true, this next model is the real thing'. We use models all the time to estimate reality. And so now there are some novel thoughts on membrane diffusion. Is the passive diffusion model correct? Probably not. Having sat through a Paul Dobson lecture and initially raised my eyebrows, the one thing he and Kells do is make you think. And that can't be bad now, can it?

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25. MoMo on May 2, 2012 3:09 PM writes...

When it comes to membranes all of the theories are true- and all of the theories are false.

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26. Douglas Kell on May 6, 2012 7:24 PM writes...

So many comments, some very odd indeed, and you'll have to wait for the rebuttal to see what the issues actually are, but folk may care to ponder the following (answers in CAPS):

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? EXPECT AWAY. IF EFFLUX GETS STUFF OUT THEN INFLUX GETS IT IN. ISSUE IS THE ACTUAL RATES AND MECHANISMS.

There's just too much literature supporting passive transport. NO THERE IS NOT, BUT THERE IS A LOT THAT IS SIMPLY *INTERPRETED* AS SUCH. IF PASSIVE PERMEABILITY OCCURRED WIDELY CELLS WOULD NOT HAVE OSMOTIC PROPERTIES. THEY DO. THINK ABOUT IT.

Active transport proteins did not exist then and appeared much later in relatively advanced organisms. PHARMACEUTICAL DRUGS DID NOT APPEAR EARLY IN EVOLUTION EITHER. RED HERRING.

now that the human genome is published, the number of transporters is limited. WELL IT IS ABOUT ONE THOUSAND...

I'm betting that we'll find that only very few of them are important to drug transport. WRONG QUESTION. RIGHT QUESTION IS DO MOST DRUGS HAVE A TRANSPORTER, NOT DO MOST TRANSPORTERS HAVE A DRUG?

I think that if most drugs depended on transporters to get in, then (for anti-cancer or anti-microbials) we would see more resistance mutations in such transporters. Those mutations seem to be quite rare, though I'm not sure we've looked for them well enough... GETTING WARM, BUT IF MULTIPLE TRANSPORTERS ARE ACTIVE AN INDIVIDUAL MUTATION WILL HAVE LITTLE EFFECT. AND WHEN TESTED EXPERIMENTALLY (NO 'SPECULATION') MULTIPLE TRANSPORTERS *ARE* ACTIVE. SENSITIVE ASSAYS NEEDED FOR GWASs - FOR ONE SEE
Lanthaler K, Bilsland E, Dobson P, Moss HJ, Pir P, Kell DB, Oliver SG: Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast. BMC Biology 2011; 9:70.

If its indeed the case that carrier mediated transport dominates different organelles should end up with different concentrations of drugs as they have different sets of transporter proteins. This could be tested using fluorophores. IT HAS AND IS

I go with the side with the actual data... NOT ONLY DATA BUT INTERPRETATION. BUT DATA WITH SOME REAL GENETIC/PROTEOMIC BACKUP ARE BEST... SEE LANTHALER PAPER ABOVE.

Puff the Mutant Dragon on April 28, 2012 12:03 PM writes...
I tend to agree that "speculation" is an accurate way to characterize the K-D paper. PUFF THE MUTANT - SEE THE MUTANT DATA DESCRIBED ABOVE...

simplequestion on April 30, 2012 5:08 AM writes...If passive diffusion is the rule, how do we manage to formulate drugs liposomes? give the size and the gradient, I would expect those liposomes to empty themselves ASAP... JOLLY GOOD POINT. OVER TO THOSE WHO KNOW ABOUT THESE THINGS, BUT I SHALL LOOK INTO IT.

