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p5p bioavailability


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#1 ajnast4r

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Posted 03 February 2009 - 06:59 AM


does anyone have any info on p5p bioavailability? i was under the impression it would much higher serum levels of p5p than other forms of b6 but this suggests otherwise:

http://www.efsa.euro...f?ssbinary=true


As only dephosphorylated vitamers can be transported into the cells (Coburn et al., 2003) the
bioavailability of intact pyridoxal 5’-phosphate upon oral intake would be low. Bioavailability
of vitamin B6 from pyridoxal 5’-phosphate requires hydrolysis of the phosphate group before
absorption through the intestinal layer may occur.



#2 Michael

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Posted 03 February 2009 - 07:27 PM

does anyone have any info on p5p bioavailability? i was under the impression it would much higher serum levels of p5p than other forms of b6 but this suggests otherwise:

http://www.efsa.euro...f?ssbinary=true

As only dephosphorylated vitamers can be transported into the cells (Coburn et al., 2003) the bioavailability of intact pyridoxal 5’-phosphate upon oral intake would be low. Bioavailability of vitamin B6 from pyridoxal 5’-phosphate requires hydrolysis of the phosphate group before absorption through the intestinal layer may occur.



Almost all authorities agree on this point generally. But note, first that they say that "only dephosphorylated vitamers can be transported into the cells ", which is not the same as having it absorbed into serum; and remember that when they say that "Bioavailability of vitamin B6 from pyridoxal 5’-phosphate requires hydrolysis of the phosphate group before absorption through the intestinal layer may occur", and that such hydrolysis results in pyridoxal, not simple B6 (pyridoxine). Additionally, some preliminary evidence that while most P5P is indeed dephosphorylated before absorption, some remains intact and is absorbed, either by passive diffusion across the ECF, or perhaps active transport (1-3). Any of these mechanisms could lead to very different pharmacodynamics between B6 and P5P, irrespective of how many molecules of the core pyridoxine structure gets out of the intestinal lumen and into the serum (simple bioavailabiltiy).

IAC, the key point for me is not the ultimate answer to this particular issue, but the outcome on actual health parameters. (4) is an in vivo study showing that P5P lowers AGE/ALE even more than pyridoxamine, and leads to better health outcomes; ther is no equivalent data for pyridoxine, and until someone does a comparative study with a B6 arm showing that it performs as well or better, the take-home message is to take P5P.

That said, I'm continuing to take most of my total B6 as pyridoxamine rather than P5P, because it has actual human clinical trial data on safety and (very limited) efficacy in AGE-related health outcomes,(5) and we don't have such result for P5P for AGE levels or AGE-related health outcomes in any organism, & can even say that it isn't effective in lowering cardiovascular morbidity and mortality after CABG, as animal studies had suggested (6).

Moreover, high-dose B6 has been reported to cause a reversible neuropathy, which has not been reported (as I would assume that it would be) for quite high dose P5P in the pharma trials ((6) and its Phase II precursor), which may also somehow involve the pharmacokinetics or pharmacodynamics; I'd say IAC it's wise to constrain one's total intake of all of forms of B6, and especially of B6 proper.

It's also worth noting that peak and total AUC bioavailability of P5P is higher from conventional rather than enteric-coated dose forms in humans (7), and when taken 15 mins after a meal rather than on an empty stomach or at the beginnning (8).

NB: there there is again an issue of possible vestigal CoI here, for which I again urge all readers to see my discl0sure, tho' I swear up and down that my comments are made in good faith and public interest, not out of any anticipation of personal gain.

-Michael

1. Intestinal absorption of pyridoxal 5'-phosphate at physiological levels in rats.
Morita E, Shirakami Y, Mizuno N.
J Nutr Sci Vitaminol (Tokyo). 1988 Dec;34(6):553-65.
PMID: 3244043 [PubMed - indexed for MEDLINE]

2: Intestinal absorption of pyridoxal-5'-phosphate: disappearance from perfused segments of rat jejunum in vivo.
Middleton HM 3rd.
J Nutr. 1979 Jun;109(6):975-81.
PMID: 448455 [PubMed - indexed for MEDLINE]

3: Characterization of pyridoxal 5'-phosphate disappearance from in vivo perfused segments of rat jejunum.
Middleton HM 3rd.
J Nutr. 1982 Feb;112(2):269-75.
PMID: 7057264 [PubMed - indexed for MEDLINE]

4. Nakamura S, Li H, Adijiang A, Pischetsrieder M, Niwa T.
Pyridoxal phosphate prevents progression of diabetic nephropathy.
Nephrol Dial Transplant. 2007 Aug;22(8):2165-74. Epub 2007 Apr 20.
PMID: 17449494 [PubMed - indexed for MEDLINE]

5. Williams ME, Bolton WK, Khalifah RG, Degenhardt TP, Schotzinger RJ, McGill JB.
Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy.
Am J Nephrol. 2007;27(6):605-14. Epub 2007 Sep 6.
PMID: 17823506 [PubMed - indexed for MEDLINE]

6. Efficacy and safety of pyridoxal 5'-phosphate (MCx1) in high-risk patients undergoing coronary artery bypass graft surgery: the MEND-CABG II randomized clinical trial.
MEND-CABG II Investigators, Alexander JH, Emery RW Jr, Carrier M, Ellis SJ, Mehta RH, Hasselblad V, Menasche P, Khalil A, Cote R, Bennett-Guerrero E, Mack MJ, Schuler G, Harrington RA, Tardif JC.
JAMA. 2008 Apr 16;299(15):1777-87. Epub 2008 Apr 1.
PMID: 18381567 [PubMed - indexed for MEDLINE]

7. Bioavailability of pyridoxal phosphate from enteric-coated tablets. I. Apparent critical dissolution pH and bioavailability of commercial products in humans.
Kaniwa N, Ogata H, Aoyagi N, Koibuchi M, Shibazaki T, Ejima A, Takanashi S, Kamiyama H, Suzuki H, Hinohara Y, et al.
Chem Pharm Bull (Tokyo). 1985 Sep;33(9):4045-9. No abstract available.
PMID: 4092300 [PubMed - indexed for MEDLINE]

8. Variability in absorption lag time of pyridoxal phosphate under fasting and pre- and post-meal conditions.
Takahashi H, Ogata H, Nagai N, Sugito K, Shimamura H.
Biopharm Drug Dispos. 1994 Aug;15(6):505-17.
PMID: 7993988 [PubMed - indexed for MEDLINE]

Edited by Michael, 03 February 2009 - 07:39 PM.


