Absorption
From the FDA Drug Safety Oversight Board Meeting, June 18, 2009 Public Summary ...
"1. PEG is a long-chain polymer of ethylene oxide commercially available in molecular weights of 300 g/mole to 10,000,000 g/mole. Many products contain an average molecular weight of 3350 g/mole and thus are given the name PEG-3350. PEG-3350 products exist in a stable powder form. Approved products instruct patients to dissolve the PEG-3350 powder in a liquid and use immediately. The approved products have been tested under these conditions and are stable. It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.
2. PEG products that are available over-the-counter can be used without medical oversight.
3. There is a perception that PEG is safe because it is minimally absorbed from the stomach and intestines. However, little is known about whether absorption in children differs from adults, especially in children who are constipated, have underlying intestinal disease, or are very young.
4. Children are receiving adult doses of PEG in some cases.
5. Children may be more susceptible to variations in PEG product quality.
6. Effects of large doses of PEG given over a long duration (e.g weeks or longer) is not known."
In response to our petition, the FDA granted a $325,000 study to Children's Hospital of Philadelphia (CHOP) to measure breakdown and absorption in children. The study did NOT begin enrolling participants before the grant expired and will now be undertaken by the FDA. https://grants.nih.gov/grants/guide/rfa-files/RFA-FD-14-088.html
From the FDA drug approval document below ... " The reviewers noted that PEG3350 pharmacokinetic data are lacking and that the applicant had pointed to literature to support their contention that PEG is not absorbed. The reviewers agreed that the submitted literature suggests that PEG absorption is minimal; however, these studies did show PEG is absorbed and renal excretion was documented. The reviewers initially recommended a pharmacokinetic evaluation of PEG3350 as a post marketing commitment ."
pg.10 - https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000SumR.pdf
Begin forwarded message:
From: Mike Koehler
Date: December 10, 2020 at 6:55:00 PM EST
To: Carol Chittenden
Although the sponsor claims PEG-3350 to be an inert nonabsorbable solute,
there is recent information (Baker RW, Ferrett, J, J. Chromatogr. 1983; ,i§o
273:421-425) to indicate that, in healthy individuals, it is absorbed on the average
about 2.Sr. (0.39-2.67%} and the absorption can be increased to almost
3~ in individuals with food allergy or eczema (Jackson PG,,!! !J,, Lancet
J98l;i:J285-86).
The package insert will have to be revised to comply with 21 CFR 201.57.
Also, the use of the word "nonabsorbable'' in connection with PEG-3350 will
have to be deleted.
Excretion
Again, it is unclear how much polyethylene glycol is eliminated by the body. This article states that, in constipated patients, Miralax recovery is incomplete and highly variable …
http://www.druglib.com/druginfo/miralax/description_pharmacology/
According to this study, up to 4% of PEG 6000, a larger molecule, is metabolized in humans. It stands to reason that if a larger molecule is metabolized, PEG 3350 may be metabolized.
http://dmd.aspetjournals.org/content/35/1/9/T1.expansion.html
Gut Permeability
Urinary excretion ...
https://www.gastrojournal.org/article/0016-5085(86)90261-1/pdf
Urinary excretion with intestinal permeability ...
https://www.dropbox.com/s/gohme3b98x7vu9s/urinary%20excretion%20of%20polyethylene%20glycol%203350%20during%20colonoscopy%20preparation.pdf?dl=0
People with Crohn’s Disease, another condition that causes increased permeability, absorb more PEG 400 than those with healthy intestines. Although PEG 400 is a smaller molecule than PEG 3350, this points to the increased permeability in people with compromised intestines. http://www.annals.org/content/105/6/883.short
In patients with certain viruses, intestinal permeability was increased, allowing more PEG to pass through the intestinal wall. http://www.ncbi.nlm.nih.gov/pubmed/2693681.
