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Volume of Distribution: Part II

"But to me nothing - the negative, the empty - is exceedingly powerful."

~Alan Watts

We are young and our minds are open to everything. Nothing is bound. We make no a priori determination about experience and importance. All is experience. All is important. The volume in which experiences distribute - infinite.

Our first thoughts rarely find their way to binding. They are communication at its basic, primal level. From early communication we experience the reactions of others. These reactions are added to our files from which we build our first meaningful thoughts.

Thoughts distribute into space, occasionally finding--and binding to--an open mind. We are young with open minds ready to be filled, and unknowingly accepting of each and every thing. We age and the ideas and thoughts are following their natural gradient from outside to inside our minds. We still believe we have far less to contribute than we have ability to consume, and consume we do. We collect information and slowly assimilate this into our own ideas, forming them into more meaningful outward gestures. We begin to see the power of our own ideas on others.

Constantly bombarded, spaces to bind become more rare. Also, and perhaps more importantly, we begin to screen the incoming ideas and images and experiences. The rate limiting step becomes our perception. Inside of us is a space between what we form and what we communicate. Zero distribution.

Competition between our own ideas and external thoughts and ideas soon dictate which find acceptance and finally purchase and are assimilated, filed away. Some days we are non-consumers. We only produce. Some other contributors are open to our ideas and our thoughts bind, there, chiseling at the assimilation formed inside of them.

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...

Hocus Pocus, hard to Focus

"One of the symptoms of an approaching nervous breakdown is the belief that one's work is terribly important."

~Bertrand Russell

Sitting here at my desk, where I have sat with my back at the entrance to the lab for 4 years. Sitting next to the door with the traffic of busy scientists scurrying about, the sounds of conversations and lunch time laughter just outside, the familiar jingle of the bosses' keys as he prepares to make his rounds.

Sitting here staring at my own writing. Getting little accomplished.

Its hard to focus on this now. Its getting to be very hard to maintain the level of integration an enthusiasm I need to finish all of this. I have been studying the same thing extremely hard for several years, and I think its safe to say I need a change. I am feeling burned out.

"Keep the larger, long term goal in your mind," someone said to me. "Remember this is the only way you get out!"
Yeah, yeah. Blah blah blah. I know all that. Right now, though, I am to the point of hearing my inner voice, that little person living inside of me always driving me to meet some impossible, unachievable expectation, now saying "Looks good enough. Pack it in."

And its hard. Its a tug-of-war inside of me; one hand knowing I can do better, the othe hand knowing it really doesn't matter and I am so damned sick of seeing it, why do I bother?

And on it goes. Another day to fight the urge to "pack it in." Another day in the ever growing saga.

Private (and not so private) Parts.

“When did I realize I was God? Well, I was praying and I suddenly realized I was talking to myself.”

~Unknown (Maybe Dog?)

Try to stay with me, here. This is going to sound convoluted (it is) but I swear its the truth.

Where is the best place to have a conversation about the conversation you are going to have with your mother regarding leaving your wife (which apparently the family loves) to marry your cousin (who also is currently married)?

Why, I believe the correct answer is the Metro Bus.

I listened to this guy because that is what you do when people are talking on their phone 12 inches from your ear, with their back to you. What is probably, and admittedly, more amazing to me is what was going through my head during this tell-all. Very public tell-all.

Beginning with discussions of wedding rings. Sounded nice, sort of sweet, you know, newly-wed gibberish.

And then talking about "the conversation" and "are you ok with me saying this..." which included some discussion of "well when she asks 'what about Beth' I will just remind her how she has heard me vent about her so much and I just have made the choice to be with someone else..." Followed by a short discussion comparing the two women and really what good was marriage when all you could think about was this other person who was FAR superior in every way. Oh, and so much better in bed, too.

My attention was clearly locked in on this conversation now. I couldn't actually believe I was hearing these things out loud on the bus, but it got better--much better. Or worse, depending on how empty or full your cup is.

"Well, when she says 'But she's your cousin...' I will just tell her I can't control how I feel..."

SCREEECH goes the record player and everyone on the bus turns and looks, mouths gaping, eyes wide in shock and awe.

That's what should have happened, anyway, after that part. Instead no one reacted although everyone heard it. And why not react? This is great stuff! Now we are really getting somewhere!! A guy on the bus talking to HIS COUSIN about the conversation he is going to have with his MOTHER about leaving his wife for her. Wow. Rich. And I thought the bus ride was dull.

The next thing I heard was "What, that time in the closet?"
Pause.
"So you have had sex three times in the last 8 years?"
Pause. At this point, I thought maybe the cousin on the other end of the phone was single. Until this:
"Oh, so you have had more sex with me than with your husband in the last 10 years?"
Woah, daddy. This is no longer PG-13. Kids, you better go now.

Remember, this is on the bus.

And there is more. Much more sordid, icky details (apparently the Mother with whom the conversation is to be held is very detail oriented, so they had to get specifics straight--barf). However I don't want to share those. What was I thinking during all this? It is kind of an interesting thing to share. Do not worry, I won't be detail oriented. For you business types (the one of you reading this) I will keep it at the 30,000 foot level and use broad strokes.

