Grapefruit juice / CYP2D6: clarifying a common misconception

[Paracelsus]

Grapefruit juice / CYP2D6 : clarifying a common misconception.

Many of you probably know that grapefruit juice (GFJ) is a potentiator of many recreational drugs, including benzodiazepines, DXM, opiates and others. This has been confirmed through many studies and countless experience reports.

Before continuing reading, please take a quick look at the following threads (to get an idea what they are about):

Grapefruit juice... opposite with codeine
Possible grapefruit juice potentiation for a greater tramadol experience

You have probably seen that GFJ is the common point of the listed threads. More exactly, in all these threads are posts that say that GFJ inhibits the liver enzyme cytochrome P450 2D6 (CYP2D6).

But, GFJ does NOT inhibit CYP2D6 or affect it in any other way. The myth that GFJ inhibits CYP2D6 is quite old. I don’t know anything about its origins, but it is today generally accepted amongst members of communities like this one. I am posting this to repair some of the damage done by me and others (because unfortunately, I have also helped spreading this myth) and to bring some light into discussions that are stuck in the idea that GFJ inhibits CYP2D6.

For the skeptics amongst you (it’s good to be a skeptic – otherwise I probably wouldn’t have posted this), I tried to get some evidence (from medical papers and such) to support my statement that GFJ doesn’t affect CYP2D6.

Part 1: Evidence that GFJ doesn’t affect CYP2D6.

The effects of a combination of tramadol and GFJ are unlikely to be caused by CYP2D6 inhibition.

A search for “tramadol grapefruit” on PubMed revealed nothing, unfortunately.

But several experience reports (including two experiments conducted by SWIP himself) suggest that GFJ potentiates tramadol significantly. SWIP would say GFJ doubles intensity and duration of the effects of tramadol, and I am sure many fellow experimenters (DrMuffy, Bajeda, etc.) would agree. But since we have no clear evidence (from medical studies) that GFJ potentiates tramadol, this is not a solid argument (SWIPs drug-damaged synapses probably fooled him to believe that GFJ potentiates tramadol). Go ahead and consider this as being evidence if you trust SWIPs crazy neurons

The metabolite of tramadol responsible for most analgesia and euphoria (mu-opioid activity) is its O-demethylated metabolite, O-desmethyltramadol (O-DMT) [1]. This has been confirmed through some studies which have shown that CYP2D6 poor metabolizers got much less analgesia from tramadol [2]. While tramadol itself has a mu-opioid receptor affinity 6000-fold lower than that of morphine, O-DMT is much more potent, its affinity for mu-opioid receptors being only 20-fold lower than that of morphine [1]. So, without CYP2D6 (or with CYP2D6 inhibited), no (or less) O-DMT. Without (or with less) O-DMT, no (or weaker) effects. As a conclusion, if GFJ would inhibit CYP2D6, it would weaken tramadol. But in reality, GFJ does exactly the opposite. So GFJ doesn’t inhibit CYP2D6.

A study about dextromethorphan (DXM) and GFJ showed that CYP2D6 activity remains the same when GFJ is taken with DXM.

In this study, subjects were given 30 mg DXM hydrobromide with 200 ml water/GFJ/seville orange juice (SOJ), the latter being identical to GFJ from a pharmacological point of view. This was done five times (first time with H2O, then GFJ, then H2O, then SOJ, then H2O), with three-day breaks inbetween. Eight hours after DXM was administered, urine was collected and analyzed for DXM and metabolites (dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan) [3].

Originally Posted by 3

Table 2.
Partial metabolic clearances of DM (DXM) to O- and N-demethylated metabolites as indexes of CYP2D6 and CYP3A activities obtained after oral administration of DM with H2O, GJ (GFJ) and SOJ in individuals who are EM (extensive metabolizers).
--------------------------------------------------------------------
DAYS EM (n=9)
------------------------------------------------
...............O-DEM CYP2D6 (L/h)............ N-DEM CYP3A (L/h)
1 (H2O) .....0.43 +/- 0.02 ........................0.14 +/- 0.04
2 (GJ) .......0.46 +/- 0.01 .......................0.09 +/- 0.03
3 (H2O) .....0.45 +/- 0.01 .......................0.11 +/- 0.04
4 (SOJ) .....0.42 +/- 0.04 .......................0.10 +/- 0.01
5 (H2O) .....0.44 +/- 0.02 ........................0.12 +/- 0.01
--------------------------------------------------------

[...] Very little change was observed (Table 2) on all 5 study days when DM was O-demethylated to DX (dextrorphan) via CYP2D6 enzymes found in the liver in volunteers who were deemed EM. This confirms lack of inhibition of CYP2D6 enzymes by GJ and SOJ.

The partial metabolic clearances of the metabolites of DXM show the indexes for the activity of the enzymes responsible for these metabolic pathways. In the middle column, the indexes of CYP2D6 activity are shown. It is clearly visible that these do not vary significantly whether the liquid consumed with the DXM was H2O, GFJ or SOJ [3]. So GFJ, SOJ and water all have the same effect on CYP2D6 – zero.

