8The Lipid Solubility, Diffusion Through Membranes and Drug Distribution Page!
Biological membranes exhibit semipermeability (selective permeability). Membranes tend to exclude certain substances from entering or leaving a cell. As the majority of the surface area of a membrane is composed of phospholipids, substances diffusing through membranes must have some degree of lipid solubility. Thus, the factors that determine the ability of a substance to diffuse through membranes are the factors which determine the lipid solubility of the diffusing substance. Ultimately, these factors determine the rate of absorption and extent of distribution of drug molecules in the body.
8Some factors determining lipid solubility and extent of drug distribution throughout the body are:
i) chemical nature of the molecule (brief explanation)
ii) atomic or molecular formula weight (directly proportional to size) (brief explanation)
iii) valence or charge (polar versus nonpolar) (brief explanation)
iv) sphere of hydration (charge density and effective diameter) (brief explanation)
v) prevailing concentration gradient (slope or steepness of the gradient) (brief explanation)
vi) pKa of the diffusing substance and the pH of the environment (brief explanation)
vii) route of administration (brief explanation)
8Diffusion Coefficient and Apparent Volume of Distribution: Lipids (fats), including steroid hormones and lipid soluble vitamins are described as "fat soluble." The steroid hormones are small, uncharged, cholesterol-based molecules which diffuse easily through membranes. The lipid solubility of drugs, toxins, nutrients and vitamins are often expressed as "diffusion coefficient" or "apparent volume of distribution" (Vd). The diffusion coefficient refers to the rate of diffusion of a given molecule through vegetable oil, usually corn or peanut oil (as lipid solubility increases, the diffusion coefficient increases from 0 to 1; substances with diffusion coefficients approaching 1.0 are highly lipid soluble and easily diffuse across membranes).
8Remember that a drug is not said to have entered the body until it enters the bloodstream. That means that drugs appear first in the plasma, next in the ISF and finally in the ICF.
The apparent volume of distribution (Vd) is a bit more complex. Vd indicates the theoretical volume of water in which a drug would have to be distributed if the drug was distributed evenly and at the same concentration found in the bloodstream (plasma). That sounds complicated... and it can be... and here is why. Some drugs are so highly lipid soluble that they quickly leave the bloodstream and enter adipose cells. Drugs with very high lipid solubility, then, may quickly and nearly completely evacuate the bloodstream. The result is that the concentration of the drug is so low in the bloodstream, that if the drug were "really" to be evenly distributed in solution at the same concentration as found in the bloodstream, the drug would have to be distributed in a theoretical volume of water many times greater than the actual volume of fluid in the body... and this is where the term "apparent" volume of distribution comes from... because sometimes, the "apparent" volume of water required would be greater than the amount of water present in the body.
Determining the Apparent Volume of Distribution (this particular
paragraph is intended to be of interest to those with great interest in
math or pharmacology)...
We can determine apparent volume of distribution (Vd) by dividing the dose of drug administered by the amount of the drug in the bloodstream following distribution of the drug.
Suppose that we injected someone with a total "dose" (i.v. bolus) of 10 grams of aspirin. Following distribution, we found a plasma concentration of 0.5 mg/ml in plasma. If we divide 10 g (10,000 mg) by 0.55 mg... that is a dilution factor of... 10,000 divided by 0.5 = 20,000. But we know that a mg of water has a volume of 1 ml. That means... our drug must have been distributed to a theoretical volume of of 20,000 ml's or 20 liters of water. Our patient had a body mass of 50 kg. When we divide the theoretical volume of water in which the aspirin was distributed (20 L) by the mass of the patient (50 kg), we get a theoretical volume of distribution of 0.4 L/kg of body mass.
Think about the value of 0.4 L/kg of body weight... we know that the average human is about 55% water... which would represent 0.55 L of water per kg of body weight... if we divide 0.4 L by 0.55 L... that gives us a value of 0.73... or 73%... telling us that aspirin is distributed to about 73% of the water in the body... that is a fairly well distributed drug, but certainly not a highly lipid soluble drug... Now... if we determined a volume of distribution in excess of 0.55 L per kg, that is a very well distributed drug. If apparent volume of distribution increased beyond this level... to 1.0 L per kg of body weight or more, we could assume that the drug in question is a very highly lipid soluble drug, and is accumulating in fat tissues.
But determining a specific moment at which to take a measure of concentration of the drug in the blood is impossible. So, to get around this problem, we take multiple measures of the drug concentration in the blood, and then multiply the area under the concentration versus time curve by the linear portion of the curve showing elimination rate of the drug from circulation. Alternately, we can use the flat, terminal portion of the plasma drug concentration line to extrapolate back to a hypothetical blood concentration at time zero (the moment of administration), and simply divide the dose of drug administered by this extrapolated zero time value.
Despite the fact that determination of an accurate apparent volume of distribution (Vd) requires some mathematical expertise, the concept is actually a simple and very useful one. The more lipid soluble the drug, the faster that drug will diffuse out of the bloodstream and the higher will be the Vd. We typically express the Vd in terms of volume per kg body weight (L/kg)... so that most Vd's fall between 0-1 L/kg. If a drug has a Vd of 1.0 L/kg, it is much more lipid soluble than a drug with a Vd of 0.5 L/kg. Recognize, however, that you don't have 1 L of water per kg of body mass, because 1 L of water has a mass of 1 kg, and we already know that our body is not composed of 100% water... so such a high value for Vd (1 L/kg) would tell us that the drug is very lipid soluble, and would readily pass through cell membranes to reach intracellular sites of action! Aspirin, for example, has a Vd of 0.4 L/kg.
8Note about gases: Most gases diffuse easily through aqueous solutions and membranes, although some diffuse more easily (eg. CO2 is about 20 times more diffusible in water than is O2). This is great in terms of delivery of O2 and removal of CO2 but causes problems when people are exposed to toxic gases, which also diffuse easily into the tissues.