Pharmacokinetics of Absorption: 3 Metabolic Processes that Affect Bioavailability

First Pass Effect, Enterohepatic Recirculation and P glycoproteins

Drug absorption is the first important step needed for a drug to impact the body. The first pass effect, enterohepatic recirculation and p glycoproteins determine how much of the absorbed drug gets to the site of action.

When we develop a dosing regimen, we consider how much of the drug needs to be administered, how often and by what route in order to have a sufficient concentration at the target site to produce the desired effect. This is the study of the pharmacokinetics of drug absorption.

What is Pharmacokinetics?

As a drug moves through the body it undergoes alot of structural changes. Pharmacokinetics determines what happens between the administration of a drug and observation of the clinical effect.

Pharmacokinetics is the study of how the body interacts with a drug once it is administered

We must make the distinction between pharmacokinetics and pharmacodynamics. Pharmacodynamics refers to how the drug affects the body.

Pharmacokinetics consist of 4 processes often referred to by the pneumonic: ADME

Let’s look at absorption in detail.

Absorption

Drug administration is the first step needed for drug absorption. There are many ways to administer medications including: oral, intravenous, intramuscular, subcutaneous, intraocular to name a few.

The rate and extent of drug absorption will be greatly affected by the route of administration as well as the properties of the drug itself.

Bioavailability

The extent of drug absorption is referred to as bioavailability. Bioavailability the ratio of the amount of drug administered to the amount of drug that enters systemic circulation. We will most often express this as a percentage.

Medications that are administered intravenously have 100% bioavailability because it is being injected directly into systemic circulation. All other routes of administration will be subjected to some form of metabolism prior to entering circulation.

There are 3 key metabolic process that will affect drug absorption and bioavailability.

1. First Pass Effect

The first pass effect refers to the metabolism of a drug that occurs BEFORE it enters systemic circulation.

When a drug is taken orally, it goes through this process of absorption through the digestive tract and filtration through the liver causing some drug loss before it gets into systemic circulation. This is referred to as the first pass effect. It determines how much active drugs is available to exert its effect. This is referred to as the drugs’ bioavailability.

If a route of administration bypasses that gastrointestinal tract, drugs received via these routes will avoid the first pass effect. Drugs given via the buccal and sublingual route like fentanyl and nitroglycerin avoid the first pass effect.

The recommended dosages of drugs account for the anticipated initial pass through the liver that will decrease the amount of active drug that enters systemic circulation. First pass effect becomes clinically relevant when we consider patients with significant hepatic impairment.

If a patient has significant hepatic impairment it is possible that higher concentrations of active drug will make it into the target tissues producing an exaggerated response including the risk of toxicity. This is why it is important to review hepatic dosing in patients presenting with significant impairment.

Some clinically relevant drugs that have a significant first pass effect include: diltiazem, doxepin, metoprolol, morphine and verapamil.

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2. Enterohepatic Recirculation

Enterohepatic recirculation is a pharmacokinetic phenomenon that involves the circular movement of bile between the liver, gall bladder and small intestines. To understand the effect on drug absorption we must first understand the role of bile in digestion.

As bile and food moves through the intestines together during digestion, bile salts are being reabsorbed through the intestinal wall into the portal venous system that takes it back to the liver where the bile salts are secreted back into bile.

Bile salts repeat this cycle of flow between the intestines, liver and gall bladder 8 times a day. This is referred to as enterohepatic recirculation. With each cycle approximately 90% of bile salt is reabsorbed. The rest continues through the gastrointestinal tract and is excreted in feces.

Enterohepatic Recirculation and Drugs

Some drugs, once in the liver, form a complex with glucuronic acid. 55-72% of the drug will be conjugated, with the rest entering into systemic circulation. The portion that undergoes glucuronidation is excreted into bile and stored in the gallbladder. It becomes part of the enterohepatic cycle.

1. The drug is secreted back into the small intestine as a conjugated drug.
2. The conjugated complex is very polar so it is not reabsorbed through the small intestines.
3. Instead it stays in the intestines where enzymes and bacteria hydrolyze it back to the parent drug.
4. The parent drugs is now able to be reabsorbed from the small intestine, transported to the liver, becomes conjugated again and excreted with bile back into the small intestine. This cycle repeats.