Accumulation of calcium oxalate crystals resulting from the potential metabolism of
polyethylene glycol to ethylene glycol, which is subsequently excreted as oxalic acid, was
suggested as a possible mechanism for the apparent kidney effects (Prentice and Majeed, 1978; As demonstrated in rat perfusion studies, polyethylene glycol polymers can permeate the intestinal epithelium via aqueous channels (Krugliak et al., 1989; Kim, 1996).
pg. 8 -
https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2007.414?fbclid=IwAR1JYWIlYz3J3998gDS-sqeA7JNIvGntU_hvGkm9ypnV1Zr7Xv_ewIbTERc
Use of polyethylene glycol is not recommended for breastfeeding women because it is not known whether PEG passes into breast milk. This leads parents to wonder all the more whether it permeates compromised intestines.
Metabolism
FDA’s guidance document on food and color additives offers a layperson’s guide to absorption, metabolism, distribution, and elimination criteria for food products, which mirrors parent questions on PEG metabolism …
“Does the product or its metabolites alter or interfere with absorption, metabolism, or excretion of normal nutrients or metabolic intermediates?
Does the product or its metabolites alter the action of commonly used drugs?
Is the product absorbed, metabolized, distributed, stored or excreted differently in man than in test animals?
Does the product or its metabolites accumulate in tissues, and what are the toxicological consequences if there is accumulation?
If the product is poorly absorbed, does the high concentration in the gut affect gut morphology, physiology, or biochemistry? Are any changes in the gut morphology or biochemistry associated with the development of neoplasms of the gut?
Does the product alter the composition or nature of the gut flora? If it does, what are the toxicological consequences of the changes?”
Cell Death
The following article published in 2006 is exploring the effect of oral polyethylene glycol in increasing the rate of apoptosis (cell death) of the intestinal epithelium. This change is seen as a benefit to reducing colon
cancer, and the effect is apparently rapid. This is how the study described this effect of PEG on the mucosa:
"Taken together, these facts suggest that PEG has an abrasive effect on the mucosa. How could abrasion be protective? Although it is highly controversial, the elimination of cells from the top of crypts might be enough to stop carcinogenesis, by preventing the top-down movement of transformed cells (38). This would explain why the inhibition was reversible in part when treatment was discontinued (6). Similarly, chemical peeling with PEG and salicylic acid strikingly suppresses skin tumor development in mice (39). "
http://www.ncbi. nlm.nih.gov/ pmc/articles/ PMC2643349/
"1. PEG is a long-chain polymer of ethylene oxide commercially available in molecular weights of 300 g/mole to 10,000,000 g/mole. Many products contain an average molecular weight of 3350 g/mole and thus are given the name PEG-3350. PEG-3350 products exist in a stable powder form. Approved products instruct patients to dissolve the PEG-3350 powder in a liquid and use immediately. The approved products have been tested under these conditions and are stable. It is unknown if prolonged duration in solution would change the chemical properties of PEG-3350, and what the actual content of ethylene glycol or diethylene glycol or other low molecular weight PEG would be under such conditions.
2. PEG products that are available over-the-counter can be used without medical oversight.
3. There is a perception that PEG is safe because it is minimally absorbed from the stomach and intestines. However, little is known about whether absorption in children differs from adults, especially in children who are constipated, have underlying intestinal disease, or are very young.
4. Children are receiving adult doses of PEG in some cases.
5. Children may be more susceptible to variations in PEG product quality.
6. Effects of large doses of PEG given over a long duration (e.g weeks or longer) is not known."
In response to our petition, the FDA granted a $325,000 study to Children's Hospital of Philadelphia (CHOP) to measure breakdown and absorption in children. The study did NOT begin enrolling participants before the grant expired and will now be undertaken by the FDA. https://grants.nih.gov/grants/guide/rfa-files/RFA-FD-14-088.html
From the FDA drug approval document below ... " The reviewers noted that PEG3350 pharmacokinetic data are lacking and that the applicant had pointed to literature to support their contention that PEG is not absorbed. The reviewers agreed that the submitted literature suggests that PEG absorption is minimal; however, these studies did show PEG is absorbed and renal excretion was documented. The reviewers initially recommended a pharmacokinetic evaluation of PEG3350 as a post marketing commitment ."
pg.10 - https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203595Orig1s000SumR.pdf
Begin forwarded message:
From: Mike Koehler
Date: December 10, 2020 at 6:55:00 PM EST
To: Carol Chittenden
Although the sponsor claims PEG-3350 to be an inert nonabsorbable solute,
there is recent information (Baker RW, Ferrett, J, J. Chromatogr. 1983; ,i§o
273:421-425) to indicate that, in healthy individuals, it is absorbed on the average
about 2.Sr. (0.39-2.67%} and the absorption can be increased to almost
3~ in individuals with food allergy or eczema (Jackson PG,,!! !J,, Lancet
J98l;i:J285-86).
