graperuit juice and cytochrome P450 pathway

[LewdTenant]

the bulk of this post is presented at the link below. The other 3 links further down were used to add insight to the article.

Anyone who has a medical background that has any info on Cyp450 that the would like to share or trash this thread. Feel free to do so.

This is groundwork I am laying for a post on bromocriptine.

http://www.holistic-online.com/Herba...tions-home.htm


I was researching bromocriptine and there were warnings of not taking the drug with anything that intefered with the P450 pathway. This was in Lyle McDonald's Ebook on Bromocriptine. I made a post asking questions about the p450 pathway on another board but nobody was able to answer.

I was finally able to find a site that explained it in laymans terms even though some technical jargon is used.

There are a lot of medications that at least partially use the P450 pathway so I just want everyone to be aware of the possible drug interactions. A number of the drugs listed that compete with the P450
pathway are discussed on most AS boards.

Although steroids partially uses the P450 pathway. I'm still learning about how to apply this information. I have not seen it listed as an inducer or inhibitor, but that does not mean that other drugs will not create problems with the absorption of AS.

some good links on CYP450.You can find lists of inhibitors,substrates, and inducers:
http://www.aafp.org/afp/980101ap/cupp.html
http://medicine.iupui.edu/flockhart/
http://www.anaesthetist.com/physiol/...ol/cyp/cyp.htm

Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).

grapefruitjuice works an inhibitor.

How Grapefruit juice works

When we take a medicine orally (by mouth), it has to get into our blood stream to do its job. (The medications that are intravenously administered, sidesteps this process and gets directly into the blood stream. That is why many of the medications that can be administered orally and intravenously, can be safely used in the intravenous route, while the oral route are subject to interactions.) The absorption usually takes place in the large or small intestines. The liver plays a key role in many of these metabolism b y removing a significant amount of the medication from the serum. For many medications, there is an optimum concentration of the active ingredient that need to be present in the serum for a certain amount of time for it to work. So, two factors are important. The maximum concentration of the active ingredient in the serum (called Cmax). The time factor is determined by plotting the concentration in the blood stream versus time and determining the area under the curve (AUC). Obviously, more AUC means we had been exposed to this ingredient for a longer time. Any mechanism that alters the optimum values of Cmax and AUC can affect the way the drug reacts. We will see later that grapefruit affects both Cmac and AUC for several prescription medications that take advantage of the Cytochrome P450 isoenzyme for the metabolism of the drug.

All drugs and many other substances within our body such as prostaglandins, fatty acids and steroids, utilize one or more of the cytochrome P450 isoenzymes in their respective metabolic (elimination) pathways. It turns out that one of the most important dietary factors that affects this isoenzyme is a bioflavinoid and possibly other ingredients contained in grapefruits and in grapefruit juice.

INTERACTIONS OF GRAPEFRUIT WITH MEDICATIONS
Grapefruit juice affects the bioavailability (therapeutic concentration) of a very wide variety of drugs. All drugs, to greatly differing degrees, achieve their respective target therapeutic levels by two main regulatory pathways, both involving one or more of the 30+ related cytochrome P450 isozymes.

The initial elimination route, called the presystemic "first-pass" metabolic pathway, involves the the gut (small intestine), the portal vein and the the liver. Depending on the drug or food supplement in question, this critical "first-pass" metabolic degradation will directly determine both the peak and mean concentrations of the drug or its metabolite in the blood stream.

Some drugs, such as terfenadine (Seldane) requires 100% breakdown by this presystemic "first-pass" metabolic pathway to convert it to its active and less toxic metabolite, terfenadine carboxylate. Any drug, (such as erythromycin, ketoconazole (Nizoral)) or food such as grapefruit juice, that inhibits or competes for the enteric (gut) cytochrome P-450 3A4 isozyme, will partially or completely block this metabolic step (breakdown) of terfenadine, and will result in the absorption of unmetabolized terfenadine, with the potential for very serious toxic reactions including ventricular tachyarrithmias (cardiac arrest) and death.

