Absorption in Pharmacokinetics

Absorption is the first step in the pharmacokinetic process involving the passage of drugs from outside to inside the body. It is also often the rate-limiting step of ADME; as we will see, many drugs have very poor absorption parameters and much of a drug dose never gets into the body. Absorption often focusses on the oral route (drugs taken by mouth) because this is the most common route of drug administration. However the absorption phase can also describe the minor routes of drug administration such as intramuscular, transdermal, rectal and many others. Understanding absorption will be critical for understanding drug exposure, onset and duration of action.

Routes of Administration

Route of administration describes the method of delivering drug into the body. The most familiar route of administration is the peroral route whereby drug is swallowed (eg as a tablet or liquid) and enters the bloodstream by absorption in the lower GI tract. The peroral route is favoured for its convenience and reasonably broad application. However, not all drugs can be absorbed from the GIT and must be administered directly into the bloodstream (eg intravenous, intrathecal). Other drugs undergo extensive first-pass hepatic metabolism and must be given by a route that bypasses the liver (eg sublingual, rectal). Most of this lesson will focus on the peroral route but there will be some attention given to other minor routes.

Several routes of administration. Brackets indicate common abbreviations used in prescribing and medical charting.
Route Description
Peroral (p.o.) Swallowed and absorbed from lower GIT
Intravenous (i.v.) Injected into a vein
Intramuscular (i.m.) Injected into a muscle
Subcutaneous (s.c.; subcut.) Injected under skin
Intraarticular Injected into a joint
Intrathecal Injection into the spinal cord
Sublingual (s.l.; subling.) Absorbed from under the tongue
Buccal (bucc.) Absorbed from the inside of the cheek
per rectal (p.r.) Absorbed from the rectum
Per vaginal (p.v.) Absorbed from the vagina
Transdermal (t.d.) Absorbed through the skin
Topical (top.) Acts directly at the site of application
Inhalation (inh.) Absorbed via the alveoli in the lungs

Quanitifying Drug Absorption: Bioavailability

Before going further to discuss mechanisms and factors affecting absorption, it's worth defining our qualitative measure of drug absorption: bioavailability.

Before reaching the systemic circulation, peroral drugs face several barriers including the harsh acidic environment of the stomach, the poorly permeable membrane of the intestines and the highly metabolically active liver. Bioavailability (F) accounts for all of these barriers and expresses the fraction of administered drug that reaches the systemic circulation.

You may recall that the AUC, area-under-the-curve, of the plasma concentration-time curve represents the drug exposure during the specified time-interval. For bioavailability calculations we use the AUC between time 0 and time ∞ (ie the total drug exposure).

$$ F = \frac {per oral\ AUC_{0\rightarrow\infty}} {intravenous\ AUC_{0\rightarrow\infty}} $$

Absolute vs Relative Bioavailability and Bioequivalence

Bioavailability may be expressed in absolute terms (as above) or relative terms (ie comparing two routes). To control for different doses, we can include the dose in calculations of relative bioavailability (for example, comparing peroral to per rectal below)

$$ F_{(relative)} = \frac{AUC_{0\rightarrow\infty(p.o)}\times dose_{(p.r)}}{AUC_{0\rightarrow\infty(p.r)}\times dose_{(p.o)}} $$

Relative bioavailability can be useful when switching a patient to a different route of administration or form (eg peroral tablet to per rectal suppository). If relative bioavailability is known, you can estimate an equivalent per rectal dose like so…

$$ dose_{(p.r)} = F_{(relative)}\times dose_{(p.o)} $$

A second important application of relative bioavailability is in drug regulation. When a company introduces a generic drug to market regulators will ask the company to demonstrate that the 90%CI of the relative bioavailability of their product (relative to the existing approved brand) falls within 0.80-1.25. If this range is achieved, the new generic is said to be “bioequivalent”.

The Fate of Drugs Before Reaching the Systemic Circulation

Understanding the journey that drugs take from their site of administration to the systemic circulation helps in predicting their pharmacokinetic behaviour. Different routes of administration follow distinct pathways, each with important implications for bioavailability, onset of action, susceptibility to first-pass metabolism and other pharmacokinetic characteristics.