The package insert will have to be revised to comply with 21 CFR 201.57.
Also, the use of the word "nonabsorbable'' in connection with PEG-3350 will
have to be deleted.
Excretion
Again, it is unclear how much polyethylene glycol is eliminated by the body. This article states that, in constipated patients, Miralax recovery is incomplete and highly variable …
http://www.druglib.com/druginfo/miralax/description_pharmacology/
According to this study, up to 4% of PEG 6000, a larger molecule, is metabolized in humans. It stands to reason that if a larger molecule is metabolized, PEG 3350 may be metabolized.
http://dmd.aspetjournals.org/content/35/1/9/T1.expansion.html
Gut Permeability
Urinary excretion ...
https://www.gastrojournal.org/article/0016-5085(86)90261-1/pdf
Urinary excretion with intestinal permeability ...
https://www.dropbox.com/s/gohme3b98x7vu9s/urinary%20excretion%20of%20polyethylene%20glycol%203350%20during%20colonoscopy%20preparation.pdf?dl=0
People with Crohn’s Disease, another condition that causes increased permeability, absorb more PEG 400 than those with healthy intestines. Although PEG 400 is a smaller molecule than PEG 3350, this points to the increased permeability in people with compromised intestines. http://www.annals.org/content/105/6/883.short
In patients with certain viruses, intestinal permeability was increased, allowing more PEG to pass through the intestinal wall. http://www.ncbi.nlm.nih.gov/pubmed/2693681.
Accumulation of calcium oxalate crystals resulting from the potential metabolism of
polyethylene glycol to ethylene glycol, which is subsequently excreted as oxalic acid, was
suggested as a possible mechanism for the apparent kidney effects (Prentice and Majeed, 1978; As demonstrated in rat perfusion studies, polyethylene glycol polymers can permeate the intestinal epithelium via aqueous channels (Krugliak et al., 1989; Kim, 1996).
pg. 8 -
https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2007.414?fbclid=IwAR1JYWIlYz3J3998gDS-sqeA7JNIvGntU_hvGkm9ypnV1Zr7Xv_ewIbTERc
Use of polyethylene glycol is not recommended for breastfeeding women because it is not known whether PEG passes into breast milk. This leads parents to wonder all the more whether it permeates compromised intestines.
Metabolism
FDA’s guidance document on food and color additives offers a layperson’s guide to absorption, metabolism, distribution, and elimination criteria for food products, which mirrors parent questions on PEG metabolism …
“Does the product or its metabolites alter or interfere with absorption, metabolism, or excretion of normal nutrients or metabolic intermediates?
Does the product or its metabolites alter the action of commonly used drugs?
Is the product absorbed, metabolized, distributed, stored or excreted differently in man than in test animals?
Does the product or its metabolites accumulate in tissues, and what are the toxicological consequences if there is accumulation?
If the product is poorly absorbed, does the high concentration in the gut affect gut morphology, physiology, or biochemistry? Are any changes in the gut morphology or biochemistry associated with the development of neoplasms of the gut?
Does the product alter the composition or nature of the gut flora? If it does, what are the toxicological consequences of the changes?”
Cell Death
The following article published in 2006 is exploring the effect of oral polyethylene glycol in increasing the rate of apoptosis (cell death) of the intestinal epithelium. This change is seen as a benefit to reducing colon
cancer, and the effect is apparently rapid. This is how the study described this effect of PEG on the mucosa:
"Taken together, these facts suggest that PEG has an abrasive effect on the mucosa. How could abrasion be protective? Although it is highly controversial, the elimination of cells from the top of crypts might be enough to stop carcinogenesis, by preventing the top-down movement of transformed cells (38). This would explain why the inhibition was reversible in part when treatment was discontinued (6). Similarly, chemical peeling with PEG and salicylic acid strikingly suppresses skin tumor development in mice (39). "
http://www.ncbi. nlm.nih.gov/ pmc/articles/ PMC2643349/