On 21 Mar 2007 at 22:25:00, "Walt Woltosz" (walt.-at-.simulations-plus.com) sent the message
The following message was posted to: PharmPK
An absorption window can be thought of as a window in time or in
distance (or location). I'm not fond of the term at all (I like "reserve length" even less), but if it must be used, I think it is more appropriate to think of it in terms of distance (from the pylorus) rather than time.
Most drugs are not absorbed in the stomach in any significant amount, so the opportunity for absorption usually begins with gastric emptying. Once the drug enters the small intestine, it enters an environment where six primary factors affect how well it will be absorbed:
(1) PERMEABILITY FOR PASSIVE DIFFUSION: Passive diffusion accounts
for most drug absorption, although in our experience, more and more carrier- mediated compounds seem to be appearing in discovery and development. The basic permeability will change with ionization and for some drugs, with tight junction gap (see 4 below). The permeability in jejunum is the standard for comparison, based on the compounds that were measured in human jejunum by Hans Lennernas and Gordon Amidon for the Biopharmaceutics Classification System. Human jejunum effective permeability (Peff) is often estimated from cell culture experiments or in silico predictions, and then for simulations, permeabilities in other regions of the intestinal tract are adjusted as required to account for the factors listed below.
(2) TRANSPORTERS: If the drug is a substrate for carrier-mediated
transport, passive diffusion will be supplemented or hindered by the local expression level of the transporter(s), which may differ along the intestinal tract (e.g., PepT1 or bile acid carrier for influx transport, or P-gp for efflux transport). For influx transporter substrates, regions with high transporter expression will have high permeability, while other regions may be much lower. For efflux transporters, regions with high expressions will have reduced permeability unless the transporters are saturated. For P-gp substrates, most marketed drugs that are P-gp substrates easily saturate the transporter, so the effect is small.
(3) LOCAL PH: The local pH in any region affects both solubility and permeability, and for some drugs, degradation rate.
If the drug has low solubility, it may not dissolve quickly at the pH in some regions, and in fact it may precipitate. For example, a base (especially with a pKa below about 6) that is completely dissolved in stomach (pH < 2) may precipitate when it transits into the small intestine and colon (pH 4.5-7.8). During fed state, this may be offset in the proximal
small intestine due to the presence of bile salts. Precipitation can be fast or very slow, so this effect may be significant for one drug but not for another that can remain supersaturated for a long time.
As the degree of ionization changes with pH, regions with pH that cause ionization to be higher would expect to show lower passive permeability. Note that for low solubility drugs, this may be offset by an improvement in solubility. Of course, if the drug is completely in solution, then only a decrease in permeability might be observed.
Some drugs are degraded in the lumen in a pH-dependent manner (e.g., Valacyclovir). For such drugs, some regions may cause rapid degradation, while others may show little or no degradation. Degradation can be avoided by formulating so that the drug is not in solution in regions of high degradation rate, but is released/dissolved in a more favorable region.
(4) TIGHT JUNCTION GAP: Some drugs (e.g., atenolol) are absorbed
primarily via paracellular transport. The tight junction gap in the proximal small intestine is the widest, narrowing as the distance from the duodenum increases, and much less in colon. For such drugs, if they are not in solution in regions with sufficiently large tight junction gap, then the opportunity for absorption is decreased dramatically.
(5) SURFACE AREA: The overall absorbing surface area in the small
intestine and colon decreases aborally. I don't think this is the cause for the appearance of an "absorption window" because these changes are gradual in the small intestine. Because the colon does not have villi (only microvilli), the surface area in colon is much less than in small intestine, so a drug that is poorly absorbed in colon might have the entire small intestine as its "absorption window"
(6) RESIDENCE TIME IN THE ABSORBING REGIONS: For drugs that are
affected by any of the above factors, the amount of time the drug is in solution in the region(s) that favor absorption will be important. Transit times vary widely among subjects and within subjects, so data for such drugs can be problematic to analyze due to high variances likely to be encountered over multiple data sets.
A further complication is that what is often called an "absorption window" is actually a "bioavailability window".
The modern definition of absorption is entering the apical membrane of the enterocytes (or the paracellular pathway beyond the tight junctions).
Drug that has left the lumen has been absorbed, regardless of what happens to it after that. Drugs that are metabolized in the gut wall (e.g., by 3A4) may be well absorbed, but poorly bioavailable (e.g., midazolam and saquinavir).
Because the expression level of 3A4 is highest in the proximal small intestine, and decreases rapidly with distance from the pylorus, drugs that are substrates for 3A4 metabolism may exhibit a "bioavailability window" that begins after the 3A4 expression level has dropped.
Oral absorption can be complex, but fortunately for most drugs, only one complexity at a time is an issue. Now and then we see drugs with
combined effects, such as Valacyclovir, a drug which undergoes pH-dependent degradation that is also a Pept1 substrate and an HPT1 substrate, or a drug like saquinavir, which is both a 3A4 substrate and a P-gp substrate.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
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