Oral Route

When a drug is swallowed, it begins a relatively straightforward journey through the gastrointestinal tract. When swallowed, the tablet or capsule passes through the oesophagus into the stomach where it may begin to disintegrate and dissolve. However, the stomach's thick mucus layer and relatively small surface area mean that most drugs are not meaningfully absorbed here. However, gastric absorption can be consequential for a limited number of low molecular weight, acidic drugs if used at high doses. The most notable examples are alcohol (which is taken in sufficient doses to be absorbed somewhat in the stomach) and aspirin (which is a weak acid so has favourable absorption properties in the low pH environment of the stomach, discussed more in Factors Affecting Drug Absorption). Other conditions that can promote gastric absorption of drugs are listed below

  • Low acid secretion—proton pump inhibitors, Helicobacter pylori infection
  • Low mucus secretion—NSAIDs, H. pylori, alcoholism
  • Severely reduced gastric emptying rate—gastroparesis, opioids
  • Abnormally-high concentration—overdose

After the stomach, the drug enters the duodenum (the first portion of the small intestine), which is the primary site of drug absorption. The small intestine offers ideal conditions for absorption:

Drugs absorbed here cross the intestinal epithelium (enterocytes) via various mechanisms (discussed in Mechanisms of Drug Absorption) and then enter the underlying capillary network.

Blood from the entire GI tract (excluding the lower rectum which will be discussed in Rectal Route) drains into the hepatic portal vein, which carries absorbed drug directly to the liver before it can reach the systemic circulation. This means that most oral drugs must survive a “first pass” through the liver, where they may be inactivated by liver enzymes. This first-pass effect can dramatically reduce the amount of active drug reaching systemic circulation.

After passing through the liver, drug that has escaped metabolism enters the hepatic veins, which drain into the inferior vena cava and then to the right atrium of the heart, finally entering the systemic circulation for distribution throughout the rest of the body.

There is one notable exception to this portal pathway: highly lipophilic drugs can be absorbed into the intestinal lymphatic system and hitch a ride with chylomicrons instead of directly into the capillaries associated with the intestines. The lymph drains into the thoracic lymphatic duct which travels superiorly and dumps its contents into the blood at the left subclavian vein (at the base of the neck). This allows it to bypass the liver entirely and avoids first-pass metabolism. Physiologically, this system is utilised by lipid-soluble nutrients (vitamins A, D, E, K, essential fatty acids). Pharmacologically, some highly lipophilic drugs are absorbed via this pathway such as cannabinoids (CBD and THC), griseofulvin, some antiretroviral agents (lopinavir, efavirenz) and a small number of drugs that are formulated inside lipophilic nanoparticles to aid delivery to their site of action (paclitaxel Lipusu®). For these drugs, the extent of lymphatic absorption is enhanced when taken with fatty meals.

Intramuscular and Subcutaneous Routes

Both intramuscular (i.m) and subcutaneous (s.c, subcut.) routes involve injection of drug into soft tissues, but they differ in the depth of injection and the characteristics of the tissue into which drug is deposited.

With intramuscular injection, drug is deposited directly into skeletal muscle tissue—usually one of the large muscles of the shoulder, thigh, hip or buttock. Muscles themselves are hungry for energy and so have excellent blood supply which allows for rapid drug absorption from this tissue. The drug diffuses from the injection site into the interstitial fluid within the tissue and then crosses the capillary endothelium to enter the bloodstream. The rate of absorption is highly dependent on blood flow to the capillary bed of the muscle; exercise increases blood flow (accelerates absorption) whereas shock and heart failure reduces it (slowing absorption).

Subcutaneous injection places drug into the hypodermis (the layer of loose connective tissue and fat beneath the dermis). This tissue has a relatively sparse blood supply compared to muscle, so drug absorption is generally slower and more sustained than with i.m injection. This property makes s.c injection ideal for drugs requiring steady, prolonged absorption, such as insulin. Like i.m injection, the drug diffuses through interstitial fluid into local capillaries and enters the systemic circulation via peripheral veins, completely bypassing hepatic first-pass metabolism.

