As defined in FDA guidance, bioavailability is “the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action.” While the definition appears sufficient, there a level of ambiguity in the scientific literature has led some people to confuse oral absorption with oral bioavailability. Because the terms are often erroneously used interchangeably, it is necessary to define them separately in order to clearly distinguish one from the other.

The best way to understand these terms is to understand the barriers a drug molecule must cross to get from the dosage form in the gut to the bloodstream. While the primary physiological barriers are the gut epithelium and the liver, each of these comprises multiple components. In addition, since drug can only be absorbed in its molecular form, dissolution and maintenance of the drug in a dissolved form comprises a third de facto barrier.

Imagine that we follow a drug from the time it is swallowed as a tablet to the time it enters the bloodstream. The first step in its journey is a quick trip down the patient’s esophagus, usually in the company of a healthy gulp of water. In the stomach, the tablet starts to erode and/or split apart, releasing small grains of drug, and these grains begin to dissolve to release drug in its molecular form. The extent of dissolution depends on how the tablet is formulated and on how soluble the drug is in stomach acid, and on intrinsic kinetic factors.

Dissolution will continue as drug particles pass out of the stomach into the upper duodenum, but the solubility of the drug may change due to the higher pH of the duodenum relative to the stomach, and this trend will continue as the drug migrates further down the intestines and the pH increases further. Some weak base drugs that dissolved freely in the low pH of the stomach may actually precipitate back out due to the higher pH. In other cases, drug molecules may adsorb onto food particles and simply be carried through the intestinal tract and, along with any undissolved drug, eliminated in the stool.

The gut epithelium is composed of a monolayer of cells specialized for efficient but somewhat selective transfer of molecules from the intestinal lumen to the blood. Although there are several mechanisms by which nutrients pass across the epithelium, almost all drugs cross the barrier by passive diffusion, meaning that a drug molecule diffuses through the cell membrane on the luminal side, across the cytoplasm, and then back out of the cell through the opposite cell membrane. Since the drug is already in solution, the primary barrier to transport is not the aqueous cytoplasm but the lipidic cell membranes. Charged and other highly polar molecules will not readily diffuse into the cell membrane and are therefore poorly absorbed unless they are substrates for active transporters or, under specific conditions, can pass through the junctions between cells (paracellular transport).

Fifty years ago, the intestinal epithelium seemed like a fairly simple barrier, but scientists have come to appreciate its complexity. For example, many drugs are extensively metabolized by cytochrome p450s and other enzymes present at the epithelium. Additionally, p-glycoprotein and other efflux pumps are expressed in intestinal cells, and these specialized transmembrane proteins function to push molecules back out of the epithelial cells into the intestinal lumen. Thus the intestinal barrier is both physical and biochemical.

Although the term bioavailability is frequently misused, it is quite strictly defined when used correctly. Intestinal absorption, however, is a bit more ambiguous, largely due to the different systems that may be used to measure it, which range from cultured cell monolayers, to excised animal intestines to live animals with portal vein sampling. The expression of metabolic enzymes and efflux pumps varies from species to species and from cell type to cell type. Additionally some components of the epithelial barrier, such as the mucous layer that protects the cells from the intestinal contents, may not be present in monolayer systems but will be in systems that use full intestines or pieces of excised intestine. Additional layers of complexity are added if absorption is determined in vivo by sampling from the portal vein. Each system will give a different answer for intestinal absorption and so the term needs to be interpreted in the context of how it is reported.

Once across the intestinal epithelium, some highly lipophilic drugs may enter the lymphatic system, but the vast majority of absorbed molecules end up in the portal vein, the role of which is to provide direct transport to the liver. The liver has two primary functions that reduce the bioavailability of drugs beyond the intestinal barrier. The first function of the liver is metabolism, whereby drugs are chemically converted, most commonly to more hydrophilic entities that can more readily be excreted. The second function is biliary excretion, whereby drugs and/or their metabolites are expelled into the bile to be transported back into the intestinal lumen through the common bile duct. To further complicate the picture, drugs excreted unchanged in the bile may be re-absorbed in a second trip through the intestinal tract.

Oral bioavailability can be thought of as the total amount of drug taken by a patient in a pill, capsule or liquid minus the amount that does not dissolve or precipitates back out, minus the amount that gets metabolized before it is absorbed, minus the amount that is spit back out by efflux pumps, minus the amount that is simply not absorbed, minus the amount that is metabolized in its first pass through the liver, minus the amount that is excreted in the bile but is not reabsorbed in its next trip through the intestines. But, of course, pharmacokineticists do not measure each of those parameters individually to obtain an overall value for oral bioavailability.

