When a drug makes it into the bloodstream (which is no sure thing, on my side of the business), it doesn't just float around by itself. Blood itself is full of all kinds of stuff, and there are many things in it that can interact with drug molecules.
For one thing, compounds can actually wander in and out of red blood cells. This usually isn't a big deal, but once in a while a compound will find a binding site in there, which had flippin' well better not be on the hemoglobin protein. Depending on the on- and off-rates, this can either add a welcome time-release feature to the dosing or it can be a real pain. I haven't heard as much about interactions with white cells, but since they're a much smaller fraction of the total blood it's not something we'd be likely to notice.
More commonly, drugs stick to some sort of plasma protein. The most common one is serum albumin, and another big player is alpha-1 acid glycoprotein, or AGP. Albumin's found in large amounts and has several distinct binding sites. Acidic drugs are well known to hold on to it. As far as I'm aware, no one's absolutely sure what it's there for, but it must be pretty important. The multiple binding sites make it seem like could be some sort of concentration buffer for several different substances, but which ones? (I've never heard of an albumin knockout mouse - I assume that it would be lethal.)
The same comments about good and bad effects apply. A lot of effort has gone into schemes to predict plasma protein behavior, with success that I can charitably describe as "limited."The real test is to expose your compounds to fresh blood and see if you can get them back out. Some degree of protein binding is welcome, and you can go on up to 99% without seeing any odd effects. But at 99-and-some-nines you can start to assume that something is wrong, and that the interaction is too tight for everyone's good.
But when you're doing your blood assay, you had better make sure to try it with all the species that you're going to be dosing in. There's a kinase inhibitor from a few years back called UCN-01 that provides a cautionary tale. It was dosed up to high levels in rats and dogs, wasn't bad, and passed its toxicology tests, and went into human trials. They started out at one-tenth the maximum tolerated rat dose in the Phase I volunteers, which should be a good margin. But when they got the blood samples worked up, everyone just about fell out of their chairs.
There was at least ten times the amount of drug circulating around than they'd expected, because it was all stuck to AGP and it just wasn't coming off. A single dose of the drug had a half-life in humans of about 45 days, which must be some sort of record. Well, you might think, what's the problem. A once-a-month drug, right? But it doesn't work like that: the compound was so tightly bound that it would never reach the tumor cells that it was supposed to treat. All it was doing was just riding around in the blood. And the clinical program really dodged one from the safety perspective, too, because as they escalated the dose they would have eventually saturated all the binding that the AGP had to offer. Then the next higher dose would have dumped a huge overage of free drug into the blood, and all at once. Not what you're looking for.
The compound is still being investigated, but it's having a rough time of it. It's been in numerous Phase I trials, with all sorts of dosing schedules. A look through the literature shows that the compound is mainly being used as a tool in cell assays, where there's no human AGP to complicate things. With so many kinase inhibitors out there being developed, it's going to be hard to find a place for one with such weird behavior.