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.