**8****The 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.

**8**Some 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)

**8****Diffusion 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" (V_{d}). 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).

**8**Remember 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 (V _{d})** is a bit more
complex. V

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 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 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 . 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 well distributed
drug, and is accumulating in fat tissues.a very highly lipid soluble
drugBut 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
Despite the fact that determination of an accurate _{d}. We typically express the V_{d}
in terms of volume per kg body weight (L/kg)... so that most V_{d}'s
fall between 0-1 L/kg. If a drug has a V_{d} of 1.0 L/kg, it is
much more lipid soluble than a drug with a V_{d} 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 V_{d} (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 V_{d} of 0.4 L/kg. |

**8****Note about gases**: Most gases diffuse easily through aqueous solutions and membranes, although some diffuse more easily (eg. CO_{2} is about 20 times more diffusible in water than is O_{2}). This is great in terms of delivery of O_{2} and removal of CO_{2} but causes problems when
people are exposed to toxic gases, which also diffuse easily into the tissues.

Copyright © 2000. All rights reserved.

Revised: January 05, 2009