Many physiological factors affect and alter drug absorption from the g.i. tract. Ionization, the conc. of free and bound drug, solubility, formulation etc. But isn't it true that more there is free unionized unbound portion of a drug available, more of it is rapidly metabolized and exerts its toxicity? Plasma protein binding reduces the free concentration of drug. If more of the active ingredient (herein drug) is present unbound to plasma protein (in free state), does it mean that a much greater amount of it will be rapidly absorbed from the gastrointestinal tract? But why this is reverse in the case with unionized drugs?
Dear Sidharta,
The reduction of the amount of free unionized drug due to plasma protein binding enhances its absorption from the g.i. tract because the absorption of a drug from the G.I follows Fick's low:
Absorption from the G.I. =K x (concentration in the GI (out) -concentration in the blood (in)
If concentration (in) is reduced the absorption is increased.
Hoping this will be helpful,
Rafik
Dear Sidharta,
The reduction of the amount of free unionized drug due to plasma protein binding enhances its absorption from the g.i. tract because the absorption of a drug from the G.I follows Fick's low (passive diffusion):
Absorption from the G.I. proportional to (concentration in the GI (out) -concentration in the blood (in)
If concentration (in) is reduced the absorption is increased.
Hoping this will be helpful,
Rafik
Thanks Dr. Rafiq for your explanation. So it follows Fick's law.
Dr. Hussain is correct to specify some error in the question. It confused me when I came over this concept of protein bound drug in the GI. Kindly refer to this statement at the bottom of the page 12 of this edition, a widely followed book in the curriculum: it clearly says that if the concentration of the drug is reduced due to protein binding, its absorption in the gut lumen is increased.
In authors' (Prof.Satoskar & Bhandarkar's) words: "If the plasma concentration of a drug present in a free, unionized form is rapidly reduced by binding with plasma proteins, its absorption from the gut lumen is enhanced"
As Dr. Rafiq explained above, this corresponds to Fick's law wherein if the concentration of a drug is reduced, its absorption is enhanced.
https://books.google.co.in/books?id=7d493VOD4P8C&printsec=frontcover#v=onepage&q&f=false
Best Regards,
Sidharta
Dear Dr. Hussain,
Specifically, are you saying that the concentration of unbound drug or free drug with respect to the portion bound to plasma? Assume a drug (unionized) ingested in time T1 has a plasma concentration of C at time Tt+1 and then binds to plasma protein which reduces its free concentration to C-Cf which is Cb that is bound to plasma proteins. Most drugs have a high affinity for plasma proteins. So the full concentration of the drug is say, C=Cb+Cf
Perhaps the author mentions about that portion of the drug which is still unabsorbed from the g.i. tract.
Here comes the role of saturation kinetics which states that when a large amount of drug floods the blood, its fractional binding may be lower. The bound fraction is in equilibrium with the free drug, so when the concentration of the free drug is reduced by metabolism (or excretion), the bound fraction dissociates. The author confuses at this point.
When will be the concentration of the free drug in the GI tract higher?
The role of diffusion kinetics: if the concentration of the free drug in the GI tract is higher than the concentration of free drug in the plasma, then the drug will diffuse inside / taken up from the GI lumen. This concept may be accepted.
3. So, we are comparing and compartmentalizing the concentration of the drug into 3 compartments:
i. plasma bound
ii. free drug in plasma
iii. drug in the GI tract (assuming enterohepatic circulation). Now, this last fraction, how can this drug be in a “free” state?
This may depend on:
- At what rate the drug is extracted by the liver?
- If a small fraction of highly protein bound drug is displaced, the concentration of the free form will double, and so will diffuse into tissues or get metabolized and excreted. So, from where will the unbound free fraction in the GI tract come from?
It is really confusing, but interesting as well.
Regards, Sidharta
I couldn't find it after browsing the book (not all pages are available though), but I'll be back with the more advanced edition of this book or relevant papers of the authors related to this topic (if available). Anyway, in conceptual paradigm, it is well accepted that non-ionized (unionized) drugs are absorbed better from the upper g.i. tract (weak acids like aspirin absorbed better from the stomach) and weak bases (unionized) absorbed better from the alkaline environment of the intestinal lumen. The author refers to unionized drug (perhaps basic drugs) which are readily absorbed from the lumen, and if the concentration of the free form is reduced in plasma, its absorption is enhanced. According to your statement, it is not correct to expect that the drug will "sit" in its unionized form and has a window of absorption. Can you clarify a bit about this window of absorption? Also, what potential changes can occur to an unionized drug in the g.i. tract during its transit?
Regards, Sidharta
Yes Prof. Hussain it is indeed pleasant corresponding with you, since I could learn more about the subject matter from an expert like yourself.
BTW, it appears that the absorption of aspirin is not just confusing, but intriguing. A drug in unionized form is more lipophilic, so it is expected to be absorbed better from the small intestine (in case of basic drugs). As you have mentioned why aspirin in solution form is rapidly absorbed from the stomach, I think it is due to the fact that since it becomes more neutral, its permeability is enhanced, but again this is confusing regarding its solubility, since solubility is favoured by charged form. Aspirin is given in a solution to make it more charged and render it soluble, but then it will not be highly permeable through the stomach lining (since it is not neutral). Just my guess, perhaps it is transformed into neutral form which increases its permeability.
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