What's the evolutionary rationale for broad specificity influx transporters? Plenty of reasons for efflux pumps but I can't really see any for influx. Especially since there are thousands of transporter proteins. If there were only a few then that would be a good argument for broad specificity but with many you would expect high specificity. NO EVOLUTIONARY RATIONALE AS DRUGS DID NOT APPEAR EARLY IN EVOLUTION. BUT NB THAT PHARMA COMPANIES EFFECTIVELY *APPLY* SELECTION FOR DRUGS THAT GET IN, AND SUCH DRUGS *ARE* STRUCTURALLY RELATED TO METABOLITES: Dobson PD, Patel Y, Kell DB: "Metabolite-likeness" as a criterion in the design and selection of pharmaceutical drug libraries. Drug Disc Today 2009; 14:31-40. SPECIFICITY IS WHAT IT IS. NO SERIOUS ENZYME KNOWN TO ME USES ONLY ONE SUBSTRATE AT ALL.

I hope they aren't wasting any grad students time on this. ASSUME 'THEY' IS 'US'. THE WORK WAS FUNDED AT THE POSTDOC LEVEL. BUT IT WOULD ACTUALLY BE A GOOD TRAINING FOR GRAD STUDENTS SO THEY SEE WHAT A PROPER SCIENTIFIC ARGUMENT IS BASED ON. THAT INCLUDES KNOWING THE LITERATURE AND READING IT CAREFULLY. MAYBE START WITH WHAT WE ACTUALLY WROTE AND THE 300+ REFERENCES...

I DO HOPE THIS HELPS US ALL TO DISCOVER SOME DRUGS THAT WORK OUT.

Douglas Kell (not hiding behind a silly pseudonym).

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27. Rick Wobbe on May 8, 2012 8:09 AM writes...

Douglas, Thanks for the spirited replies. It's part of the fun of good scientific arguments.

I'm still struggling to understand what, if any, general message can be taken away regarding how drugs are taken up by cells. Caco and MDCK are OK (but don't forget that the "C" stands for canine!), but arguably still imperfect, examples of cells specialized to be gatekeepers of what's allowed "inside" the body and what's kept or ushered outside the body. Both in the body and in in vitro experimental systems, their transport behaviors depend as much on the tissue architecture surrounding them as on an individual cell's protein expression pattern. That makes me reluctant to generalize observations on drug transport/diffusion in those cells to other cell types, i.e. the ones bearing the drug's target.

The reverse argument makes me skeptical of what experiments with other cell types (e.g. fibroblasts, HeLa cells, lymphocytes, etc.) tell us about how intestinal and kidney epithelial cells serve their gatekeeping function. To make matters worse, uptake of, for example, HIV protease inhibitors tells us less than you'd think/wish about how taxol is taken up by cancer cells. I believe we have explored far too little of the vast matrix of drug-cell type-tissue organization interactions to try to make statements claiming that thus-and-such always happens, or never happens, or generally happens, or happens some consistent fraction of the time.

With regard to liposomes, it's a common misconception that they're used to boost uptake of drugs that would otherwise have poor cell membrane permeability. In reality, using amohotericn B as a example, their utili stems from their ability to either package toxic drugs so their less toxic or to improve their PK by prolonging their circulation. Unless something has changed since I last looked carefully at it, experiments trying to use liposomes to boost cellular uptake of drugs that have a hard time achieving therapeutic cellular concentrations, have generally yielded disappointing results, with nucleic acids being one exception. So I'd be careful about using data from liposome experiments to address the hypotheses being debated here.

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28. PPedroso on May 8, 2012 12:28 PM writes...

@26

How do you explain that physical properties of drugs, especially lipophilicity, correlates well with intestinal permeability in vivo?

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29. AndD on May 8, 2012 4:02 PM writes...

PPedroso - I was thinking the same question. I would have thought that if active uptake mechanisms dominated, any attempt to predict in-vivo permeability from phys chem and molecular descriptors would be doomed to failure, but for many drugs, such predictions seem to give reaonable results.

Of course, the concentration of an oral drug is highest in the intestine, and will be lower in other parts of the body for an orally administered drug, so it is possible that active processes become more significant at lower drug concentrations, but still unconvinced it would become the dominant means of transport.