I started out thinking it was kind of a cute conversation about newly-weds.
--Nice. Flowers and honeymoon and happy new couple getting married,

I was shocked and seriously curious when the fact came out that this guy was discussing the discussion he would have with mom re: leaving his wife.
--Morbid curiosity, voyeuristic weirdness. But stronger still came the searing feeling of why on EARTH is he discussing this in public? He clearly has been having an affair and lying to is wife and others. And he is sitting here talking about it on the fucking bus! And then... it was strange. I dissociated my personal feelings from it and thought of it another way. And please do not read this thinking I condone this sort of behavior. I feel certain people who know me will know this, but I just want to make sure there is NO mistake, I don't like it. However, I started thinking something like 'wow, he doesn't care who is hearing this. He is sitting here making obviously a difficult choice and about to have an intense conversation and he seems so committed and accepting of his choice that he can sit and talk about it freely, with a bus load of people around. And while still in revulsion to the whole concept, I suddenly had this hint of admiration for someone who truly did NOT care for what the people around him thought. And I realized, then, that I have always had that admiration for people who, regardless of the popularity of their choices, can stand up and say what they think.


Its his freakin' cousin.
-Barf.


That conversation (mercifully) ended. He quickly scrolled through his contact list and found someone, a guy, and started talking to him. It sounded very businessy, talking about making deals, working deals, options still in the works, who can swindle who---this guy sounded like a big time business guy. And then I heard the names of several NFL stars.

Fantasy football???

He was talking about trading fantasy football players as if it was a big time business deal, at 6:50 in the morning, fresh off a conversation that I would have been sick to my stomach about for MONTHS. Well, let's face it, my life will never be in a position to have that sort of conversation. If it was, I would be such a wreck I probably would take a swig of some of the fine chemicals we have here in the lab. But I wouldn't hang up and then talk FANTASY FUCKING FOOTBALL.

Head spinning, I got off the bus at the medical center to go through my day of writing and analyzing, this guy walking in front of me. I wondered what he did during the day. I wondered what on earth his life had been like. I wondered, also, what the other people obviously hearing this conversation on the bus thought. I wondered if they thought like I did.

Eventually I stopped feeling unnerved by that guy and settled into work.

I can't help but wonder how that conversation with his WIFE is going to go.

Its ok, little mousie. Not many more of you have to die.

Generalizations

"Calendars are for careful people, not passionate ones."

~Chuck Sigars

I find myself here, yet again, looking back over the time I have not been writing on my blog, wondering why. Well, I know why: I have been working my skinny little butt off at school, in the hopes of finding, in the pitch black, the switch on the wall that makes this carnival ride stop... but its dark in here, and I can't find the switch so easily. The other part of my brain is warning me that the switch does not exist.

My general exam is coming in a few weeks, and I have already had a couple of interviews for jobs--kinda premature at this point, but for fuck's sake, I need something to keep my going. And besides; my general exam should have happened a year ago, so my work is practically done. I am really not worried about this exam--after everything they have thrown at me for so long, I am just trying to make my deadline and get this over with. I do not know what they could possibly do to me now. Besides keep me longer. And I don't honestly think they will.

DId you all read that? There should have been a giant gasp after that last sentence.

"What? You don't think they will keep you any longer just because its in their power?"
No. They would have to pay me. They like money and its too hard to come by. Therefore, its in their best interest to let me out now before I get vindictive.

I interviewed at a large multi-faceted company in North Chicago for what seems to be the ULTIMATE job that am looking for. The job is ideal, the company offers extremely good salary, cash bonus at signing, a pension plan, 401k with matching, and yearly bonuses. Holy shit, in the days of dreary outlook, even for people WITH jobs, HOW MANY COMPANIES OFFER THOSE THINGS???

But the reality of the situation is that I can not see myself living there unless I interview at a few other places and find out that THAT job truly is The One.

So I have been spending my time since that extremely motivating excursion (its motivating to be wined and dined by a large pharmaceutical company that is interested in me liking them as much as I am interested in them liking me) first scheduling and now writing my general exam. Its a beast. Its the sum total of my current value as a grad student. I am not scared, I can look back, finally, and see all the work that I have done and the data that work has generated and understand how it all fits together into a nice package. And it really does. And I created it--no one else on earth can say that they have done what I have done. No one. Thats pretty cool.

And I can not wait for it to be over.

Instead of gong home, playing and training and blogging with the girl, I sit ad write. I work late, I sneak in training while I work at school. I take my computer with me everywhere so I can sneak in a moment to write. I am doing experiments and tissue analysis and data analysis and creating vast incredibly organized spreadsheets that take 5 minutes to scroll through from 7 AM till 7 PM. Then I come home and eat dinner and walk the dog and go to bed and lay there thinking about the work I didn't get done and how best to attack it the next day.

No Seahawks, no blogging, no random bullshit. Work, work, work.

They finally got me, didn't they? And, yes, as a result, now its time to graduate.

But do not fear, the two of you reading this. Do not think that I have become a slave, because its not that at all, really. The end is near, and when it is upon us, we shall throw our hands in the air and party. We shall dance. We shall laugh and look back like everyone before me; with the hilarious rose-tinted glasses covering my bitter eyes, putting wise words of retrospection in my mouth, savoring the sheer moment of completion.