Part 2: How GFJ acts as a potentiator.

Since now you probably understood that GFJ doesn’t inhibit CYP2D6, you might ask yourself how GFJ acts as a potentiator (because it certainly is a potentiator). Two mechanisms are probably responsible for this. I will explain them briefly here.

CYP3A inhibition

GFJ is proven to inhibit CYP3A. In the already mentioned study about DXM and GFJ, CYP3A activity was 64.3% of its normal value after 200 ml GFJ was administered. This inhibition appeared to be quite long-lasting, CYP3A activity still being at 78.8% of its original value after 4 days (see the table above quote – right column, days 1 & 2) [3]. There are tonloads of other studies about GFJ inhibiting CYP3A. Go look.

In some cases, CYP3A inhibition results in lower amounts of ‘unwanted’ N-demethylated metabolites, which means more substance is available to be metabolized into active (‘wanted’) metabolites and less active metabolites are N-demethylated to other inactive metabolites. In the case of codeine, less of the unwanted norcodeine would be formed, so more codeine would be available to be metabolized into morphine [4]. In the case of DXM, less of the inactive 3-methoxymorphinan (3-MM) is formed, so more DXM can be metabolized into DXO. And less DXO will be metabolized into the inactive 3-hydroxymorphinan (3-HM,3-OH) [3]. Therefore, CYP3A inhibition is an important factor in the potentiating effects of GFJ.

P-glycoprotein and bioavailability

Originally Posted by 3

Table 1
PK Parameters of DM when administered with H2O, GJ and SOJ in volunteers who are EM.
---------------------------------------------------------------------------
PK Parameters.......CTL Day 1...GJ Day 2...CTL Day 3...SOJ Day 4...CTL Day 5
---------------------------------------------------------------------------
Total % excreted 4.04 ± 5.0 ...14.1 ± 6.3* 9.2 ± 3.6 ...13.3 ± 8.1* ..10 ± 2.57
F ...........................0.10 ............0.54*.....0.29.............0.46*...... ..0.29
FH .........................0.99 ............0.99.......0.99.............0.99...... ... 0.99
FA .........................0.29 ............1.0.........0.65............0.94 ..........0.71
FG .........................0.35 ............0.54.......0.44.............0.49...... ....0.41
---------------------------------------------------------------------------
Note: F: bioavailability [F=FH x FG x FA]; FH: (CYP3A/CYP2D6) escaping metabolism in the liver where FH=1-(CLH/QH) and CLH=CLT and QH assumed 1.5 L/min; FG: (CYP3A) fraction escaping metabolism in the intestinal gut wall; FA: (P-glycoprotein) fraction that is absorbed; CTL: control days when DM was taken with water.
P value <0.05 when all 5 treatments are compared between each other. * Day 2 and 4 are not significantly different from each other.

The values above show that bioavailability (F) of DXM was raised to 540% (0.54) of its original value (0.1) when GFJ was consumed concomitantly with DXM. After 4 days, bioavailability was still 290% (0.29) of its original value, which means that bioavailability will return to baseline some 8 days after grapefruit juice was consumed. Note that 3 days were left between each two of the study days and 200ml GFJ where administered on day 2 [3]. This significantly raised bioavailability (here attributed to P-glycoprotein inhibition) is probably a main factor why GFJ is a potentiator of many drugs.

References

1. Grond S, Sablotski A. Clinical pharmacology of tramadol. Clin Pharmacokinet
2004; 43 (13): 879-923

2. Poulsen L, Arendt-Nielsen L, Brosen K, et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60 (6): 636-44

3. Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: The role of gut CYP3A and P-glycoprotein. Life Sciences 71 (2002) 1149-1160

4. Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2004; 351: 1827-31

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P.S.: If my statements would not be proven to be wrong, I think it would be good to search for all posts stating that GFJ inhibits CYP2D6 and insert a note similar to the following example:

[Drugs-Forum note: Factual errors are contained in this post. Grapefruit juice does not affect CYP2D6 activity. See this thread for more information.]

The note would be suitable for old posts and threads. For active threads, I think it would be OK to just post that GFJ doesn’t affect CYP2D6 and link to this thread. Does anybody agree or have a better idea?

Reputation Comments on this post:

	Very informative post!
	good work
	The paradoxical 2D6 inhibition to increase effets of tram. & DXM bothered me too. Excellent that someone looked into...
	Fantastic post, much needed information, swim was a believer as well, but will do his own research as well. It's the sc...
	Good Job, it would be nice if you could edit out the artifacts from the tables. semicolons mostly.
	Excellent contribution.
	Wonderful work here, concise and easy to read.
	Brilliant read; P-GP is rarely considered by the layman in drug metabolism.
	Had no idea this was the case... thanks for the info