Factors Affecting Drug Absorption

Physicochemical Factors Affecting Absorption

Drugs are chemical entities and as such, the ways they interact with biological systems (ie the human body) are governed by their chemical features.

The structures of these chemicals—the number and identity of different atoms in the molecule, their connections and 3-dimensional arrangements—determine their physicochemical properties and therefore the absorbability properties of the drug.

As we will soon see, a drug that is to be given by the peroral route, should ideally have the following physicochemical properties:

• Small size
• Fair water solubility but also fair lipid solubility
• Few hydrogen-bond donors/acceptors
• Predominantly non-ionised at intestinal pH
• Good stability in acidic environments

Dose

According to Fick’s first law of membrane diffusion, membrane flux is directly proportional to the concentration differential across the membrane. Using Fick’s insights, we can see that a higher concentration of drug inside the GI tract will translate to a more dramatic concentration gradient and therefore a higher rate of absorption.

There is a rather unsurprising method to achieve higher drug concentration in the GI tract: swallow more drug (ie higher dose).

Molecular Size

Only small molecules can diffuse across the plasma membrane. We can assess molecular size by looking at the drug’s molecule weight. A fair cutoff is 500 g/mol.

There are some drugs with very high molecular weight (eg biologics, insulin) but these are not absorbed well and must be administered by a parenteral route (eg i.v, s.c).

Solubility

Drug must be dissolved in order to participate in membrane transport of any kind; drug that is still in solid form cannot be absorbed. The fluid of the intestinal lumen is aqueous (water-based) so soluble drugs should have the following chemical features that promote hydrophilicity:

• Polarity—water is a polar solvent so dissolves similarly polar drugs.
• Hydrogen-bond participants—water does hydrogen bonding so will associate with drugs which have hydrogen-bonding groups such as -NH₂, -OH, =O, -F.

But, water solubility should only be moderate, not extreme. The interior of the plasma membrane—which drugs must diffuse across—is lipid-rich. Drugs must be hydrophilic enough to dissolve in the intestinal fluid but also lipophilic enough to cross the plasma membrane.

We can evaluate lipophilicity using the partition coefficient (LogP), a ratio of the drug’s concentration in a lipid phase vs aqueous phase. The figure below depicts how LogP is calculated.

For good membrane diffusion, a LogP around 1-5 is ideal and reflects fair solubility in both water and lipid. When LogP is too low (ie hydrophilic drug, LogP < 1), the drug will mostly reside in aqueous solvents and have difficulty crossing the lipid-rich plasma membrane. When LogP is too high (ie lipophilic drug, LogP > 5), the drug will most reside in the lipid-rich interior of the plasma membrane and will be unable to diffuse into the intracellular space. The figure below depicts this.

Medicinal chemist Charles A. Lipinski gives us four suggestions for evaluating “drug-likeness” with respect to absorbability of novel compounds. Lipinski’s Rule of Five are useful tips for evaluating which drugs might have good absorption properties. They are as follows:

• 1. No more than 5 hydrogen-bond donors.
• 2. No more than 10 hydrogen-bond acceptors.
• 3. Molecular mass no more than 500 g/mol.
• 4. LogP no more than 5.

pK_a

A final physicochemical property of drugs that affects their absorption is ionisation. Many drugs are weak acids or weak bases (or both) and can be ionised under certain pH conditions (meaning they lose or gain a proton giving them a negative or positive charge respectively). Charged molecules are extremely lipophobic and will have great difficulty crossing the lipid-rich plasma membrane.

The degree of ionisation of a drug is related to the pK_a of the drug and the pH of the intestinal environment according to these rearranged Henderson-Hasselbalch equations:

$$weak\ acid: \frac{[ionised]}{[non-ionised]} = 10^{pH-pK_a}$$

$$weak\ base: \frac{[ionised]}{[non-ionised]} = 10^{pK_a-pH}$$

These equations tell us that weak acids will mostly exist in their ionised form when pH > pK_a. Likewise, weak bases will mostly exist in their ionised form when pH < pK_a. Since the pH of the small intestines is roughly 7.5, we can say that weakly acidic drugs ought have pK_a over 7.5 and weakly basic drugs ought have pK_a under 7.5 if they are to be well absorbed (non-ionised).

