Grapefruit's Irreversible Inactivation of Key Defense Against Toxic Effects Of Many Drugs (Ivermectin Binary Weapon)

Untold Citrus Carnage

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CYP3A4 Basics

CYP3A4 is an essential enzyme belonging to the cytochrome P450 family, specifically the subfamily CYP3A. It plays a crucial role in the metabolism of numerous drugs and endogenous substances in the human body. The co-administration of grapefruit, a known CYP3A inhibitor, significantly enhances the absorption of numerous drugs that undergo metabolism by this crucial CYP3A enzyme.

The specific component in grapefruit that inhibits CYP3A4 is a group of compounds called furanocoumarins, including bergamottin and 6',7'-dihydroxybergamottin (DHB). These compounds can interfere with the activity of the enzyme and reduce its ability to break down drugs efficiently. (src)

“The most important [bodily action to terminate drugs] is 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”

“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).”

In addition to furanocoumarins, grapefruits are recognized for their quercetin content, which, in conjunction with the furanocoumarins, appears to exert an inhibitory influence on P-gp activity.

In a Harvard Medical cautionary article about the dangers of mixing grapefruit juice:

“A single glass can produce a 47% reduction of the intestinal enzyme [CYP3A4] that regulates absorption.”

The article mentions a number of drugs that are “substantially boosted” by grapefruit juice, including valium, midazolam, Zoloft, etc..

ScienceDirect has an interesting meta analysis of a number of grapefruit studies showing large marked increases in drug absorption for many substances that are metabolized by CYP3A4 when combined with grapefruit juice: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/grapefruit-juice

Here is another good overview of the grapefruit-enhanced absorption and toxicity of numerous pharma drugs: https://www.bjmp.org/content/drug-interactions-grapefruit-juice

“The susceptibility varies between individuals depending upon their genetic expression of CYP3A4, the effects being more prominent in those with high small intestinal CYP3A4 content”

Ivermectin, Midazolam, Morphine & Paxlovid Are All Metabolized by CYP3A4 Enzyme

Numerous drugs, such as ivermectin, midazolam, morphine, and paxlovid (& many others), are metabolized by CYP3A4. Analysts estimate that around 60% of drugs are metabolized by the cytochrome P450 class of enzymes, with CYP3A4 accounting for half of the metabolic activity.

Grapefruit Increases Absorption Of Many Drugs Metabolized By CYP3A4

Dronedarone

Dronedarone with grapefruit juice (300 mL, 3 times/d) resulted in a systemic drug concentration that was 300% of that of a control (Src)

Simvastatin

“Grapefruit juice greatly increased the serum concentrations of both simvastatin and simvastatin acid. The mean Cmax of simvastatin was increased 9.4-fold (range, 5.1-fold to 31.4-foldl) and the mean AUC was increased 16-fold (range, 9.0-fold to 37.7-fold) by grapefruit juice.” (Src)

Felodipine

In a paper called ‘Acute effects of drinking grapefruit juice on the pharmacokinetics
and dynamics on felodipine - and its potential clinical relevance’ by Edgar et al (full report) researchers examined the effect of different amounts of grapefruit juice on the uptake of CYP3A4 substrate felodipine.

There were three treatments that were administered to each of the 9 subjects: control (water), 200 ml grapefruit juice, 200 ml grapefruit juice double strength.

Morphine

In a paper called ‘Enhancement by Grapefruit Juice of Morphine Antinociception’ by Okura et al (full report) researchers examined the change in morphine’s antinociception (how slowly the rat’s tail responds to painful heat stimuli), with and without 2ml grapefruit juice

“The antinociception of morphine (30 mg/kg, per os (p.o.)) was significantly enhanced by the oral administration of grapefruit juice (2 ml/rat)”

“P-glycoprotein at the blood–brain barrier modulates the antinociceptive effect of morphine by regulating its transport from the blood into the central nervous system”

“Grapefruit juice and its constituents are considered to affect the functions of drug transporters such as P-glycoprotein, multidrug resistance protein 2 (MRP2) and organic anion transporting polypeptide (OATP), in addition to the drug metabolism enzyme CYP3A4. Of these enzymes and transporters, P-glycoprotein can affect morphine’s disposition”

“In conclusion, grapefruit juice is suggested to potentiate the antinociception of morphine associated with an increase in intestinal absorption”

Midazolam

In a paper called ‘Interaction between grapefruit juice and midazolam in humans’ by Kupferschmidt et al (full report)

“After oral administration, pretreatment with grapefruit juice led to a 56% increase in peak plasma concentration (C_max), a 79% increase in time to reach C_max (t_max), and a 52% increase in the area under the plasma concentration-time curve (AUC) of midazolam, which was associated with an increase in the bioavailability from 24% (water) to 35% (Grapefruit juice). After oral administration of midazolam, pretreatment with grapefruit juice was associated with a 105% increase in t_max and with a 30% increase in the AUC of α-hydroxymidazolam.”

Praziquantel

“Interaction between Grapefruit Juice and Praziquantel in Humans” by Castro et al

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC127135/ (Full report)

Lovastatin

“Grapefruit juice contains psoralens which produce “suicide inhibition” of CYP3A4 (a reactive intermediate forms a covalent bond to irreversibly inactivate the enzyme). This causes large increases in blood levels of drugs that are metabolized by CYP3A4, notably lovastatin (see below data from [15]). Untoward reactions from this effect have been noted for midazolam, triazolam and buspirone (impaired CNS function), and felodipine (hypotension).”

Felodipine

The first time this grapefruit enhancing of drug absorption was published was in a 1991 paper called ‘Interaction of citrus juices with felodipine and nifedipine’ by Bailey et al. (full report)

“Vasodilatation-related side-effects were more frequent [with grapefruit juice].”

“The AUC of felodipine with grapefruit juice was 284 (range 164-469)% that of felodipine with water”

Multiple Ivermectin Studies BANNED Concurrent Consumption Of Grapefruit Juice

https://www.principletrial.org/files/trial-documents/ivermectinparticipantcardv1-0_15-03-2021pn.pdf

https://www.principletrial.org/

Another Ivermectin Study Bans Grapefruit Juice

In a study called called ‘Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers’ by Muñoz et al, researchers explicitly forbade participants from consuming grapefruit juice before being dosed with the experimental pesticide. https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006020

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