Oral bioavailability is the percentage of the total dose that reaches the bloodstream, but it does not all reach the bloodstream at once, and so one cannot simply take a blood sample, find out how much drug is in it and divide that amount by the dose. In practice, oral bioavailability is determined by comparing the overall profile of drug in the bloodstream following oral administration to the overall profile of drug put into the bloodstream directly by intravenous injection. This is done by determining the area under the blood concentration versus time curve (AUC) for both routes of administration and dividing the dose adjusted oral AUC by the intravenous AUC. The AUC is determined by integrating the curve of blood concentration versus time, essentially breaking the curve into small time intervals, calculating the product of interval duration and average concentration for each interval, and then summing all of these products over a period of time adequate to describe the overall concentration time relationship.

The concept of oral bioavailability is critical to the study of clinical pharmacokinetics of drugs on the market or under development.

Just as importantly the bioavailability of an active molecule at the discovery stage is a key determinant of whether its development as an oral dosage form is feasible. To some extent poor oral bioavailability can be compensated for by increasing the dose of a drug administered, but this carries significant risk, especially for drugs that have very low oral bioavailability. For example, if a drug is only 5% bioavailable, that means that 95% of the drug is blocked from reaching the bloodstream by poor solubility, poor intestinal permeability, extensive metabolism, efflux, or a combination of factors. If a patient is just slightly deficient in one of these factors such that only 90% is blocked, then twice as much drug will get into his bloodstream, and, in some cases, this could be toxic. When prescribing a drug that has both poor oral bioavailability and a narrow therapeutic window, a doctor must consider factors such as expression of metabolic enzymes and liver and kidney function when determining the appropriate dose.

Whether oral bioavailability can be improved depends on the reason it is limited in the first place. If a drug’s bioavailability is limited by its solubility, the formulator may reduce the size of drug particles to increase dissolution, include excipients that help solubilize the drug, present the drug in a pre-solubilized form, or target drug release to gastrointestinal region where the drug is more soluble. If a drug simply has poor permeability, it may be possible to improve oral bioavailability by formulating the drug with agents that enhance absorption by other mechanisms, such as paracellular transport. If oral bioavailability is limited by metabolism or efflux, it is theoretically possible to include inhibitors of these functions in the dosage form, but this is generally not done due to safety concerns.

For drugs that are active systemically, oral dosing is almost always preferred due to the ease and comfort of swallowing a pill versus receiving an injection. As such, oral bioavailability is a critical attribute of a drug substance that should be studied early on in the process and should be considered along with pharmacological and toxicological factors when selecting lead drug candidates. While it is relatively simple to administer a solution or suspension of drug to an animal and collect blood samples for pharmacokinetic analysis, a more thorough evaluation should include in vitro as well as in vivo studies as well as some formulation exploration and pharmacokinetic modeling. These additional studies will help elucidate the mechanisms underlying the bioavailability limitations, which is key to understanding whether bioavailability can be improved and how variable it is likely to be in the patient population.

Smaller discovery stage companies should consider enlisting the services of a pharmaceutical consulting company to oversee the various studies needed to assess bioavailability and determine the potential for improvement through formulation design. Since such studies encompass a variety of disciplines, the project management services provided by such a company will also be critical in keeping track of all the moving pieces.

While various alternative routes of delivery have been studied for systemic delivery, it is unlikely that any will ever compete with oral delivery as a preferred route. Despite the complex processes involve, it is still the most convenient way of taking medicine for the majority of the patients, and since the gastrointestinal tract’s natural function is absorption into the bloodstream, oral dosing offers the best opportunity and the lowest risk. Because of this, oral bioavailability will remain a factor at the forefront of drug discovery and drug product development.

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Bruce Rehlaender, Ph.D., Principal, Formulation Development, PharmaDirections, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We direct development for virtual biotechs.

Bruce Rehlaender, Ph.D., Principal, Formulation Development at http://www.PharmaDirections.com, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We design and direct preclinical programs for biotech.

Author Bio: Bruce Rehlaender, Ph.D., Principal, Formulation Development, PharmaDirections, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We direct development for virtual biotechs.

Category: Medicines and Remedies
Keywords: Pharmaceutical Consulting, Project Management, Formulation Development, Preclinical, CMC