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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 13 of 13. This is the beginning of the thread.
Posted by JGalt on November 1, 2001, at 10:05:01
On a post further up on this page "Provigil Poopout: 2 yrs better than ever", Rick posted that one of Modafinil's primary metabolization enzymes was CYP 3A4. Assuming that is the case, it may turn out that instead of using Serzone to increase modafinil's effectiveness, one could use Grapefruit Juice instead, which blocks CYP 3A4. This blockage occurs mostly in the gut, and I do not know whether mod. is metabolised in the gut or elsewhere, but it would certainly be nice if it was in this case. Personally I'd love to have a better/longer acting modafinil at the price of drinking a glass of grapefruit juice a little before taking it. Anyone have any info on whether or not Mod. is metabolized primarily in the gut or elsewhere? Xanax and many other benzo's are affected by it, as well as caffeine and bunch of other drugs, so does anyone have some research on where Mod. is metabolised? I'll get around to looking it up later if no one does, but I overspent my stay online as it is. Just as an aside, is anyone on this board taking benzo's also taking grapefruit juice and thus able to lower the benzo dosage?
JGalt
Posted by JohnX2 on November 1, 2001, at 12:40:30
In reply to Modafinil+Grapefruit Juice, posted by JGalt on November 1, 2001, at 10:05:01
I'm not sure how modafinil is packaged, but
generally the coatings (waxes,fillers,sugars,
glycerin,gelatin,etc) give the digestive property.The sustained released meds that generally go after
the intestinal route have fillers around them that require a
more neutral ph to break down (so the stomach
acid doesnt cause a meltdown). They tend to sit
around in the intestines and get absorbed slowly.Interestingly as a side note, some meds will goof
up intestinal absorbtion. There is friendly bacteria
in the intestinal track that can get goofed up
by amphetamines for example. Activated
Vitamin B-12 in particular is manufactured in
the intestinal track by bacteria. (There are
sublingual active forms of b-12 for people on
diuretic meds).I'm not sure if this would make a difference with regards
to the liver enzyme trick. The grapefruit juice
or Serzone would inhibit the enzyme in the liver
directly. I'm guessing, but could find out
the exact answer from a pharmacist, that any medication
that requires the liver to metabolize would be
affected regardless of where it is absorbed.
Ulitmately the med gets into the blood plasma
which funnels through the liver.I'll look into this and get back to you.
PS. you are learning too many of the tricks
too fast.-john
> On a post further up on this page "Provigil Poopout: 2 yrs better than ever", Rick posted that one of Modafinil's primary metabolization enzymes was CYP 3A4. Assuming that is the case, it may turn out that instead of using Serzone to increase modafinil's effectiveness, one could use Grapefruit Juice instead, which blocks CYP 3A4. This blockage occurs mostly in the gut, and I do not know whether mod. is metabolised in the gut or elsewhere, but it would certainly be nice if it was in this case. Personally I'd love to have a better/longer acting modafinil at the price of drinking a glass of grapefruit juice a little before taking it. Anyone have any info on whether or not Mod. is metabolized primarily in the gut or elsewhere? Xanax and many other benzo's are affected by it, as well as caffeine and bunch of other drugs, so does anyone have some research on where Mod. is metabolised? I'll get around to looking it up later if no one does, but I overspent my stay online as it is. Just as an aside, is anyone on this board taking benzo's also taking grapefruit juice and thus able to lower the benzo dosage?
>
> JGalt
Posted by houstongirl on November 1, 2001, at 17:34:26
In reply to Re: Modafinil+Grapefruit Juice » JGalt, posted by JohnX2 on November 1, 2001, at 12:40:30
My pdoc told me that Modafinil is more effective when taken on an empty stomach.
Also, be careful with the grapefruit juice. There can be interactions there. Maybe with Depakote? I know I'm not supposed to have grapefruit juice but I forgot for which med I'm on (modafinil, Depakote and Celexa...)
Cristy
Posted by Cam W. on November 1, 2001, at 17:53:37
In reply to Re: Modafinil+Grapefruit Juice » JGalt, posted by JohnX2 on November 1, 2001, at 12:40:30
JGalt & John - A couple constituents (maybe more) of grapefruit, naringenin and 3,4-dihydrobergamottin (sp?) are potent inhibitors of CYP-3A4 in the liver. The only problem with using grapefruit juice is that you would need to know the exact concentration of each of these components in every glass of grapefruit juice, and then adjust the amount of grapefruit juice needed for each dose. Each tree could possibly have unique concentrations of the flavinoids due to varying polymorphisms of the gene(s) that code for them.