For both routes, very large molecules (particularly therapeutic proteins and monoclonal antibodies) may be absorbed via the lymphatic system rather than directly into blood capillaries. The lymph eventually drains into the venous system at the junction of the left subclavian and internal jugular veins.

Importantly, i.m and s.c routes bypass the GI tract entirely and therefore avoid the harsh acidic environment of the stomach and the first-pass hepatic metabolism, as the blood from peripheral tissues drains into the systemic venous circulation rather than the portal system.

Factors affecting absorption from i.m and s.c sites include injection volume, drug formulation, local tissue blood flow, and the presence of vasoconstrictors (which slow absorption) or spreading agents like hyaluronidase (which enhance it).

Comparison of intramuscular and subcutaneous routes.
Intramuscular Subcutaneous
Target site Muscle tissue (deep to the fascia) Adipose tissue of the hypodermis
Target site vascularity High Low
Clinical pharmacokinetics Fast onset (<30 minutes) Slower onset (>30 minutes)

Rectal Route

The rectal route can be beneficial for several reasons. It offers a useful alternative when oral administration is not feasible due to vomiting, difficulty swallowing, unconsciousness or children who cannot yet follow instructions. It also offers some pharmacological advantages in that it brings drug to the systemic circulation without first-pass hepatic metabolism and it can be used for drugs that are irritating or destroyed in the stomach. Dosage forms available for rectal administration include suppositories (solid dosage form) and enemas (liquid dosage form).

The venous drainage of the rectum is anatomically important and has significant pharmacokinetic implications. The rectum is supplied by the superior rectal vein, the middle rectal vein, and the inferior rectal vein. Only the superior rectal vein drains into the inferior mesenteric vein, (that drains into the portal system); the middle and inferior rectal veins drain into the inferior vena cava without passing through the liver. This means that a majority of the rectal dose is not subject to hepatic first-pass metabolism; the middle and inferior rectal veins cumulatively contribute about 50–75% of drug absorption from the rectum.

In practice, the proportion of the rectal dosage that undergoes first-pass metabolism is unpredictable because suppositories often migrate superiorly where drainage to the portal system predominates. However, partial avoidance of first-pass metabolism is still a significant advantage of rectal administration, particularly for drugs with extensive hepatic metabolism.

Sublingual and Buccal Routes

The sublingual and buccal routes allow drug to be absorbed by placing medication under the tongue or against the cheek respectively. Drug dissolves inside the oral cavity and is absorbed directly through the oral mucosa into the bloodstream. These routes can be particularly valuable for specific clinical applications.

The oral cavity has a rich blood supply. Venous drainage occurs via the lingual and facial veins, which drain into the internal jugular vein then the superior vena cava. Blood collected from the oral cavity does not pass through the liver before reaching the heart. This means that sublingual and buccal routes completely bypass first-pass hepatic metabolism, making them ideal for drugs that would otherwise be extensively metabolised if swallowed.

The sublingual area (under the tongue) has particularly rich vascularity and a thin, permeable mucosa, allowing for rapid drug absorption and quick onset of action. This makes sublingual administration ideal for emergency situations requiring fast relief, such as glyceryl trinitrate for angina and buprenorphine for pain. The buccal mucosa (inside of the cheek) is slightly less permeable but with a larger surface area it is helpful for sustained-release formulations.

These routes do have limitations. Only small doses of highly potent drugs can be administered due to the limited surface area of the oral mucosa. The volume of dissolution (saliva) is also relatively small so drugs must have good solubility. The taste of the medication can be a big issue for compliance as the drug cannot be swallowed and must remain inside the mouth for several minutes.

Transdermal Route

The transdermal route involves administration of drug onto the outermost layer of the skin (in the form of a cream or medicated patch) to be absorbed into the systemic circulation. This is distinct from cutaneous routes which apply the medication product directly to the site of action. Cutaneous products may be applied to the skin in exactly the same way as a transdermal product but only the transdermal drug is given for a systemic effect (eg corticosteroid cream for eczema vs sex steroid cream for hormone replacement therapy). Cutaneous drugs are very easy to formulate whereas transdermal drugs are among the most difficult to formulate.