Enterohepatic recirculation therefore prolongs the systemic exposure to drugs that undergo hepatic conjugation.

Clinically significant drugs that undergo hepatic recirculation includes valproic acid, digoxin, nafcillin and rifampin.

3. P-Glycoprotein

P-glycoprotein (P-gp) are efflux pumps. Simply put, they pump drugs back into the gastrointestinal tract and therefore have a direct effect on the amount of drug absorbed and bioavailability. The amount of drug pumped back into the intestinal lumen for elimination varies per drug but can be as much as 75%. P-gp efflux pumps can be found in the esophagus, stomach, and small and large intestines.

Some drugs can induce the activity of P-gp efflux pumps. Others inhibit the activity of efflux pumps. Some drugs are simply substrates of P-gp pumps.

P-gp substrates have no effect on the activity of the pump. It is simply a dug with properties that make it a target for efflux back into the tract. The bioavailability of substrates is affected by the presence of inducers and inhibitors.

Induction will increase the activity of the efflux pump and therefore increase the amount of drug being pumped back into the intestines. Less drug in available for systemic circulation (decreased bioavailability). This could result in reduced clinical efficacy. Drugs that increase the activity of P-gp efflux pumps are P-gp inducers.

Inhibition of P-gp efflux pump will decrease their activity and result in less drug being pumped back into the intestines. More drug is available for systemic circulation (increased bioavailability). This could increase the risk of toxicity. Inhibitors of P-gp efflux pumps are called P-gp inhibitors.

Drugs that are inhibitors or inducers may also be substrates of P-gp efflux pumps but not always.

The study unit Cytochrome P450 & P-Glycoproteins provides more detail about these transport proteins.

The Significance of the Liver

By now, I hope it is abundantly clear that the liver plays a huge role in regulating what enters and leaves the body. Any drug that enters systemic circulation, regardless of route, will circulate through the liver.

All drugs will encounter the liver while in the body. Some drugs are slowly metabolized by the liver, so there is not a significant change in drug concentration as it filters through. These are the drugs that will not require dose adjustment in patients with hepatic dysfunction.

Other drugs are rapidly metabolized as they filter through the liver. These are the drugs that will experience a significant first pass effect. These are the drugs that will require dose adjustment in the setting of significant hepatic impairment. The decreased ability to metabolize those drugs means that higher concentrations will accumulate with repeated dosing. Morphine, metoprolol and isosorbide dinitrate are examples of drugs that are rapidly metabolized by the liver and undergo significant first pass effect.

Other Factor Affecting Absorption

Drugs administered intravenously have 100% bioavailability. Any medication that is dependent on absorption will have less than 100% bioavailability. In addition to the three pharmacokinetic phenomena detailed above, bioavailability of medications are affected by many other factors including drug formulation and patient specific factors like diet and gut motility.

1. Drug formulation: tablet, capsule, solution, suspension, delayed release formulations, extended release formulations etc.
2. Diet: stomach contents can significantly affect the absorption of certain medications. Tetracyclines will bind with milk forming a complex that prevents its absorption. Drug like cholestyramine can bind with other medication preventing their absorption.
3. GI Motility: diabetic patients and patients on opioids can experience reduced GI motility including a reduction in the rate of gastric emptying. Absorption occurs when drugs are emptied out of the stomach and into the small intestine. When the rate of this transfer is slowed down this reduces the concentration of drug in the small intestine, which reduces the drug’s concentration gradient across the intestinal wall for absorption, leading to lower drug concentrations.

Clinical Application

I hope this study unit has helped you truly understand the how oral medications move through the body and the significance of the liver in bioavailability, toxicity and elimination. Renal dose adjustments are more readily thought of in clinical practice relative to hepatic adjustment. Hopefully this unit will encourage you to explore both absorption and hepatic causes when a patient has an unexpected response to a medication.

For instance a patient with significant hepatic impairment who has persistent pain despite treatment with oral morphine may need to switch therapies because morphine requires hepatic conversion to its active metabolite. A patient who is progressing in liver disease who is suddenly having an exaggerated response to metoprolol may need changes to therapy because elimination of metoprolol is predominantly via hepatic transformation.

While the response to any of those clinical scenarios may be instinctive i.e. change the medication class or reduce the dose, being able to present the likely cause or even anticipate its occurrence is what makes you stand out as an expert in your field.

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