HoustonGirl - It is the Celexa that you would have to avoid taking with grapefruit juice. Taking them together could theoretically increase blood levels of Celexa by a significant amount
Posted by JGalt on November 1, 2001, at 18:48:03
In reply to Re: Modafinil+Grapefruit Juice » JGalt, posted by JohnX2 on November 1, 2001, at 12:40:30
Hunh...grapefruit juice even raises (no pun intended) blood levels of viagra. Considering the price of non-blackmarket Viagra, one would be wise to get an Rx for the highest dosage viagra (rarely much more expensive than the lower dosages), split it 4 ways, and then use grapefruit juice to make up the difference.
Anyway. Back to the modafinil and grapefruit juice for our purposes. According to "The Diagnostic and Treatment Models, FAQ 4" at http://www.bitemarks.com/dtmodels/faq4.html. "Grapefruit juice will only affect the "first-pass" small intestine - liver metabolic pathway and not any secondary elimination metabolic processes." and "Grapefruit juice did not significantly block cytochrome P-450 3A4 isozymes in the liver hepatocytes" Okay, so that answers that...if the drug in question is significantly metabolized by 1st pass elimination on the CYP 3A4 isoenzyme (also 1A2 and 3A3 to a lesser degree, however, this does help w/ keeping caffeine active, have to remember that), grapefruit juice will raise the levels which reach your blood stream. Some drugs this can have more than a 20! fold increase in blood levels (not most).
Also interesting from the same site: "The cytochrome P450 isoenzyme suppression activity of grapefruit juice was found to be accumulative, with an estimated half life at around 12 hours. The suppression effect at the enteric (gut) level, appears to be caused by a degrading (destruction) and not only suppression of the Cytochrome P450 3A4 isozyme. The return of cytochrome P450 3A4 isoenzyme activity appears to require de novo cytochrome P450 isozyme synthesis, further prolonging the effects of grapefruit juice."
K...now that that's over with...
I did a little medline research and came up with surprisingly little on enzymes and modafinil... What was shown was that chronic modafinil usage increases its own metabolism (in this case, it increased metabolism 20% after 9 weeks of daily 400mg administration) as modafinil is a mild inducer of 3A4, which is, according to the literature, is indeed a main method of metabolism. There seems to be no information on an interaction between grapefruit juice and it, but given that it is a relatively new drug and overdoses are rarely fatal, the lack of information on an interaction certainly does not mean that there isn't one.
The literature does suggest that over half of the modafinil ingested is metabolized by the liver, so it would seem that given what we know about modafinil and grapefruit juice, the interaction I had hoped for probably does not exist in amounts large enough to bother with the taste of grapefruit juice for. Of course, other drugs that use the 3A4 enzyme in the liver might represent a way of increasing levels of modafinil, but of course that drug would have to be beneficial enough to use and thus I'm probably not up for doing the research to find out if there is anything I'd like to use with modafinil that uses the 3A4 enzyme, though Rick pointed out that Klonipin does...I'm sure there are many others. Oh well, I'll just catalogue this in the back of my mind and if I have the choice of a drug that would use 3A4 in the liver and one that would not, all other things being equal, I will know I now have good reason to use the one that uses 3A4 (provided I properly reduce dosages of both). Also good to know about the grapefruit+caffeine or benzo's, viagra, and many other drugs. Thought previously it was mostly just BP meds.
JGalt
Posted by Cam W. on November 1, 2001, at 18:50:55
In reply to Re: Modafinil+Grapefruit Juice, posted by JGalt on November 1, 2001, at 18:48:03
Posted by Rick on November 1, 2001, at 18:52:11
In reply to Modafinil+Grapefruit Juice, posted by JGalt on November 1, 2001, at 10:05:01
JGalt
Since I take four meds that can theoretically interact with grapefruit juice (modafinil, clonazepam, nefazodone and omeprazole), I try to subjectively assess any interaction. (Obviously, I can't speak directly to your question of whether grapefruit would potentiate modafinil effects in the absence of Serzone and the other meds.)
What I've found is that grapefruit *may* make me feel just a tad more "up" and feel a tad more of a "dried-out" feeling overall (not "dehydrated" --it's hard to describe).
But this may be just a citricebo effect. Frankly, the grapefruit doesn't seem to make any significant difference in how my meds work. Of course, as CAM pointed out, grapefruits are not created equal, and the fact that I don't eat or drink it in large servings may figure in as well. However, I do -- halfheartedly and probably unnecessarily -- tend to avoid grapefruit on days when upcoming events make me reticent to potentially "mess with success".
One thing's for sure -- whether or not I drink any *caffeine* certainly makes a more noticeable difference than grapefruit (makes me more wired -- surprise, surprise!)