Drugs given for transdermal absorption must cross the skin to get to the deeper vascularised tissues. There are two pathways available for drugs: transcellular and intercellular. The transcellular pathway involves diffusion directly through the membranes and cytoplasm of keratinocytes in the epidermis. This is the most “straight line” path but presents significant resistance. An alternative, low-resistance option is the intercellular pathway which is movemenent between the cells of the epidermis.

Once drug reaches the dermal layer, it simply enters the blood stream through the same dermal capillaries as is used in subcutaneous injection route.

Mechanisms of Drug Absorption

For the most part, the most significant barrier to peroral drug absorption is the membranes of cells which make up the intestinal epithelium (enterocytes) and the blood vessels (vascular endothelial cells) which drugs must traverse in order to enter the circulation.

Drugs cross biological membranes through several mechanisms which can be broadly categorised into three simple mechanisms: passive diffusion, facilitated diffusion and active transport. These processes govern uptake of drugs from the GIT lumen into enterocytes (at the apical face) and then back across the membrane to enter the interstitial space (at the basal face) where it can be taken up into the blood.

Figure illustrating the mechanisms of drug absorption across the intestinal epithelium.
Mechanisms of drug absorption across the intestinal epithelium include passive diffusion, facilitated diffusion, and active transport.

Passive Diffusion

The predominant mechanism for most drugs involves simple diffusion across the plasma membrane of enterocytes without assisstance from any specialised proteins in the membrane. You may already be familiar with Fick’s first law of diffusion from your previous biochemistry studies. Fick tells us that solutes, such as drug molecules, move across their concentration gradient from areas of higher concentration to areas of lower concentration.

Fick’s law can be expressed mathematically as:

$$J = -D \frac{dC}{dx}$$

where J is the diffusion flux (amount of substance per unit area per unit time), D is the diffusion coefficient, and dC/dx is the concentration gradient. In the context of drug absorption, this means the rate of absorption is directly proportional to the concentration difference between the GI lumen and the blood, and to the drug's ability to partition into and diffuse through the lipid membrane.

Several drug properties favour passive diffusion. Small molecular size, modest lipophilicity and moderate pKa all suggest a good capacity for simple diffusion.

Since simple diffusion does not rely on any carrier protein, channel or pump, it is much more reliable mechanism. It is non-saturable at high drug concentrations and is not subject to inhibition by other competing substances that may be taken alongside the drug. When designing small molecule drugs, pharmacologists and medicinal chemists often look for drugs that have physiochemical properties that are conducive to simple diffusion.

Facilitated Diffusion

For some drugs (eg large molecules, charged molecules) a strong concentration gradient may not be enough. If diffusion is hampered by adverse physiochemical properties, diffusion may be facilitated by a carrier protein—usually a channel through the plasma membrane. This form of membrane transport still relies on a concentration gradient (like passive diffusion) and no energy needs to be input—similar to simple diffusion. Unlike simple diffusion, facilitated difussion demands a channel. Membrane channels are a finite resource and can be saturated if drug concentration is very high or if there are competing solutes in the GI tract lumen.

Active Transport

Some drugs are taken up from the GI tract lumen by carrier proteins that use ATP (energy) to move solute across the membrane. Since energy is input, drug can be moved across the membrane even when there is no concentration gradient.

Examples of transporters include:

  • Organic anion transporters (OATs)
  • Organic cation transporters
  • Peptide transporters (PEPT1/2)
  • Membrane thickness

Like facilitated diffusion, active transport has the important drawbacks that it can be saturated by high drug concentrations and can be inhibited by competing substances. We wil revisit this concept of transporter competition in Absorption Phase Drug Interactions.

Efflux Transporters

Efflux transporters are an opposing force in drug absorption. These are active transporters in the membrane of enterocytes however they move drug molecules out of the enterocyte and back into the intestinal lumen—counter to absorption.

The most notable is P-glycoprotein (P-gp, also known as MDR1 or ABCB1), which is expressed on the apical (luminal) surface of enterocytes. P-glycoprotein exists in the body as a protective mechanism, pumping potentially toxic substances out of enterocytes so they cannot be absorbed. But it has very poor substrate specificity and affects the absorption of many drugs. Moreover, drugs can also inhibit or induce P-gp, complicating absorption interactions even further as we will see in Absorption Phase Drug Interactions.

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