What is first-pass metabolism?

From the Guidelines

First pass metabolism is decreased in older adults due to decreased gut wall transporters, which can lead to increased oral bioavailability of certain drugs, such as diltiazem, opioids, propranolol, simvastatin, and verapamil 1.

Factors Affecting First Pass Metabolism

• Age-related changes in the pharmacokinetic parameters of cardiovascular drugs, including decreased gut wall transporters and first pass metabolism, can affect the bioavailability of oral medications 1.
• The decrease in first pass metabolism can lead to increased oral bioavailability of certain drugs, which may require dose adjustments to minimize the risk of adverse effects 1.
• Other factors, such as decreased liver mass and hepatic blood flow, can also impact the metabolism of drugs and increase the risk of adverse effects 1.

Clinical Implications

• Understanding the changes in first pass metabolism with age is crucial for appropriate dosing and selecting the most effective administration route for medications in older adults 1.
• Clinicians should be aware of the potential for increased oral bioavailability of certain drugs in older adults and adjust doses accordingly to minimize the risk of adverse effects 1.
• The use of alternative routes of administration, such as sublingual, transdermal, or rectal, may be considered to bypass the liver and avoid first pass metabolism 1.

From the FDA Drug Label

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous dosing) of about 40%.

• First pass metabolism of diltiazem is extensive, resulting in a significant reduction in bioavailability.
• The absolute bioavailability of diltiazem is approximately 40% due to this first-pass effect 2.

From the Research

First Pass Metabolism

• First-pass metabolism occurs when a drug is metabolized between its site of administration and the site of sampling for measurement of drug concentration 3
• The liver is usually assumed to be the major site of first-pass metabolism of a drug administered orally, but other potential sites include the gastrointestinal tract, blood, vascular endothelium, lungs, and the arm from which venous samples are taken 3
• Bioavailability, defined as the ratio of the areas under the blood concentration-time curves, after extra- and intravascular drug administration, is often used as a measure of the extent of first-pass metabolism 3

Factors Affecting First Pass Metabolism

• The extent of first-pass metabolism in the liver and intestinal wall depends on several physiological factors, including enzyme activity, plasma protein and blood cell binding, and gastrointestinal motility 3
• Models that describe the dependence of bioavailability on changes in these physiological variables have been developed for drugs subject to first-pass metabolism only in the liver, such as the 'well-stirred' and 'parallel tube' models 3

Clinical Implications

• Many clinically important drugs undergo considerable first-pass metabolism after an oral dose, including alprenolol, amitriptyline, dihydroergotamine, 5-fluorouracil, hydralazine, isoprenaline, lignocaine, lorcainide, pethidine, mercaptopurine, metoprolol, morphine, neostigmine, nifedipine, pentazocine, and propranolol 3
• One major therapeutic implication of extensive first-pass metabolism is that much larger oral doses than intravenous doses are required to achieve equivalent plasma concentrations 3
• The first-pass effect can pose obstacles to the treatment of disease, and strategies need to be developed to address the problem that first pass can cause, such as avoiding drug interactions or modifying the drug to avoid first-pass metabolism 4

Drug Interactions and Modifications

• Clinicians need to be aware of the problem of first-pass metabolism and the danger areas with certain drugs 4
• Chemical modification of a drug can be an alternative to avoid needing to take first-pass metabolism into consideration 4
• Certain drugs, such as nifedipine and propranolol, can have significant effects on metabolic control in patients with hypertension and non-insulin dependent diabetes mellitus 5
• Diltiazem and propranolol have been compared in the management of chronic stable angina, with both drugs showing similar efficacy 6
• A validated method for simultaneous quantification of ten antiarrhythmic drugs and a metabolite in human plasma by liquid chromatography-tandem mass spectrometry has been developed and applied to therapeutic drug monitoring 7