DRUG DISTRIBUTION

What happens when a drug is distributing between two compartments in the body (between the stomach and blood, or the bowel and blood, for example)?

Here, we look at how much of the drug is in the permeant form. If the drug is in the permeant form in the stomach it can get through the wall and into the blood. Once it gets into the blood, if it stays in the permeant form it will just shuttle back and forth—this is not absorption. If, however, the drug is converted to the impermeant form in the blood, it won’t be able to cross back over and will be trapped in the blood—this is absorption. The drug must be permeant in the stomach, and impermeant in the blood to be defined as well-absorbed.

Example :

If we have a weak acid, put it in the stomach (pH= 1.4), and the drug pK_a is 4.4, what percent is in each form?

-pH is less than pK_a (acidic) means an excess of protons, so most of the drug will be protonated.

-What % will be in AH form?

We are 4 pH units more acidic than pK_a, so that means that 99.9% is in the AH form (permeant) in the stomach. So it can pass into the plasma.

-Once the permeant form is in the blood, it will re-equilibrate (deprotonate) into the A^- form… how much?

-We can assume that [AH] comes to equilibrium across the membrane. ----The pH in the blood is 7.4, so our weak acid will deprotonate, immediately converting to the A^- form. In the deprotonated form, A^- is not able to cross back over the membrane and is thus stuck in the blood.

-We can calculate that the [A^-] is 1000% more prevalent in the blood than the [AH] form.

What if we had a weakly basic drug?

The reverse process would occur; BH⁺ would deprotonate to B, and B would be the permeant form. In blood, 99.9% would remain as the permeant form, and the drug would go back across the membrane and not be absorbed in any discernable amount. You can’t have absorption of a weakly basic drug in the stomach if its pK_a is much less than the pH. If you injected the drug into the blood, it would get excreted into the stomach!

The general rule is that drugs get trapped in the compartment that they are ionized. That way they’re impermeant. This translates into the fact that weak acid drugs accumulate in the more alkaline compartment, whereas the weak base drugs accumulate in the more acidic compartment.

Category: Pharmacology Notes