BTW, I take 100 mg/day of modafinil, all in the morning. I found that, at least in combo with the other meds, this works better for me than 200 (as a single or divided dose). But as I said, I'll temporarily bump it to 200 every so often for a little renewed "oomph". I usually get the subtle euphoric feling when I do that.
Rick
> On a post further up on this page "Provigil Poopout: 2 yrs better than ever", Rick posted that one of Modafinil's primary metabolization enzymes was CYP 3A4. Assuming that is the case, it may turn out that instead of using Serzone to increase modafinil's effectiveness, one could use Grapefruit Juice instead, which blocks CYP 3A4. This blockage occurs mostly in the gut, and I do not know whether mod. is metabolised in the gut or elsewhere, but it would certainly be nice if it was in this case. Personally I'd love to have a better/longer acting modafinil at the price of drinking a glass of grapefruit juice a little before taking it. Anyone have any info on whether or not Mod. is metabolized primarily in the gut or elsewhere? Xanax and many other benzo's are affected by it, as well as caffeine and bunch of other drugs, so does anyone have some research on where Mod. is metabolised? I'll get around to looking it up later if no one does, but I overspent my stay online as it is. Just as an aside, is anyone on this board taking benzo's also taking grapefruit juice and thus able to lower the benzo dosage?
>
> JGalt
Posted by Rick on November 1, 2001, at 19:10:22
In reply to Re: Modafinil+Grapefruit Juice, posted by houstongirl on November 1, 2001, at 17:34:26
> My pdoc told me that Modafinil is more effective when taken on an empty stomach.
Ive found this to be true to a moderate extent -- just what you'd expect given the drug's pharmacology. I usually take my Provigil (and everything else) first thing in the morning and then eat breakfast 1/2-1 hour later.
This raises what may sound like a silly question, but something I've always wondered: How long after you've taken a med can you eat without violating the "empty stomach" edict? The answer must be related to the digestive system. Or am I on the wrong tract?
Rick
Posted by Cam W. on November 1, 2001, at 22:45:32
In reply to Stomach Wants to Know: How LONG must I be empty? » houstongirl, posted by Rick on November 1, 2001, at 19:10:22
Rick - I guess the real answer would depend on the dissolution rate of the tablet and it's subsequent absorption rate into the body. I should clarify that when one swallows a medication, it is still "outside" of the body. The alimentary tract, the tube from your mouth to your anus, is technicall outside of your body. When the medication is broken down (in the stomach or intestines) it enters the body passively (through osmosis, via a concentration gradient) or actively (via a molecular transport system in the small intestine wall) through a process called absorption.
As a rule of thumb, most medications which are intended to be taken on an empty stomach, are to be taken:
"an hour before or two hours after a regular mealtime"
Close to a mealtime the body begins to prepare itself for the expected food (producing extra acid and digestive enzymes). The extra acid and enzymes at this time can inactivate &/or breakdown some molecules of medicine. Some drugs (eg tetracyline, for instance) can bind divalent cations (Ca2+, Al2+, etc.) into it's interior, preventing the absorption of that molecule, which is eliminated in the feces.
And you thought the answer was going to be simple. - Cam
Posted by JGalt on November 1, 2001, at 23:05:54
In reply to Re: Stomach Wants to Know: How LONG must I be empty? » Rick, posted by Cam W. on November 1, 2001, at 22:45:32
It is amazing how much more powerful some (emphasis) drugs/supplements can be when taken on an empty stomach as opposed to a full one.
I happen to notice a significant benefit from DL-Phenylaline or N-Acetyl-Tyrosine if taken w/ B-vitamins and Vit. C on an empty stomach (ie, nothing else than maybe a little sugar). This effect is there even w/o selegiline (though much more prominant with). Ephedrine, caffeine, and some other stimulants also seem to work a lot better on an empty stomach. Modafinil I can't comment on, with what little I have I wasn't even going to try it on a more than empty stomach. Many other psychotropic drugs I've tried are either much more powerful if taken on an empty stomach, or have a more rapid onset of action.
As a result of all this, I've found that eating no more than twice a day seems to help keep certain drugs have a more consistant feeling and action, I always keep any drug that I suspect is worsened by food at least 3 hrs after any meal and 1-1.5 hrs before.
Cam, one thing I have to ask you about...you mention that grapefruit and the compound narnigen (contained in grapefruit) inhibit 3A4 enzymes in the liver. I had always previously thought that this was the case as well, but all the backed literature I found claimed that it almost completely only blocked that enzyme in the intestines. Any idea where we found/heard this about it being in the liver and whether or not there's any truth to it?
Rick, I see your point on not being able to distinguish each individual drug's effects. i can certainly understand.