Stability

Drugs must survive the harsh acidic environment of the stomach which can be as low as pH 1.0-3.5 during fasting. Drugs that are unstable in acidic conditions may degrade before they can reach the intestines and be absorbed, thereby reducing bioavailability. Drugs which are destroyed by stomach acid are described as "acid labile" and must generally be given by a parenteral route (such as i.v or i.m injection) are manufactured with a special protective coating.

Some drugs are particularly vulnerable to acid degradation. For example, penicillin G (benzylpenicillin) is rapidly hydrolysed in gastric acid, which is why it must be given parenterally. In contrast, penicillin V (phenoxymethylpenicillin) is not destroyed by stomach acid and can be given orally. Similarly, the proton pump inhibitors (eg omeprazole) are acid-labile and require enteric coating to protect them during while they pass through the stomach.

Beyond acid stability, drugs may also be susceptible to enzymatic degradation in the GI tract. Digestive enzymes like pepsin, trypsin, and various peptidases can cleave peptide bonds. This is highly problematic for peptide-based drugs which have historically offered huge therapeutic potential (eg insulin, GLP-1 agonists, biologics) but are limited by the fact that they must be given parenterally. This is a highly active and lucrative area of research; various strategies are being investigated to allow peptide-based drugs to be taken orally. For those interested, Chen et al give an excellent review of strategies currently being explored.

Physiological Factors Affecting Drug Absorption

Intestinal Surface Area

Recall that Fick’s law of membrane diffusion expresses membrane flux (rate of drug movement across the plasma membrane) in terms of amount of substance per unit area per unit time. Trivially, we can see that smaller surface area of the intestines will equate to slower drug absorption.

Now consider that there are a few conditions in which the surface area of the intestines is dramatically reduced.

• Some GI infections (eg giardia, rotovirus, Salmonella and others) can cause villous atrophy—flattening of the villi that contribute most of the surface area of the small intestines.
• Some autoimmune diseases (eg Celiac disease and Crohn’s disease) can also injure the villi as well as having other effects on the intestines that reduce drug absorption.
• Surgical resection of the small intestine is used in some cases of Crohn’s disease, hernias and cancer.

In all of these conditions, we can expect drug absorption to be impaired.

Gastric Emptying Time

The stomach acts as a “waiting room” for drugs that have been swallowed and eventually empties its contents into the duodenum (the first part of the small intestine) where drug absorption begins. The amount of time taken for stomach contents to pass into the duodenum is the gastric emptying time. This is important for drugs because this is the last step before the drug reaches the site of absorption; most drugs cannot start to be absorbed until gastric contents are emptied.

When gastric emptying time is short, drugs will be absorbed more quickly (reduced t_max). Since drug is absorbed more rapidly, a higher c_max is reached. Conversely, when gastric emptying is delayed, drugs will be absorbed slowly, t_max is longer and c_max is lower.

Gastroparesis is the condition in which gastric emptying is delayed and can be caused by various diseases including diabetes, viral infections, Parkinson’s disease, multiple sclerosis and scleroderma. Dumping syndrome is the opposite condition, rapid gastric emptying, and usually occurs as a complication of stomach surgery. However, delayed emptying (gastroparesis) is the principle pathology of gastric emptying and is concerning because it can lead to nausea, vomiting, malnutrition and hypoglycaemia (as well as affecting drug absorption). The class of medications used to treat gastroparesis are known as “prokinetic” agents (eg metoclopramide, domperidone, erythromycin).

Summary of effects and causes of faster/slower gastric emptying.

	Faster gastric emptying	Slower gastric emptying
Effects	lower tmax higher cmax unchanged AUC	higher tmax lower cmax unchanged AUC
Non-drug causes	large volume meal postsurgical complication	fatty meal cold fluid diabetes
Drugs causes	opioids α2 agonists tricyclic antidepressants calcium channel blockers D2 agonists GLP-1 agonists cyclosporine cannabis	D2 antagonists erythromycin prucalopride mirtazapine

Intestinal Motility

Once drug reaches the small intestine, the rate at which it moves through determines the contact time available for absorption—you’ll remember that Fick tell us diffusion does not occur instantly and occurs over time. Intestinal motility refers to the contractions of intestinal smooth muscle that propel contents along the GI tract.