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30. Georg-Martin Crapper on May 8, 2012 5:21 PM writes...

In my experience, it is much more common to find A to B permeability greater than B to A permeability (i.e. efflux ratio > 1) than vice versa when analysing Caco-2 and MDCK results for compounds in pharmaceutical databases. It would be prudent to check the distributions of efflux ratios in large pharmaceutical industry Caco-2 and MDCK databases before asserting the importance of influx. It's not a big request since one would only be asking for the distibutions of efflux ratio and not the data or structures.

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31. Georg-Martin Crapper on May 8, 2012 5:28 PM writes...

TYPO in comment #30

That should have been: "In my experience, it is much more common to find B to A permeability greater than A to B permeability (i.e. efflux ratio > 1) than vice versa when analysing Caco-2 and MDCK results for compounds in pharmaceutical databases."

Apologies for typo and any confusion.

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32. simplequestion on May 9, 2012 2:40 AM writes...

I would like to comment on entry 27.
I think you missed my point about liposome. I don't really comment on their ability to help cross membrane. I am more commenting on their nature. Correct me if I am wrong but liposomes are just lipid bilayer make spherical and you tend to fill them with small molecule. My point is if small molecules really diffuse passively through lipid bilayer you shouldn't be able to formulate anything with liposome even less find them any therapeutic use.

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33. Douglas Kell on May 10, 2012 5:21 PM writes...

"How do you explain that physical properties of drugs, especially lipophilicity, correlates well with intestinal permeability in vivo?"

PLEASE READ THE PAPERS WHERE IT IS ALL EXPLAINED. THE NEXT REBUTTAL WILL DEAL MAINLY WITH OTHER STUFF. SOMETIMES THERE IS A CORRELATION (INCL WITH GENERAL ANAESTHETICS), OTHER TIMES NOT - SEE THE DATA IN THE PAPERS. THE MECHANISM (PROTEIN CARRIERS OR CONCEIVABLE DIFFUSION VIA PHOSPHOLIPID) IS NOT RELATED TO LIPOPHILICITY per se AS PROTEINS HAVE HYDROPHOBIC POCKETS, ESP MEMBRANE ONES THAT ARE BIOPHYSICALLY SIMILAR TO LIPIDS. BUT SO DOES THE WATER-SOLUBLE LUCIFERASE. READ THE PAPERS AND REFS.

Kind regards,
Douglas Kell.

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34. Rick Wobbe on May 15, 2012 9:37 AM writes...

32, simple question,
Ohhhhhhhh. I see what you mean. Sorry.

I would be reluctant to infer what you are suggesting from liposome data for two primary reasons: a, liposomes are very different from cell membranes in terms of composition and, therefore, physicochemical properties (e.g. fluidity, structural homogeneity); b, there's too little published data and existing publications focus, not surprisingly, on successful formulations (i.e. those where the drug is effectively trapped), so it's skewed against the kind of observations you're talking about. However, there are lots of publications using artificial membrane bilayers that address your point. Based on those experiments, drugs partitioning into membranes then back out the other side clearly does happen. The physiological implications of that can be debated endlessly, as this blog post and commentary shows...

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35. Douglas Kell on August 27, 2012 6:31 AM writes...

The follow-up rebuttal went off to DDT. 565 references, plus new analyses of carriers for EACH of the 'top 10' selling drugs, inter alia, and much more material on promiscuity of drugs binding to proteins including transporters. Hope it meets unbiased referees and that folk will find the arguments and facts useful.

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36. Robert Fraczkiewicz on March 6, 2013 12:29 PM writes...

If passive diffusion does hardly matter, or does not occur at all, then one explains the existence of efflux transporters? Transport something in, in order to transport it out? This does not make sense from the evolutionary point of view.

Permalink to Comment

37. Amit on April 3, 2014 6:50 AM writes...

i would like to know how a lipophilic drug works inside the aqueous compartment of cell. for example orlistat.

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