Houstongirl, I agree, its probably not something to experiment with unless you're pretty sure you're not going to have a serious reaction, or you greatly reduce the dosage of the suspected interaction drug to start off with to make sure it doesn't go bad. Indeed the combination of grapefruit plus certain heart meds is rather lethal. I was just looking for a way to get off cheap with drugs I know would not have such negative reactions.
JGalt
Posted by Cam W. on November 2, 2001, at 0:19:29
In reply to Re: Stomach Wants to Know: How LONG must I be empty?, posted by JGalt on November 1, 2001, at 23:05:54
JGalt - If memory serves me correctly, I believe that the naringenin reference was in a Medscape article. I will dig through my files to find it in the morning. - Cam
Posted by Sunnely on November 2, 2001, at 23:15:44
In reply to Re: Stomach Wants to Know: How LONG must I be empty?, posted by JGalt on November 1, 2001, at 23:05:54
> Cam, one thing I have to ask you about...you mention that grapefruit and the compound narnigen (contained in grapefruit) inhibit 3A4 enzymes in the liver. I had always previously thought that this was the case as well, but all the backed literature I found claimed that it almost completely only blocked that enzyme in the intestines. Any idea where we found/heard this about it being in the liver and whether or not there's any truth to it?
*************************************
Naringin is the main bioflavinoid in grapefruit juice. Naringin is not a potent cytochrome inhibitor, but is partially metabolized by intestinal bacteria to naringenin, which is a potent inhibitor of CYP450 enzymes, and was originally thought to be the component of grapefruit juice responsible for the interactions, although it was thought possible that another unidentified component in grapefruit juice may also have been responsible, since giving naringin alone does not seem to cause the same degree of inhibition as grapefruit juice.
Recently, researchers have isolated a group of compounds from grapefruit juice called furanocoumarins, which appear to be specific CYP3A4 inhibitors. A study of extracts of grapefruit juice interacting with rat and human CYP450 found that naringin accounted for only 10% of the inhibition of CYP activity seen with grapefruit juice. In vitro results show that a compound known as 6',7'-dihydroxybergamottin may be the chemical which accounts for the difference in effects of CYP3A substrates caused by grapefruit juice versus naringenin.
Recently, a study performed in cellular models has revealed that grapefruit juice significantly activates p-glycoprotein mediated reduction in bioavailability, partially counteracting the CYP3A4 inhibitory effects of grapefruit juice. This may explain why the effect of grapefruit juice on drug absorption is unpredictable and highly variable. P-glycoprotein is an efflux pump that, like CYP3A4 enzymes, is located at high levels in intestinal enterocytes, the primary site of oral absorption, where it actively secretes absorbed drug back into the gut lumen.
Reference: http://powernetdesign.com/grapefruit/general/mechanism.html
WHERE IS THE SITE OF CYP3A4 INHIBITION BY GRAPEFRUIT JUICE: LIVER OR GUT?
Grapefruit juice contains a number of natural substances, including furanocoumarin derivatives and others, that have the capacity to inhibit the activity of human cytochrome P450-3A (CYP3A) isoforms. Only CYP3A is affected to a clinically important extent - other CYP isoforms are not significantly affected, except possibly with very large quantities of grapefruit juice. Only the CYP3A isoforms present in the mucosal cells of the SMALL INTESTINE are inhibited by grapefruit juice. Hepatic (liver) CYP3A is affected to a small degree or not at all.
REQUIREMENTS TO GRAPEFRUIT JUICE-DRUG INTERACTIONS:
Drug interactions with grapefruit juice in general are unusual and will occur under well-defined circumstances.
1. The affected drug must be a substrate for metabolism by CYP3A.
2. The affected drug must have a low oral bioavailability due to extensive presystemic extraction (first-pass metabolism).
3. Biotransformation by CYP3A in the gastrotintestinal tract must account for a major component of this presystemic extraction.
4. An interaction with grapefruit juice is possible only when the affected drug is given orally. Parenterally (intramuscular or intravenous) administered drugs, even when they are CYP3A substrates, will not interact with grapefruit juice.
Reference: Greenblatt DJ, Patki KC, von Moltke LL, Shader RI: Drug interactions with grapefruit juice: An update (editorial). Journal of Clinical Psychopharmcology 2001;21(4):357-359.
Posted by JGalt on November 3, 2001, at 10:08:56
In reply to Re: Stomach Wants to Know: How LONG must I be empty? » JGalt, posted by Sunnely on November 2, 2001, at 23:15:44
Interesting, thanks for posting...I had wondered why those supplement companies adding naringen to their products (usually ephedrine-caffeine, but many others too) didn't ever get any better subjective effects from users, that certainly explains it.
This is the end of the thread.
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