Increased intestinal motility (such as in diarrhoea) reduces the time available for drug absorption and dissolution which decreases bioavailability. This is particularly problematic for drugs with slow dissolution rates, slow absorption rates or those absorbed only in specific regions of the intestine. Conversely, decreased motility (such as in constipation) may increase absorption time. The table below summarises some of the drugs that contribute to stimulating or slowing intestinal motility.

Drugs that affect intestinal motility.

Increase intestinal motility	Decrease intestinal motility
stimulant laxatives (senna, bisacodyl) D2 agonists (metoclopramide, domperidone) prucalopride erythromycin cholinergics (bethanechol, neostigmine, nicotine)	opioids anticholinergics (oxybutynin) tricyclic antidepressants clozapine and olanzapine

Splanchnic Blood Flow

After crossing the intestinal epithelium, drugs enter the splanchnic (intestinal) blood supply. This is discussed in more detail in Anatomy and Physiology of Drug Absorption.

The amount of blood flow through these intestinal capillaries affects how quickly drug is carried away from the absorption site. This has two immediate effects: 1) drug is carried towards the heart from where it can be distributed all over the body and 2) lower concentration of drug inside the intestinal capillary bed maintains the concentration gradients which supports further drug absorption.

Reduced splanchnic blood flow can impair drug absorption by allowing drug to accumulate on the blood side of the epithelium, diminishing the concentration gradient. This occurs in conditions of poor blood flow such as heart failure, shock, and during intense exercise when blood is diverted away from the GI tract to skeletal muscle and vital organs.

Conversely, drugs or conditions that increase splanchnic blood flow may be expected to enhance absorption. In practise, this effect is generally modest for most drugs since absorption is usually limited by enterocyte uptake and blood flow is generally good (except in those conditions listed above).

First-Pass Hepatic Metabolism

One of the most clinically significant physiological factors affecting oral drug bioavailability is first-pass hepatic metabolism. After absorption from the GI tract, drugs enter the portal circulation and must pass through the liver before reaching the systemic circulation. The liver heroically protects us from many toxins that we might consume in our diets but it also may extensively metabolise the drugs we take. If a drug is extensively metabolised by hepatic enzymes on its first pass through the liver, it will be completely unable to have any effect on the rest of the body because it is effectively destroyed before reaching the systemic circulation.

The extent of first-pass metabolism varies enormously between drugs. Naloxone, the opioid blocker, has good absorption in the intestines but very extensive first-pass hepatic metabolism (97% of naloxone is converted to inactive naloxone-3-glucuronide in the liver) so the oral bioavailability is only around 2-3% and it must instead be given by alternative routes (intranasal, i.m injection).

P-glycoprotein (P-gp)

As discussed in Anatomy and Physiology of Drug Absorption, P-glycoprotein (P-gp, MDR1, ABCB1) is an important efflux transporter found in the apical membrane of enterocytes. It pumps some drug out of the enterocyte back into the intestinal lumen, thereby opposing absorption. Drugs that are substrates for P-gp often have lower oral bioavailability due to this efflux action.

P-gp is of particular clinical importance because its activity (and hence its effect on oral absorption) can vary greatly from person to person due to genetic polymorphisms and drug interactions.

Clinically significant absorption phase interactions can occur when P-gp inhibitors/inducers are used in conjunction with substrate drugs. When a P-gp inhibitor (eg verapamil) is used with a substrate drug (eg digoxin), more substrate drug is absorbed and could cause toxicity. Conversely, when a P-gp inducer (eg rifampicin) is used with a substrate drug, less of the substrate drug is absorbed and could lead to drug failure. The impacts of drug interactions involving P-gp are discussed in more depth in Absorption Phase Drug Interactions.

In addition to drug-drug interactions, P-gp also exhibits genetic variability. Single nucleotide polymorphisms in the ABCB1 gene can alter P-gp expression and activity, contributing to variability in drug absorption between people. For example, the common C3435T polymorphism has been associated with lower expression and activity of P-gp causing more extensive drug absorption.