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#3 ajnast4r

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Posted 04 February 2009 - 08:20 PM

Fantastic reply... Thanks a lot

#4 neogenic

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Posted 06 February 2009 - 01:54 PM

The reason that has been stated that P5P doesn't have the toxicity of pyridoxine is that pyridoxine actually completes at higher doses with endogenous P5P... ironically the more pyrixodine (cheap supplemental B6) you take, the more it lowers your active co-enzyme form of B6 (P5P) from binding at the site.

P5P, like stated above can be taken in high doses. It is a clear winner. And will probably be taken away like all the other active forms soon enough. That pisses me off. They leave us with toxic B6, folate that many people can't convert to the co-enzyme form (folic acid or even folinic acid), and cyanide bound B12...as they'll probably scoop up methylcobalamin too.

Save us big pharma! It just sucks when they're taking the healthy and effective forms of vitamins.

#5 stephen_b

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Posted 06 February 2009 - 05:24 PM

IAC, the key point for me is not the ultimate answer to this particular issue, but the outcome on actual health parameters. (4) is an in vivo study showing that P5P lowers AGE/ALE even more than pyridoxamine, and leads to better health outcomes; ther is no equivalent data for pyridoxine, and until someone does a comparative study with a B6 arm showing that it performs as well or better, the take-home message is to take P5P.

4. Nakamura S, Li H, Adijiang A, Pischetsrieder M, Niwa T.
Pyridoxal phosphate prevents progression of diabetic nephropathy.
Nephrol Dial Transplant. 2007 Aug;22(8):2165-74. Epub 2007 Apr 20.
PMID: 17449494 [PubMed - indexed for MEDLINE]

Is that a fair conclusion given the high doses used in the study? In a separate discussion here, the point was made that the study you cited (reference 4) would translate to 12g of PLP for a 70kg human, which of course is far too much for safety. Another point that was made was that at such high doses, some amount P5P would be "absorbed intact without first being hydrolized allowing PLP to provide beneficial antiglycating protection".

Perhaps there is a role for sublingual P5P?

StephenB

#6 Michael

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Posted 20 February 2009 - 03:46 PM

(4) is an in vivo study showing that P5P lowers AGE/ALE even more than pyridoxamine, and leads to better health outcomes; ther is no equivalent data for pyridoxine, and until someone does a comparative study with a B6 arm showing that it performs as well or better, the take-home message is to take P5P.

Is that a fair conclusion given the high doses used in the study? In a separate discussion here, the point was made that the study you cited (reference 4) would translate to 12g of PLP for a 70kg human, which of course is far too much for safety.

As the authors of the paper note, however, they used the same dose of both PM and P5P as had originally been used to show that PM itself is effective against diabetic nephropathy in rodents. When the Pharma Co That Shall Remain Nameless translated this to human studies, they first did actual Phase I trials to test dose-ranging, and then their early Phase II trials seemed to show (ambiguous, minor) benefits at either 50 mg or 250 mg PM taken twice daily, with no clear superiority to the higher dose; in their new Phase II trial, they're testing 150 and 300 mg BID. Somewhere along the way, their pharmacologists concluded that they could expect results (if any) to occur at these levels; I admit am at some level just putting faith in the idea that they know what they're doing, and the more tenuous assumption that if this dose is justified for PM, it should also work for P5P.

I totally acknowledge that this is a far from conclusive case. As I said: I'm still putting most of my eggs in PM's basket, because we have actual human trial data (albeit not too impressive to date).

Another point that was made was that at such high doses, some amount P5P would be "absorbed intact without first being hydrolized allowing PLP to provide beneficial antiglycating protection".

First, that's, again, not a 'point,' but mere mechanistic speculation, and is refuted clearly by the fact that the animal study shows that it does work. But second, it's not even mechanistic speculation that makes sense: I suspect that the person was thinking of the early in vitro work on the "Amadorin" action of PM vs other B6 vitamers, but that wasn't the mechanism revealed and explored by the authors of the animal study:

We found that PLP inhibits AGEs formation by trapping 3-deoxyglucosone (3DG), but PM or pyridoxal does not trap 3DG ((4) op cit)

Again, however: whatever the mechanism, it worked. In vivo studies trump biochemical hypotheses every single time. "The Nature of Evidence" and all that.

Perhaps there is a role for sublingual P5P?


I don't see why sublingual P5P would be any likely to be better than gastric, and again, I'd want to see an animal study proving it (tricky, of course: you'd probably have to have implant a device that would hold the even tinier tablet under the critters' tongues, to keep them from swallowing it).

-Michael

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#7 neogenic

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Posted 20 February 2009 - 05:37 PM

In a separate discussion here, the point was made that the study you cited (reference 4) would translate to 12g of PLP for a 70kg human, which of course is far too much for safety.

As I stated above, research shows P5P doesn't have the toxicity associated with pyridoxine.

Edited by Michael, 20 February 2009 - 05:48 PM.





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