Drug absorption is the process by which a drug molecule moves from the site of administration to the systemic circulation. Following intravenous administration, there is no absorption process since the drug is directly introduced into the blood stream. However, for oral, intramuscular, subcutaneous, sublingual, buccal, transdermal, (and many other routes), there will be an absorption process that occurs. Since there are so many different variants of extravascular administration, let’s focus on oral administration to explain the concept of saturable drug absorption. Following ingestion of a drug capsule or tablet, the drug enters the gastrointestinal (GI) tract and begins to dissolve in the GI fluids and is absorbed into the body via passive and active transport systems. The drug then passes through the portal vein to the liver and then into the systemic circulation. If any of these processes becomes saturated, then increases in the administered dose will not correspond to increases in amount of drug absorbed into the body. This is called saturable drug absorption.
Dissolution
If the drug is poorly soluble in the GI fluid, then you may encounter saturation of the dissolution process. At some point, no more drug can dissolve into the GI fluid to be available for absorption. This results in a plateau in drug exposure where increasing the dose will not increase the exposure. Sometimes, dissolution can be aided by adding additives that assist in the dissolution process, or change the pH of the GI fluid to aid in dissolution.
Transport-mediated uptake
Some drugs are absorbed through transport-mediated uptake mechanisms. For example, valaciclovir is absorbed by active transport by the peptide transporter PEPT1. Drug transporters can be saturated if the substrate (drug) levels are sufficiently high. Once the transporter is saturated, no additional drug can be absorbed from the GI tract, even if it is available for transport. Similar to the example of dissolution, increases in the dose will not increase the exposure. These transport-mediated limitations are difficult to modulate without re-designing the drug molecule to take advantage of multiple transport systems.
Passive uptake
Most drugs are absorbed through passive mechanisms that are generally not saturable. These absorption mechanisms depend only on the available surface area of the GI tract and the strength of the concentration difference between the lumen of the GI tract and the portal vein. Thus, saturation of passive uptake mechanisms is very rare. On occasion, with very large doses, absorption can slow due to the large amount of drug present in a confined space. In general, saturable absorption does not occur in situations with passive uptake.
If you encounter saturable drug absorption, there is generally no harm because higher doses will not result in higher drug exposure. Understanding the type of saturation (transporter or dissolution) will be useful information to make a decision on the approach to address the issue. If the saturation is in the dissolution, it may be possible to address it with reformulation and addition of specific materials to help the drug dissolve in the GI fluid. If the saturation is due to transport-mediated uptake, there is not much you can do to change the outcome.
When you have saturable absorption, drug exposure will plateau at higher doses. When you have saturable elimination (or clearance), the total exposure will increase faster than dose at higher doses. By plotting the exposure (area under the curve or AUC) on the y-axis and dose on the x-axis, you can determine if absorption and/or elimination are being saturated across the dose range studied.
Drug developers frequently use in vitro-in vivo correlations (IVIVCs) to serve as a surrogate for human bioequivalence (BE) studies, support and/or validate the use of dissolution methods and specifications, assist in quality control during manufacturing and selecting appropriate formulations. Watch this webinar to learn about 2 important approaches to developing IVIVCs.