Fun with pharmacokinetics (part 2)

[the pharmacokinetics topic is a big one, so i decided to break it down into drug-gets-in and drug-gets-out sections. -leigh]

Distribution

That’s right, when you take a drug, it goes everywhere. It gets into your bloodstream and it goes everywhere your blood goes. Now it’s just along for the ride among your red blood cells and clotting factors and immune cells and that whole party. Wherever the blood is going, the drug is in there and it’s going too.

You can see now that the administration route has an effect here. From your lungs, it’s hitching the express train to the brain. From the stomach, not only is that going to take longer, but it goes to your liver first. The liver is your body’s drug deconstruction factory, where your metabolic enzymes (the cytochrome P450s) live. Vascular injections are immediately effective.

Also, there are lots of things your drug can bind to or equilibrate with as it travels along through your bloodstream. There are proteins in the blood that drugs bind to. Fat-soluble drugs will inevitably get into the fat depots that we all have. In the end the drug distributes to wherever it can possibly get. and that likely includes the site of action where you want it to work. But you see that a lot of things can affect how available the drug is by the time it reaches the site of action!

But the drug gets there, or we wouldn’t even bother with any of this, would we?

Extra barriers

There are a couple of areas of your body that have extra protection from the blood circulating in your body. First, of course, is the brain. The brain isolates itself with the blood-brain barrier. This is basically a specialized membrane coating of all the blood vessels that run through your brain. It still gets the nutrients it needs from the blood, but much fewer things are able to cross that extra barrier. So for a drug to be CNS active, it has to be particularly lipophilic, meaning it is ideally a small molecule that is not charged at blood pH. (Ideally.) Another barrier that exists in some of us some of the time is the placental barrier. Like the blood-brain barrier, the placental barrier protects the growing fetus from a number of things hanging out in mom’s bloodstream. This includes quite a few drugs. But again, there are things that get through it quite easily with the right properties. So while it’s helpfully protective, it’s not the intense shield we would like it to be (or some of the vital things wouldn’t make it across either!)

And the drug gets metabolized too

Now we have this drug that’s circulating all through your body. But waiting in your liver, as I mentioned earlier, are enzymes that are ready and waiting to modify any drug that they come across that fits their active site. That means as soon as the drug runs into that enzyme, it’s curtains for that particular drug molecule. (Though some drugs have active metabolites, or are administered in the inactive form and then metabolized to become active.) But there are only so many enzymes available, so if there’s a ton of drug and less than a ton of enzyme, some drug will make it through the liver intact for another run through the body. And then maybe another.

What this comes down to is that the drug concentration in your blood gets reduced on a per-time basis. We call this the half life (or alternately, the half time or t1/2). The half life, as you might guess, is the amount of time it takes the body to get rid of half the concentration of drug in your bloodstream. Depending on what mechanism is responsible for getting rid of the drug, you will have different half lives. For alcohol, interestingly, there isn’t a "real" half life but a maximal amount that your body is capable of breaking down per hour. This is called zero-order kinetics.

I think we’re going to stay away from enzyme kinetics for this post, as much as i love the biochemistry behind it.

Of course, your body is always excreting things from your bloodstream too. Your kidneys are a big player in drug excretion. They filter stuff out of your blood and you probably know the rest of the story (or, you can get more of the story at WhizBang!, our local expert blog). Drugs can be excreted through all possible excretion routes the body has to offer.

There you have it. The very long story that boils down to this:

Drug gets in, drug meets target, drug gets broken down, drug gets kicked out. The story of pharmacokinetics.