Pharmacokinetics: Drug absorption and distribution

Pharmacokinetics refers to the movement and modification of a medication inside the body. In other words, it’s what the body does to a medication and how it does it. Okay, first things first. A medication needs a way to be administered, or a route of administration. Depending on the form of the chemical preparation, like a pill, solution, spray, or ointment; and the part of the body being treated, the medication can be administered through various means or routes: such as swallowed by the mouth or orally, injected into a vein or intravenously, injected into a muscle or intramuscularly, inhaled into the lungs, sprayed into the nose or nasally, and applied onto the skin or cutaneously. Once a medication is administered, it first has to be absorbed into the circulation; then distributed throughout the body; metabolized or broken down; and finally, eliminated or excreted in the urine or feces. This process can be broken down into four components with the acronym ADME; which stands for Absorption, Distribution, Metabolism, and Elimination.

Okay, so let’s start with absorption. Absorption is the process of moving the medication from the site of administration into the circulation. With the exception of intravenous administration, a medication will need to cross one or more cell membranes before it reaches the circulation. Movement across the cell membrane can occur via passive transport, which requires no energy, and active transport, which requires energy in the form of adenosine triphosphate, or ATP. Two types of passive transport are used; facilitated diffusion and passive diffusion. Facilitated diffusion helps larger, water-soluble, and polar medications move across the membrane through transport proteins like channels and carrier proteins. Passive diffusion helps small, lipid-soluble, and nonpolar medications move across the membrane, from an area of high concentration to low concentration.

But sometimes active transport is needed, meaning that the medication is transported against their concentration gradient. This involves specific carrier proteins that use ATP as a fuel to pump medications into the cell. Now, sometimes medication molecules are so large that the cell resorts to bulk transport, also known as endocytosis, where the cell membrane invaginates and swallows up the medication forming vesicles. Now, the rate of the absorption, or how quickly this process occurs, as well as the extent of the absorption, or how much of that medication reaches the bloodstream, depend on several factors. One of them is the pH of the environment where absorption takes place. Okay, so most medications are either weak acids or weak bases, and can exist in an uncharged or charged form. The uncharged form is the lipid soluble, non-polar one, which happily diffuses through the cell membrane, while the charged form is water-soluble and polar, and thus cannot diffuse through the cell membrane easily. The ratio between the two forms is determined by the pH of the environment and the strength of the weak acid or base.

The strength is measured by pKa, which is the pH value when concentrations of the uncharged and charged forms equal each other. So, when the charged form of a weak acid, A-, shows up in an acidic environment with a lower pH and plenty of hydrogen H+ ions around, it will grab one of them and turn into its uncharged form HA. HA can then be readily absorbed across the cell membrane. On the flip side, if the charged form of a weak base, BH+, is placed into an alkaline environment with a higher pH higher and a lack of hydrogen H+ ions, it’s going to give up its own hydrogen H+ ion and become an uncharged B. It can then pass through the cell membrane just like HA. So in other words, weakly acidic medications will be better absorbed in an acidic environment, like the proximal duodenum, in contrast to weakly basic medications which are more likely to get absorbed in an alkaline environment, like the distal ileum of the small intestine. Note that even though the stomach is acidic, it’s not suitable for the absorption of even weak acids mainly because of its thick mucus layer. Okay, now another factor influencing absorption is the surface area available. A good place for absorption is the small intestine, with its circular folds, villi, and microvilli, the total surface is actually about 250 square meters, the size of a tennis court. Other factors also include the blood supply to the absorption site, and the presence of food or other material in the gastrointestinal tract that can either promote or inhibit absorption.

So, after a medication is taken by mouth, it gets absorbed through the walls of the small intestine and transported into the liver via the portal vein. Once in the liver, hepatic enzymes work on the medication to metabolize it; this process is known as first-pass metabolism or first-pass effect and is responsible for breaking down most medications into their inactive metabolites, as well as converting certain prodrugs into their active metabolites, before entering the general circulation. This however means that if a medication is taken orally, and it undergoes extensive first-pass metabolism, their concentration in the bloodstream can get so reduced that once they reach their site of action they can’t produce the desired effect. In that case, alternative routes of administration should be considered, including intravenous, intramuscular, transdermal, sublingual, or inhalational administration. What these do is bypass the first pass effect, allowing medications to go straight into the systemic circulation and produce their effect.

Okay, so, this brings us to the concept of bioavailability. Bioavailability or F is actually the fraction of an orally administered medication that eventually reaches the circulation in the unchanged form. For example, if someone takes a 100 mg of pantoprazole orally, and only 77 mg of this is absorbed into the circulation, the bioavailability is 0.77 or 77%. In contrast, if the same 100 mg pantoprazole is taken intravenously, all of it goes directly into the circulation, bypassing the gastrointestinal absorption and first pass metabolism. So medications administered intravenously will always have a bioavailability of 1 or 100%. Let’s plot all this into a nice graph to show the relationship between time on the x axis, and the plasma concentration of the medication, on the y axis, after both oral and intravenous administration. Thus bioavailability of an oral medication can be estimated by dividing the area under curve or AUC for short of the oral form by the AUC of the intravenous form. And both AUCs need to be corrected by the dose of medication or D for short, administered orally and intravenously. So the bioavailability F of a medication is AUCOral x DIntravenous/ AUC Intravenous x DOral.