General Interactions[]
The family of cytochrome p450 enzymes are important becasue they regulate the oxidation of small foreign molecules in the body. While many drugs are deactivated by the enzyme, there are some drugs that are activated by the enzyme. Some other molecules simply interfer with the action of CYP3A4.
Grapefruit- medication interactions[]
Statin Drug Interaction With Grapefruit Juice, Does Statin Drug
The most important reaction is the drug metabolism involving oxidation by enzymes belonging to the cytochrome P450 superfamily. Cytochrome P450 3A4 is particularly essential, because it is involved in the bioinactivation of about 50% of all drugs (Bailey et al. 2013). Most orally administered drugs can be metabolized twice before reaching the systematic circulation. Thus, the percentage of drugs absorbed is actually less than the drugs administered. Some drugs are reduced by their bioavailability by 75% once inside the body. For this reason, many drugs are subject to a potentially dramatic increase in systemic exposure and associated higher risk of overdose with grapefruit as a result of diminished CYP3A4 activity.
"Sequential first-pass elimination of a drug, such as felodipine, through metabolism in enterocytes of the small intestine, then hepatocytes of the liver. The percentages of the initial dose that are available before and after passage through the gut wall and liver are shown. Although felodipine is 100% absorbed from the gastrointestinal tract, its bioavailability is only 15% after oral administration"-Bailey et. al 2013
The chemicals in grapefruit involved in this interaction are the furanocoumarins. Furanocoumarins are metabolized by CYP3A4 to reactive intermediates that bond covalently to the active site of the enzyme, causing irreversible inactivation (mechanism-based inhibition) (Lown et al. 1995).
FDA page warning aboutgrapefruit- drug interactions
List of all drug interactions and CYP3A4
CYP3A4 and common medications[]
Many drug interactions are the result of an alteration of CYP450 metabolism. Drugs interaction with CYP in many ways. They can be metabolized by one CYP enzyme or by multiple enzymes. However, drugs can also be inhibitors of CYP. An inhibitor blocks the metabolic activity, but the extent to which an inhibitor affects the metabolism is based on the dose and ability of the inhibitor to bind to the enzyme. For example, Zoloft, when taken at a low dose, is considered to be a mild inhibitor, but when taken at a high dose is considered to be a potent inhibitor (Lynch et al. 2007).
Pages[]
- Alessandra: Cytochrome p450: Introduction
- Alessandra: Cytochrome p450: Biological function
- Alessandra: Cytochrome p450: Biosynthesis
- Alessandra: Cytochrome p450: Gene sequence
- Alessandra: Cytochrome p450: Amino acid sequence and composition
- Alessandra: Cytochrome p450: Secondary and tertiary structure
- Alessandra: Cytochrome p450: Domains and structural motifs
- Alessandra: Cytochrome p450: Interactions with macromolecules and small molecules
- Alessandra: Cytochrome p450: Molecular biodiversity and evolution
- Alessandra: Cytochrome p450: Literature overview
- Alessandra: Cytochrome p450: Useful online resources
References[]
Bailey, David G., et al. "Grapefruit–medication Interactions: Forbidden Fruit or Avoidable Consequences? " CMAJ 185.4 (2013): 309-16. NCBI. Web. 3 Mar. 2014.
Lowen, K. S, et al. "Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression. " Journal of Clinical Investigation 99.10 (1995): 2545-553. NCBI. Web. 3 Mar. 2014.
Lynch, Tom, Amy Price. "The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effects" Eastern Virginia Medical School, Norfolk, Virginia Am Fam Physician. 2007 Aug 1;76(3):391-396.