GI Tract pH

The pH varies considerably along the GI tract, ranging from highly acidic in the stomach (pH 1.5–3.5) to slightly alkaline in the small intestine (pH 6.5–7.5) and more neutral in the colon (pH 6.5–7.0). This pH variation affects drug absorption in several ways.

As discussed in the physicochemical factors section, ionisation state depends on both the drug’s pK_a and the local pH according to the Henderson-Hasselbalch equation. The stomach’s acidic pH favours absorption of weakly acidic drugs in their non-ionised form, though the small surface area of the stomach limits this effect. Most drug absorption occurs in the small intestine due to its enormous surface area, despite the less favourable pH for acidic drugs.

Changes in gastric pH can significantly affect drug absorption. Antacids, H₂ receptor antagonists (like ranitidine), and proton pump inhibitors (like omeprazole) all increase gastric pH. This can enhance the dissolution and absorption of weakly basic drugs but may reduce the absorption of weakly acidic drugs. Additionally, some drugs require an acidic environment for dissolution (such as ketoconazole and itraconazole), and their absorption is markedly reduced when gastric pH is increased.

Gut Microbiota

The human gut contains trillions of bacteria that can metabolise drugs and prodrugs, affecting their absorption and bioavailability. This microbial metabolism can be beneficial or detrimental depending on the drug.

Some prodrugs rely on bacterial enzymes for activation. Sulfasalazine, used in inflammatory bowel disease, is cleaved by azoreductases produced by bacteria in the colon to release the active metabolite 5-aminosalicylic acid. Similarly, digoxin can be inactivated by cardiac glycoside reductases produced by the gut bacterium Eggerthella lenta, leading to therapeutic failure in some patients who harbour this organism.

The composition of gut microbiota varies between individuals and can be influenced by diet, age, disease states, and antibiotic use, contributing to variability in drug absorption between people and over time.

Bile Acids

Bile acids are amphipathic molecules having both hydrophilic (usually a carboxylic acid) and lipophilic (usually a steroid) parts. They are synthesised in the liver, stored in the gallbladder and released into the duodenum following meal consumption. Because of their amphipathic nature, they are useful for solubilising dietary fats and fat-soluble nutrients (eg vitamins A, D, E and K). They form micelles in the aqueous intestinal environment with the hydrophilic component facing outwards towards to aqueous GI fluid and the lipophilic component facing inwards towards to fat-soluble contents. These micelles can solubilise highly lipophilic drugs that would otherwise have very poor solubility in aqueous intestinal fluid.

The clinical importance of bile acids becomes evident in conditions where bile secretion is impaired. Cholestatic liver diseases (cholangitis, some cases of viral hepatitis, alcoholic liver disease), biliary obstruction, and severe liver dysfunction reduce bile acid production and/or secretion into the intestinal lumen. Similarly, patients who have undergone cholecystectomy (removal of the gallbladder) may have altered bile acid secretion patterns, though the clinical importance with respect to drug absorption is generally modest as bile continues to be produced by the liver.

Bile acid sequestrants (such as cholestyramine and colesevelam) are medications used to lower cholesterol by binding bile acids in the intestinal lumen and preventing their reabsorption. However, these agents can also bind to other drugs as discussed in Absorption Phase Drug Interactions.

Additionally, the timing of meals affects bile acid secretion and therefore may influence the absorption of highly lipophilic drugs. Taking such drugs with fatty meals stimulates greater bile acid release, potentially enhancing their absorption which could lead to greater efficacy or toxicity.

Pharmaceutical Factors

The formulation of a drug product significantly influences the rate and extent of drug absorption. Pharmaceutical scientists design drug formulation to optimise oral bioavailability, protect drugs from degradation in the acidic stomach, and control the release profile (ie immediate vs delayed release).

Tablet Coatings

Many commercial tablets consist of a mass of active drug powder compressed into solid tablet and surrounded by an inactive coating. The most obvious reason for applying a coating to a tablet is to improve the taste (eg a sugar coating on a foul tasting drug). However, some coatings serve specific pharmacokinetic functions.

