The pharm + tox lecture series: #3 - Distribution, putting the D in ADME

To recap: Pharmacologists use a cute little acronym, ADME, to describe the path that a drug takes through the body: Absorption into the bloodstream, Distribution to the tissues, Metabolism in some of those tissues to produce metabolites, and finally Elimination in body wastes like urine and poop.

Heh. I said poop.

Today is distribution day. Well, make that more like absorption and distribution day. Allow me to explain.

Most routes of administration involve the delivery of a drug into the body at a site removed from the bloodstream. Hence the drug must pass across cell membranes (including those of the cells that make up the walls of blood vessels) to reach the systemic circulation (i.e. the bloodstream). Once it gets there, it must again pass through cell membranes to exit the blood and enter tissues (and organs, which are a specialized collection of tissues), this being the process of distribution.

All of the fluid in the body (referred to as the total body water), in which a drug can be dissolved, can be roughly divided into three compartments: intravascular (blood plasma found within blood vessels), interstitial/tissue (fluid surrounding cells), and intracellular (fluid within cells, i.e. cytosol). The distribution of a drug into these compartments is dictated by it's physical and chemical properties. I'm gonna discuss a couple of these.

Relative solubility is the solubility of a drug in lipid, which is the primary component of cell membranes, relative to it's solubility in water, the primary component of body fluids. This can be measured by mixing a known amount of drug with equal parts oil and water, and then determining the ratio of the drug concentration in the oil to that in the water (this can be accomplished easily using a radiolabeled drug). This ratio is called the partition coefficient (Po/w) and can be used to determine where a drug likes to go in the body. Any drug with a Po/w greater than 1 is generally going to be capable of rapidly passing (diffusing) through cell membranes with relative ease, and so will likely be found throughout all three fluid compartments. Drugs with low Po/w values (meaning that they are fairly water-soluble) are often unable to appreciably enter the intracellular fluid compartment and require more time to distribute throughout the rest of the body.

The size of a drug also dictates where it can go in the body. Most drugs have molecular weights between 250 and 450 Da. Antibodies and other recombinant proteins and peptides like ADH or insulin range into the thousands of daltons (insulin is about 6000 Da). Tiny drugs (150-200 Da) with low Po/w values (meaning that they are quite soluble in water) like caffeine, furosemide, and ephedrine are able to passively diffuse through cell membranes via water channels called aquaporins. Drugs over 200 Da with low Po/w values cannot passively cross membranes and so require specialized protein-based transmembrane transport systems. Their distribution throughout the compartments of the body tends to be slower. Drugs under a thousand daltons with high Po/w values are able to simply diffuse between the lipid molecules that make up membranes, while anything larger requires specialized transport.

5 chemically inspired comments:

Toaster Sunshine said...

This brings to mind a question:
Can a molecule native to the body administered exogenously be considered a drug? Or is it just a supplement? Specifically, this calls to mind hormone analogues, such as GH, or allergy medications, such as pseudoepinephrine.
Are multi-drug G-protein-linked receptors/transporters useful in drug design or are they limited in scope?

Chris said...

Hey toast.

Yes, a molecule that we produce naturally can be considered a drug. A drug, broadly defined, is any molecule that produces a biological effect. Hormones like ADH, GH, or insulin, which we usually produce naturally, are indeed drugs.

The Wikipedia article on G protein-coupled receptors (GPCRs) claims that they are the target of approximately 50% of all modern drugs. Given that many hormones and neurotransmitters, which represent important starting points for drug development, act via GPCRs to produce their effects, I'd say they are pretty darn useful.

aaron said...

It seems significant to me to note that many drugs have more than one means of effecting cells. Two examples I can think of are THC and ethanol, which bind to CB receptors and a GABA sub-site respectively, but are also able to just cross the cell membrane, because they are lipid enough (THC) or small enough (ethanol).

Chris said...

Hey aaron. You are correct, drugs can do all sorts of things to cells, from binding to receptors (like THC and ethanol binding to certain membrane receptors, as you mentioned) to inhibiting certain enzymes (e.g. penicillin and bacterial transpeptidase) to crazy stuff like modulating gene expression (e.g. tretinoin and the PML-RAR fusion gene in a particular form of leukemia called AMPL). I'm only covering the path that drugs take through the body right now, but I'll get to the pharmacodynamics, or effects of drugs, side of things soon.

Peter Lund said...