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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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May 25, 2004

Down the Hatch

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Posted by Derek

We have a lot of received wisdom in the drug business, rules of thumb and things that everybody knows. One of the things that we all know is that the gut wall isn't much fun for our drugs to get across sometimes. That's inconvenient, since most people would prefer to swallow their medicine rather than take part in the more strenuous dosage forms.

Go around asking random medicinal chemists about oral absorption of drugs, and you'll get more things that everyone knows. There will be lots of talk about solubility and allied topics like particle size, salt forms, formulations and so on. Some of this is valid (I'd vote for particle size), but some of it is hooey. For example, I'm not convinced that solubility has much to do with oral dosing (once you get past the powdered-glass stage, naturally.) I've had wonderfully soluble drug candidates that went nowhere, and I've had brick dust that showed reasonable blood levels. I'm just barely willing to admit that there's a trend (in a really wide data set), but I'm not willing to admit that it's a very useful trend. But solubility can be measured (over and over!), so there's a constituency for it.

You'll also get a lot of stuff about P-glycoprotein, and the necessity of doing some sort of cellular assay to see if your compound is affected by it. That's a protein I've spoken about from time to time, which sits in the cell membrane and pumps a variety of compounds from one side to the other. Now, Pgp is a real thing, both in the gut and in the brain. But there are a lot more transporter proteins out there than most of us realize, hundreds and hundreds of the damn things, and we don't have much of a handle on them. I think that they're a big opportunity for drug development in the coming years, assuming we start to get a clue.

People get excited about Pgp because it was one of the first ones characterized, and because it does seem to explain the failure of a few drugs. There's a cellular assay, using the famous Caco-2 colon cells that express the protein, which is supposed to give you some idea of Pgp's effect on the membrane permeability of cour compounds. Unfortunately, I'm not convinced that it gives you much more than a reading of how they behave in the Caco-2 assay, which probably isn't worth knowing for its own sake, to put it kindly. But folks are so desperate to know why their drugs don't get absorbed well (and how they can avoid wasting any more of their working lives on such) that they'll seize on any technique that offers hope.

You'll also hear about metabolism of drug by enzymes in the gut wall, but as far as I can see, that's an overrated fear. (There was a review article on this a few years back from a group at Merck, and that's what they concluded.) People like this explanation because it makes some sense. We all know about liver enzymes ripping our compounds to bits, and here they are in the gut wall! No wonder our compounds stink! And this is also something you can screen for, so you're not left sitting there alone with the black box. Far better to be able to tell everyone that you think you have a handle on the problem and that you're running assays to get around it, even if it isn't true.

Nope, our understanding of drug absorption still reeks of voodoo vapors, despite many attempts at exorcism. It's annoying and it's disturbing, but it's the state of the art. Anyone that can do better will make a fortune.

Comments (10) + TrackBacks (0) | Category: Drug Development | Pharmacokinetics


1. Klug on May 25, 2004 9:35 PM writes...

Have you heard any rumblings about crystallinity and its relationship to solubility? I've heard that different crystal morphologies are differently soluble. (This may be more of a question for a formulator than a med chem guy.)

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2. Judson on May 25, 2004 11:17 PM writes...

I thought patches were more the wave of the future for administering drugs. This might not be ideal for the person on seven anti-depressants, but it works alright so far for estrogen/progesterone and nicotine.

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3. SRC on May 25, 2004 11:47 PM writes...


Of course different crystal forms have different solubility. They differ in free energy of formation, just like allotropes of an element, so they have to differ in free energy of solution, and therefore in solubility.

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4. otey on May 26, 2004 9:17 AM writes...

Just a note to commend you for a wonderful piece today. I have nothing of substance to offer. I am not a chemist or in the pharma industry. But after reading today's entry I felt like I had a little (and refreshingly honest) window into a fascinating world.

Keep 'em coming.


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5. Derek Lowe on May 26, 2004 9:46 AM writes...

Yep, crystal form is very important, and worth a post of its own. Compounds can take on different forms depending on how they're made and processed, and sometimes this is a terrible headache in the switch to large-scale chemistry.

Patch formulations are in the always-promising category. The big problems, which are still being worked on, have been that many compounds have poor skin penetration, that your compound has to work well with slow-and-steady blood levels (rather than a big dose all at once), and that the net amount of compound that can be delivered is not large. (You'll never see an antibiotic patch, most likely, for that last reason.)

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6. David on May 26, 2004 1:23 PM writes...

Probably the best way to obtain information about oral bioavailability is to compare Subcutaneous to oral routes of administration on an in vivo endpoint of interest. Simple, quick, great for medicinal chemists, but cuts ADME people out of the loop, and that agravates them to no end. So many companies don't do the simple way.

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7. Derek Lowe on May 26, 2004 3:07 PM writes...

I've been on programs where we did some of that protocol, but sub-cu dosing is more variable than the other forms. You can do the same kind of thing by dosing i.p., just skipping the gut wall. We regularly get information like this on our best compounds.

But determining bioavailability this way doesn't clear up all the problems in earlier stages of a program. For one thing, you have to make enough of each compound to dose in vivo, and you have to have enough animals and enough workers to do them all. (Rarely have I worked on a program where we had all the in vivo support we could ask for.)

The hope of all the in vitro assays I was talking about is to avoid dosing animals altogether, at least for the first rush of compounds. Saves time, saves work, saves money, in theory. But not yet.

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8. Klug on May 26, 2004 4:02 PM writes...

What are the rules for skin delivery anyway? It seems like the general public believes that most compounds (especially the really nasty ones) are skin-absorbable. Are there general guidelines for this sort of thing?

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9. Rusty on May 26, 2004 9:01 PM writes...

I totally agree with the voodoo aspect of these assays (especially Caco-2, liver microscomal rates, solubilities, and other high-throughput ADME staples). Until an in vitro-in vivo corellation has been established, the numbers mean nothing. I, too, have made compounds with both poor crystalline and amorpous solubilities at pH 2 and 7.4 that show amazing plasma levels, despite not even registering in a Caco-2 assay. The contrary is also true. We have also advanced compounds with great PK profiles that show increadibly fast microsomal metabolism in multiple species, much to the dismay and disgust of our DMPK colleagues. The box-checking mentality can really hinder or stop good potential drug candidates.

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10. Douglas Ridgway on June 1, 2004 7:38 PM writes...

It seems obvious that solubility should impact bioavailability -- after all, if you swallow a rock, it will just come out the other end. So why does it often not seem to work that way in practice?

Three reasons:

1. Aqueous vs. physiological media

Since we eat fat, the body has become very good at making sure lipids get into the body somehow, even if they never get dissolved. Aqueous solubility underpredicts, often by orders of magnitude, solubility in intestinal fluid.

2. Solubility - permeability tradeoff

Poorly soluble compounds may be insoluble because they are lipophilic, and therefore tend to higher permeability. To some extent, sufficiently rapid transport across the gut wall once you do get dissolved can allow adequate (though solubility-limited) absorption. One ought not think about solubility in isolation.

3. Higher potency

The more potent the compound, the less needs to get in, and the larger the fraction of a dose will dissolve in a given amount of water (or intestinal fluid).
I'm not saying that solubility is not important, just that it's easy to be surprised at the exceptions.

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