Absorption
This is the movement of drug from the site of administration into the systemic circulation. After IV (or intra-arterial) administration, there is no absorption, as 100% of the drug is already in the systemic circulation. Most drugs are absorbed predominantly by passive diffusion across lipid bilayer cell membranes. Thus, in order to be absorbed, drugs generally must be lipid-soluble, and they won’t be well-absorbed if they are charged or polar. The Henderson-Hasselbalch equation predicts what proportion of a weak acid, or a weak base, will be in an uncharged form suitable for crossing cell membranes by passive diffusion, in a manner dependent on the local pH in which the drug finds itself. Weak acids exist in a predominantly uncharged form in the acidic stomach, and so are absorbed rapidly and extensively from the stomach. Weak bases exist predominantly in a charged form in the stomach, and so tend to be absorbed more extensively from the intestines where the pH is more neutral and a greater proportion of the drugs exist in an uncharged form. The more lipid-soluble a drug is, the faster it crosses lipid bilayer membranes by passive diffusion (as predicted by Fick’s Law of Diffusion) and so the faster it will be absorbed. Click here to view a short vodcast explaining how lipid solubility impacts the rate of drug absorption.
Factors which impact passive diffusion of drugs across biological membranes affect both absorption and distribution of a drug, as well as some aspects of elimination. The processes of absorption and distribution together are referred to as drug disposition.
Drugs may be absorbed by several other mechanisms, including filtration through pores or channels, passive transport (or facilitated diffusion) via a transporter protein down a concentration gradient, and active transport against a concentration gradient, often mediated by ATP-dependent transporter proteins. Filtration allows movement of polar or charged compounds across membranes, with filtration at Bowman’s capsule perhaps representing the best-known of these processes.
Absorption from most administration sites simply involves the drug moving from the site of administration into the local blood supply – so-called parenteral routes of administration. However, following enteral administration, where the drug is absorbed through the walls of the GI tract and into the portal circulation, it must first pass through the liver before it reaches the systemic circulation. If the drug is a good substrate for liver enzymes, much of it may be lost to hepatic metabolism before it ever reaches the systemic circulation. This first pass metabolism reduces the amount of drug absorbed, and so reduces the bioavailability of the drug. Consequently, higher oral doses of such drugs may need to be administered in order that enough drug reaches the systemic circulation from where it can distribute to the tissues and exert a therapeutic effect. Drugs which are high hepatic extraction ratio drugs are good substrates for liver enzymes, and tend to have low oral bioavailability.
Clinical Context
Clinicians should have awareness of the degree to which a medication is absorbed and be mindful of specific patient factors that may influence the patient’s absorption. Patients may have impediments to absorption that include administration via feeding tubes with terminal placement beyond the location in the GI tract where medication absorption occurs, changes to gut integrity such as occurs in graft versus host disease in transplant patients, concomitant use of acid-suppressing medications, or even diet. For example, the absorption of tacrolimus, an important anti-rejection medication used in transplantation, may be reduced by around 25-40% if it is taken with a high fat meal. Dasatinib is a tyrosine kinase inhibitor (TKI) used to treat chronic myelogenous leukemia; when is taken with common acid-suppressing medications such as a proton pump inhibitor, its absorption may be reduced by up to 70%.
It is also important to remember that absorption into the systemic circulation occurs with topically-administered products. Factors that disrupt the integrity or composition of the skin may lead to unanticipated systemic levels of topically-administered medications. For example, applying the anti-rejection medication tacrolimus as a topical cream to open sores covering large areas of a patient’s skin, to treat graft versus host disease (GvHD), has led to toxic systemic levels of tacrolimus. Applying dressings that cover transdermal fentanyl patches has necessitated administration of the antidote naloxone, according to case reports.
We may also take advantage of an ability to limit systemic absorption of a medication through choice of administration route. For example, direct drug administration to the site of action, exemplified by the use of topically-inhaled β-agonists to treat asthma, or use of locally-applied topical steroid creams, achieve effective therapeutic drug concentrations locally while minimising the potential for systemic side-effects. This is also possible for some enterally-administered products. For example, vancomycin is administered intravenously to treat a variety of resistant infections, but severe side-effects including nephrotoxicity and ototoxicity may result from this systemic exposure. On the other hand, with a polar surface area of 530 Å2 and an oral bioavailability of zero, when used orally vancomycin can be administered at a standard dose to treat enterocolitis caused by C. difficile, as there is no absorption into the systemic circulation and the drug remains at the site of infection within the gut lumen.