Approximately one hundred and twenty five deaths have now been linked to the concomitant use of terfenadine and one of the previously listed products that interferes with the Cytochrome P450 isoenzyme. Other drugs, e.g. prednisone, quinidine, theophylline, etc. with a high oral bioavailibility, or not competing for the same cytochrome P-450 3A4 isozyme, will not be affected by ingestion with grapefruit juice.

The second elimination pathway for all drugs involves the more predictable metabolic degradation over time by the hepatocytes in the liver, and excretion in the bile or by the kidneys. Grapefruit juice will not have any effect on the drugs that uses this second elimination pathway. It only affect the "first-pass" small intestine - liver metabolic pathway and not any secondary elimination metabolic processes. That is why some drugs are affected by grapefruit juice while others are not.

INTERACTIONS OF GRAPEFRUIT WITH MEDICATIONS


Dr. David Bailey and Associates at the University of Western Ontario, Canada showed that grapefruit juice acts by blocking (down regulating) the activity (expression) of cytochrome P450 3A4 isoenzyme in the intestinal wall, thereby preventing the presystemic "first-pass" oxidative metabolism (breakdown) for a wide variety of drugs. Grapefruit juice did not significantly block cytochrome P-450 3A4 isozymes in the liver hepatocytes. The net result of blocking this presystemic "first-pass" metabolic pathway, is the potential for a marked increase in the plasma concentration of the drug, often to the point of toxicity.

For example, in the case of a drug called felodipine (Renedil & Plendil) which they were investigating at the time, there was more than a five fold increase in the plasma concentration with grapefruit juice as compared with water.

Other studies with the cholesterol lowering drug, lovastatin (Mevacor), showed that grapefruit juice was capable of increasing the peak serum concentration of this drug up to 19.7-fold (range 5.2-19.7) and the area under the concentration-time curve (AUC) up to 26.3-fold (range 5.7-26.3).

The magnitude of the interaction with grapefruit juice appears to be highly variable among individuals, but the effect is relatively consistent for any given person. In addition, there appears to be considerable interracial genetic polymorphism of the cytochrome P450 isozyme subtypes.

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.

Further studies have shown that grapefruit juice will also block other Cytochrome P450 isoenzymes, viz. 1A2 & 3A3. The magnitude of the effects from inhibition of cytochrome P450 1A2 & 3A3 isoenzyme activity by grapefruit juice is relatively minor in comparison to its 3A4 activity, and the clinical significance is relatively unknown.

INTERACTIONS OF GRAPEFRUIT WITH MEDICATIONS

The potential for this type of drug interaction is enormous. Dr. David Bailey, stated in the September 3rd, 1998 issue of the Medical Tribune:

"Sixty percent of drugs that are (commonly) prescribed are metabolized to some extent by this enzyme, CYP3A4 (Cytochrome P450 3A4). Many drugs undergo first-pass metabolism by CYP3A4. Hence, the inhibition of this enzyme in the gut causes plasma concentrations of these drugs to increase markedly after oral administration. The result can be significant. For example, taking one tablet of lovastatin (Mevacor) with a glass of grapefruit juice is the same as taking 12 to 15 tablets with a glass of water. Certain antihistamines, benzodiazepines, cyclosporin, caffeine, calcium antagonists and cisapride are among other drugs with which grapefruit interacts. So this interaction is very important and the list (of drugs) is going to continue to grow".

The list of specific drugs and drug types which interact with grapefruit juice is slowly expanding, but still very incomplete. We will take a look at few of these where clinical data is available.