Enteric coatings are coatings made of pH-sensitive polymers. They remain intact in the acidic environment of the stomach but dissolve in the more alkaline environment of the small intestine. This protects acid-sensitive drugs from degradation in the stomach. It can also have the added benefit of protecting the gastric mucosa from drugs that may cause irritation (eg aspirin).

Modified-release coatings are a special type of tablet coating that allows control of the rate at which drug dissolves from the tablet bulk and becomes available for absorption. This can be extremely advantageous because it means patients can take a tablet just once a day instead of several times a day. Be aware that modified-release can be achieved through many other techniques other than coatings (eg matrix, HBS, OROS®).

Formulation Excipients

Even beyond the coating, tablets and capsules are much more than just compacted drug powder. They contain numerous inactive ingredients (called “excipients”) that affect the drug dissolution and absorption characteristics.

Disintegrants such as croscarmellose sodium and sodium starch glycolate cause the tablet to break apart when it contacts water. Disintegrants mostly work by creating pressures inside the tablet through swelling with water or producing gas bubbles.

Surfactant such as polysorbate 80 and sodium lauryl sulfate reduce surface tension and improve the dissolution of poorly water-soluble drugs. They help hydrophobic drug particles to disperse in the aqueous intestinal fluid, increasing the drug’s effective surface area for dissolution.

Binders, lubricants, and fillers, primarily serve purposes during the manufacturing process. However, they can also influence drug release. For example, excessive compression during tablet manufacture or the use of hydrophobic lubricants like magnesium stearate can impair disintegration of the tablet and dissolution of the drug.

The physical form of the drug itself matters as well. Particle size affects dissolution rate; smaller particles (eg micronised drugs) have greater surface area and dissolve faster. Crystal form (polymorphism) can also affect solubility; for example, different crystal polymorphs of the same drug may have different solubility parameters.

Dosage Form

The physical form (ie tablet, solution) in which a drug is administered significantly affects the rate and extent of absorption. Different dosage forms present the drug to the GI tract in different states, directly impacting dissolution and absorption kinetics. Importantly, remember that drugs must be dissolved in order to pass across the enterocyte membrane.

Solutions are drugs already dissolved in a liquid vehicle (usually water). For most drugs, the dissolution step significantly slows absorption and therefore giving oral drugs already in solution offers the fastest absorption. The drug is immediately available for absorption upon reaching the small intestine, with no dissolution step required! Oral solutions are particularly useful for drugs with poor solubility or for patients who cannot swallow solid dosage forms (eg paediatric and geriatric patients). Solutions of drugs have two distinct disadvantages in that they are less stable (if the drug is susceptible to hydrolysis) and that they are much less palatable for patients (since taste also requires dissolution).

Solid dosage forms (tablets and capsules) are the most common and familiar oral formulations. They're highly favoured due to their good stability, convenience, accurate dosing, easy storage and cheap manufacturing. However, they require disintegration of the tablet or capsule shell releasing fine particles of solid drug followed by dissolution of these drug particles in the GI fluids before absorption can begin. This makes solid forms generally the slowest to be absorbed. The rate of disintegration and dissolution can be modified through formulation design as discussed above.

Suspensions are a sort of in-between form consisting of very small particles of solid drug dispersed in a liquid medium. Because they are already in a very fine particulate form, they skip the disintegration step but must still be dissolved before absorption begins. Suspensions typically provide faster absorption than tablets or capsules but slower than solutions. They are useful for drugs with limited solubility or stability in solution (since they are not yet in solution, the drug particles resist hydrolysis), and like solutions, are easier to swallow than solid forms.

Therefore, for the same drug at the same dose, we would typically expect: solution > suspension > solid in terms of absorption rate (shorter t_max and higher c_max). This principle is exploited clinically; for example, liquid paracetamol formulations are marketed for faster pain relief compared to tablet forms.

Comparison of solid, solution and suspension dosage forms.

	Solid (eg tablets, capsules)	Solution	Suspension
Description	Solid with drug mixed with other solid excipients	Liquid with drug dissolved	Liquid with solid drug particles hanging in liquid
Absorption Rate	Slow	Fastest	Fast
Requires dissintegration?	Yes	No	No
Requires dissolution?	Yes	No	Yes

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