Drug Absorption and Distribution

Yup, I'm doing Pharmacology this semester :) This course starts off with ADME- Absorption, Distribution, Metabolism and Excretion. It's all to do with what happens to a drug once you put it into the body.

1) Explain what the term “pharmacokinetics” means and identify the 4 phases that control the fate of drugs in the body

"Pharmacokinetics" is essentially "what the body does to the drug." When you take a drug, it's not all about the effects that the drug has on the body (i.e. its pharmacodynamics)- the body may have to do stuff to it to get it to work, and the body will also have to do stuff to get rid of the drug later. The four phases are those mentioned previously: absorption, distribution, metabolism and excretion, all summed up with the acronym ADME.

2) Understand the process of drug absorption, the organs in which it occurs, the factors that govern drug uptake at absorption sites.

Absorption is the uptake of a drug into the systemic circulation. Uptake of many drugs occurs in the GI tract, since so many drugs are taken orally. Drugs are taken up into the cells through pretty much the same mechanisms in which nearly every substance is taken up into the cells: through diffusion, facilitated diffusion, active transport, phagocytosis etc. The factors that govern uptake are pretty similar to the factors that govern uptake of any other substance through these methods: highly polarised molecules don't diffuse well through the lipid membrane, facilitated diffusion and active transport require the presence of specialised proteins etc.

I'm now going to focus on three main factors that govern drug intake: size, solubility and external pH. I'll start with size: the larger the drug, the less well absorbed it is. Some dude called Lipinski once said that for optimal oral absorption, the molecular weight of a drug should be no larger than 500 g/mol.

Solubility is a bit more complicated. A highly hydrophilic drug will travel through the blood fairly readily, but it won't pass through lipid membranes as well. The opposite is true for lipophilic drugs. Most of the time, a happy medium needs to be found between these two extremes. There are two main measures used to estimate solubility in aqueous and lipid solvents: LogP and polar surface area.

LogP is the log of the partition coefficient of the drug. The partition coefficient is the ratio between the percentage of a drug that dissolves in water versus the percentage that dissolves in a lipid solvent such as octanol. LogP predicts the ability of a drug to cross a lipid membrane.

Polar surface area is simply a way at comparing the size of polar and non-polar areas on the surface of a molecule. (If you don't know much about polarity, check out my post on intermolecular bonding.) Usually this is done by a computer.

Some guy called Egan made a plot of the LogP and polar surface areas of many drugs on the market. He found that all drugs lie within a roughly oval-shaped plot on this graph. This is known as "Egan's Egg."

The reasons why external pH affects the absorption of a drug is pretty much related to the solubility. You see, many drugs have ionisable groups that may carry a charge depending on the pH (I've mentioned this before in a different context- see my earlier post on acid-base chemistry of amino acids.) If the drug is charged, then it is less likely to cross the lipid membranes of cells.

3) Understand the concept of a “prodrug.”

Absorption of drugs can be changed by adding different substituents to them. Different substituents can increase or decrease hydrophobicity (which is related to the ability to cross the membrane). The amount that the hydrophobicity increases or decreases is known as the hydrophobicity constant of that substituent.

These substituents can not only alter hydrophobicity on their own, but they can also have an effect by attaching directly to hydrophobic or hydrophilic groups originally on the drug, "masking" their effects. These "masked drugs" are also known as "prodrugs." When the drug enters the target cell, enzymes within the target cell can cleave off the groups to release the active drug.

An example of a "prodrug" is enalapril, which is a blood pressure medication. Enalapril is an inactive prodrug that contains an ester linkage at one point. Once in the body, several esterases can cleave this ester linkage to "unmask" an -OH group, forming enalaprilat, which actually does the job. Similar mechanisms can potentially also be used to ensure that drugs only have an effect in the target organ, if you can find "masking groups" that are only removed by enzymes in the target organ.

4) Explain what is meant by the term “bioavailability” and the factors that contribute to this process.

The bioavailability of a drug is the amount that reaches the systemic circulation. Of course, this is affected by the absorption processes outlined above. Bioavailability is also affected by the hepatic clearance of the drug (as stuff from the GI tract is taken to the liver for processing), though this is a topic for a later post.

A quick, somewhat important point to make is that the presence of active transporters in the GI tract may affect bioavailability. For example, p-glycoprotein is a transporter that transports many drugs back into the lumen of the GI tract. This is useful for protecting us against toxins, but not so useful when we actually want the drug to be absorbed and have an effect.

5) Show an awareness of the distribution of drugs within the body, and the tendency for particular drugs to accumulate in specific tissues.

As alluded to before, some drugs are more hydrophobic or hydrophilic than others. This can determine where drugs tend to "hang out." Hydrophilic drugs such as warfarin tend to stay in the blood and extracellular fluid and thus yield high plasma concentrations, whereas lipophilic drugs tend to yield much lower plasma concentrations as they are more readily absorbed by the tissues. This gives rise to a theoretical concept known as "Volume of Distribution" which can help to determine whether a drug is more or less readily absorbed by the tissues. Volume of Distribution can be calculated by dividing the dose in milligrams by the plasma concentration of the drug in mg/L:

Vdist (L) = dose (mg) / plasma concentration (mg/L)

Note that the volume of distribution is not an actual value, just an imaginary one to help us figure out where the drug goes. Some drugs have a volume of distribution much larger than the total volume of fluid in the body.

To explain how this concept "works," let's take a hypothetical drug that has a dose of 100mg and a plasma concentration of 10mg/L. That plasma concentration of 10mg/L is just like dissolving that original 100mg into 10L of water. Hence the volume of distribution is 10L.

Very hydrophilic drugs tend to have a low volume of distribution and are found mainly in the plasma, but as you increase the lipophilicity of a drug, the drug will find its way into interstitial and then into intracellular fluids, and so on.

Finally, a quick note on protein binding and how this affects where drugs remain. The blood contains several proteins such as albumin and alpha-glycoprotein, which help to carry drugs around the blood. Albumin mainly carries acidic drugs, whereas alpha-glycoprotein tends to carry basic drugs. This binding tends to confine the drug to plasma. It also makes extraction and excretion by the kidneys and liver a bit harder.

Tissues also have binding proteins of their own, and these can be especially significant in skeletal muscle for some drugs. The equilibrium between the free and bound drug in the tissues and plasma can complicate the distribution of drugs.

Some drugs, particularly very lipophilic ones, may also be stored in fat. This can cause issues in cases of obesity.