Summary: Medications That are Affected by Grapefruit Juice Use
these are all substrates of Cytochrome P450

Statins (Cholesterol Lowering Drugs):
-Baycol (Cerivastatin)
-Mevacor (Lovastatin)
-Lipitor (Atorvastatin)
-Zocor (Simvastatin)

Antihistamines:
-Ebastine
-Seldane (Terfenadine, taken off the U.S. market)

Calcium Channel Blockers (Blood Pressure Drugs):
-Nimotop (Nimodipine)
-Nitrendipine
-Plendil (Felodipine)
-Pranidipine
-Sular (Nisoldipine)

Psychiatric Medications:
-Buspar (Buspirone)
-Halcion (Triazolam)
-Tegretol (Carbamazepine)
-Valium (Diazepam)
-Versed (Midazolam)

Intestinal Medications:
-Propulsid (Cisapride, taken off the U.S. market)

Immune Suppressants:
-Neoral (Cyclosporine)
-Prograf (Tacrolimus)

Pain Medications:
-Methadone

Impotence Drug:
-Viagra (Sildenafil)

Miscellaneous

-Losartan (for lowering blood pressure) - Grapefruit juice inhibits the body's ability to absorb the drug.
-Digoxin (for treating congestive heart failure) - Grapefruit juice inhibits the body's ability to absorb the drug.

INTERACTIONS OF GRAPEFRUIT WITH MEDICATIONS

Foods That Affect Cytochrome P450

The following foods are known to interact with cytochrome P450 isoenzyme. If you are taking any medication that utilizes P450 for its metabolism, you may want to avoide the following foods:
Inducers
Broccoli
Fried and charcoal broiled foods
Insulin
tobacco
ethanol
St John's Wort
HIV anti-virals
barbituates
prednisone(corticosteroid)

Inhibitors
ketoconazole(Nizoral)
cocaine
Grapefruit

I believe the ones below are all inducers but did not have time to verify
Cabbage
Other Cruciferous Vegetables
Spinach
Leeks
Onion
Garlic
Parsley
Smoked fish or meat
Ham
Sausage



Conclusion

Grapefruit's effect on medications is unpredictable. It may enhance the desired effect of the drug in some instances (so that we can take a lower amount of the drug and still get the effectiveness). It also means that if you take the suggested dose of the drug, our system gets a higher than expected concentration of the drug, resulting in amplification of the side effects of the drug and sometimes resulting in dangerous situations that was unforeseen at the time of the introduction of the drug in question. The same dose of drug could produce blood levels in different individuals ranging in concentration from normal to very toxic. Depending on the individual and the drug in question, dangerously high levels of the drug could enter the systemic circulation.

[Full Frontal]

that's a pretty cool article lewd. from what i got of it grapefruit juice will always have an inhibitory effect on most cytochrome p450 enzymes involved in the first pass digestive system. if these enzymes are involved with breaking down the drug into active metabolites and detoxification then grapefruit juice taken in conjunction with these drugs would be very bad because a toxic buildup of non-active drugs can form, but if drugs do not require first pass p450 metabolism then an increase in serum concentration of these drugs would be beneficial.

so if an AS utilizes the p450 first pass enzymes for digestion then grapefruits would be very bad to take with it...

[auriflex]

Good post LT.

[LewdTenant]

that is the correct conclusion for grapefruit and also the other inhibitors and inducers. Studies are still ongoing on it's(GF) use.

lewd

Originally posted by Full Frontal

so if an AS utilizes the p450 first pass enzymes for digestion then grapefruits would be very bad to take with it...

[King Samson]

Excelent post LT. Thanks

[TheMudMan]

bump...... good read for those that haven't seen it yet.

[jeffylyte]

great post LT. some more info. though. The active ingrediant in GF juice (actually there are many, but these are 100X more potent than any of the others) that acts to inhibit CYP3A are the spiro ortho esters. This class of compounds have been patented by Bioavailability Systems LLC run by James Harris. He is currently running trials with a variety of poorly orally availble compounds. Versus the benchmark boosters of Ketoconazole and Ritonavir the spiro ortho esters show better boosting ability. (Ritonavir is the key cause without it, the protease inhibitor lopinavir is too unavailable for use).

The point is expect to see a product for a booster soon. if we are lucky, they may work well enough to boost some previously non-oral AAS into the oral route.

[powerlifter]

Solid post Bro - bumping it up for all to see

[MAXIMA5]

bump.

[aaronswt84]

im a big fan of grapefruit juice, I drink 3 glasses ed. Any ideas how this effects dbol and proviron ? If Im not mistaken it only effects oral As.