Thursday, October 15, 2009

Pharmacokinetics meets the Mystic.

"Any emotion, if it is sincere, is involuntary."

~Mark Twain

The volume of distribution of a drug is the apparent volume into which a drug distributes in the body.

For example:

You have a jug containing one liter of water. Into that one liter of water you place 1 gram of table salt and mix until dissolved. If you were to take a sample from your jug and analyze it, the concentration of table salt dissolved in water would be 1 gram of table salt per liter of water, or 1 g/L. The volume of distribution is one liter, clearly.

Our bodies behave this exact same way with some drugs. We have a certain volume of water in each of us, and some drugs dissolve and distribute only into the water in blood, and between cells, and that is a finite volume. So if you administer this sort of water-soluble drug intravenously and then take a blood sample, the concentration of the drug you measure, like the salt in the jug, will equal the amount of salt you administered divided by the volume of water in the body. That is easy enough.

In our bodies something rather interesting happens to most drugs that makes measuring this volume less straight forward.

Let's say that you have the same 1 liter of water in your jug, and to it you add 1 gram of table salt and mix it like before, until it dissolves. This time when you sample it, however, instead of the concentration of the salt being 1 g/L (which is what you added) the concentration you measure is one-tenth of that, or 0.1 g/L.

What happened?

The salt is completely dissolved. The jug holds 1 liter of water... but the concentration of salt is 1/10 that of what it should be.

In other words, it is as if you put the same 1 gram of table salt into a jug that contains 10 times the volume of water--hence the concentration you analyzed is 1/10 of what it should be. And this is the apparent volume of distribution. The volume of distribution in this case is 10 liters. It is as if some of the 1 gram of table salt dissolved into the liter of water disappeared, or that the jug is magical and can actually hold 10 times more water than it appears.

The same thing happens in the body. Drugs can distribute into the body in such a way that when you sample blood or plasma, the drug concentration indicates that it has distributed into a space 10 or 100 times larger than the actual volume capable for the human body. It seems impossible.

The reason this happens is because drug partitions inside of the body. Few drugs only stay in the water space. Most drugs bind to proteins and tissues, such that the drug in blood gets pulled from there into places that can not be "seen" or sampled. Hence, it appears that drug is missing, or, like the jug of water, the apparent body volume into which the drug was administered is larger than the body can actually hold.

There are some assumptions that go along with this, as well. For instance, we assume that no drug has been removed from the body during that time, that only distribution is taking place. This is because elimination from the body of that drug before it is measured would result in a smaller amount of drug being measured per volume, thus a falsely large volume of distribution.

The volume of distribution is a physico-chemical and biologically based parameter that, in addition to the clearance, defines the half-life, or the amount of time it takes for half of the drug in the body to be eliminated. Now it is possible to see that where the drug goes inside of the body will play a role in how often the drug is administered. A long half life might mean it takes the body longer to eliminate half of the drug per unit of time, therefore adding more is needed less frequently.

There are proteins in the body that are important for processes such as distribution, such as the nucleoside transporters. These are the proteins I have spent the last 5 years studying more than anything else. How can these affect the volume of distribution, you ask?

Those drugs I mentioned previously, the drugs that only distribute into water are hydrophilic. They do not like lipid environments. Therefore these drugs, once in the body, will tend to stay inside of spaces filled with water. This also means they will not enter cells because cells are contained by membranes composed of lipids. Therefore the cell membrane, a lipid bilayer, keeps hydrophilic drugs, or drugs that dissolve and stay in water, outside of the cell. That will significantly limit the volume into which these drugs can distribute, because 80% of cells is water, but the drug can not access this.

What if the drug COULD get access??

The proteins I study, called nucleoside transporters, serve as a way for drugs that can not passively distribute across cell membranes to get into cells and distribute into the water there. They transport drugs into cells. Now a drug that formerly was restricted to plasma water and water outside of cells has a HUGE space into which it can distribute--as long as the transporter recognizes it. Therefore, it is possible that based on which transporter recognizes which drug, the volume of distribution can change more than 100 times!!!!

If the half-life of a drug is partially dependent upon this volume of distribution, then it is possible to see how a little tiny protein on a cell membrane can make all the difference in the world as to how this drug is going to behave, and how often it will need to be administered.

I think drugs aren't the only thing with a volume of distribution effect. I think intangible things have a volume into which they distribute...


Steve Moss said...

Cool, man. So, the fullest apparent absorption of these intangibles may be influenced by more than, say, the message itself?
That was cool stuff, man.

Aaron said...

stay tuned. Didnt have enough time to get everything I wanted down. So its marinating.