Metabolism basics and grapefruit

If you want to know why you’re often told to stay away from grapefruit when you are taking medications – read on.

Metabolism is another aspect of the study of plants. Everything we ingest is called a xenobiotic – that includes food, drugs, and herbs. All xenobiotics must be metabolized and it is this aspect that can lead to interactions between prescription drugs and herbs or food.

There is one main pathway by which most drugs and herbs are metabolized. This pathway is made up of about 74 families of cytochrome P450s (or CYPs)(1). CYP proteins are found in all living things, including plants and animals. Interesting to note that rats and humans have the same series of CYPs – but they do not metabolize in exactly the same way so we cannot extrapolate directly from rat studies to humans.

CYPs are protein enzymes that metabolize compounds. A compound that is metabolized by a CYP is said to be a substrate for that CYP. However, there are 2 other aspects to the CYP metabolism. Compounds that are not metabolized by the CYPs can either turn the CYP on (up) or off (down). This is important because if a CYP activity is turned up it will metabolize your prescription drugs too fast. If a drug dose was supposed to last 8 hours it might only work for 6. On the other hand if a compound inhibits or turns the activity of the CYP down, your drug will not be metabolized as it should and as you keep taking doses at the appropriate time the drug could reach toxic levels in your body. That brings us to grapefruit.

Grapefruit inhibits CYP3A4 which is the main CYP that metabolizes many prescription drugs (2,3). The bigger problem is that unlike other CYP inhibitors, grapefruit stays around for 24 hours which means you can’t even use a time separation between the drug and the grapefruit. Most other inhibitors have a much shorter half-life (4,5). For example you can take a drug a couple of hours after using a CYP inhibitor if that inhibitor has a 1 hour half-life. In general you can take medications 2 hours after eating or taking an herb or 1 hour before eating or taking an herb in order to give the medication time to a first pass through the metabolic pathway without interference.

There is a lot more to metabolism but this at least gives you a quick look at how it works.

  2. David G.; Dresser, George; Arnold, J. Malcolm O. (2012). “Grapefruit-medication interactions: Forbidden fruit or avoidable consequences?” Canadian Medical Association Journal (Canadian Medical Association). doi:1503/cmaj.120951
  3. Veronese ML, Gillen LP, Burke JP, Dorval EP, Hauck WW, Pequignot E, Waldman SA, Greenberg HE. Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice. Journal of Clinical Pharmacology. 2003;43(8):831–9. doi:1177/0091270003256059. PMID 12953340.
  4. Greenblatt, DJ; Patki, KC; von Moltke, LL; Shader, RI (2001). “Drug interactions with grapefruit juice: an update”. J Clin Psychopharmacol 21: 357–9. doi:1097/00004714-200108000-00001.
  5. Greenblatt, DJ; von Moltke, LL; Harmatz, JS et al. (2003). “Time course of recovery of cytochrome P450 3A function after single doses of grapefruit juice”. Clin Pharmacol Ther 75: 121–9.