I'm just going to put this information up here, because it's the type of thing that could be difficult to figure out and sort through. I have no financial interest whatsoever in any company or brand, and anyone who wants to make use of this information should obviously check with his or her doctor. Purines and pyrimidines are the type of thing that, if one were to attempt to evaluate their use in some sort of "proof of concept" trial, would probably end up being used as adjunctive treatments. I don't know if anyone will read or want to make use of this information, but I just thought I'd put it up here. It's just the sort of basic information, but these types of details would conceivably be difficult for a person to intuit, on his or her own, without some sort of background. To the extent that this is a real "blog," it would seem that the blog should provide *some* relevant information. The statements in this posting are just my opinions, and, throughout this posting, I've repeatedly identified them as being my opinions.
Renshaw et al. (2001) [Renshaw et al., 2001: (http://ajp.psychiatryonline.org/cgi/content/full/158/12/2048) (http://www.ncbi.nlm.nih.gov/pubmed/11729024)] found evidence that purines had been depleted from the brains of some people with major depression and suggested that the antidepressant effects of S-adenosylmethionine, which has been used for 30 or more years in large numbers of trials to treat various neurological and psychiatric conditions, may be the result of its conversion into adenosine in the brain. This is probably true, in my opinion, and I discussed, here (http://hardcorephysiologyfun.blogspot.com/2008/12/purines-and-pyrimidines-in.html), some of the almost-endless lines of evidence in support of that concept, in relation to research on purines. The issue is not just relevant for psychiatric research, given that S-adenosylmethionine has been suggested as a therapeutic agent in a variety of different neurological disorders. Much of the animal research (and some of the human research) has used parenteral or intramuscular SAM-e, however, and those dosage forms tend to have high bioavailability.
That concept has broad relevance, but the main problem with oral purine formulations is that, in my opinion, enteric coated dosage forms severely limit the bioavailability of purines. Enteric coatings are pH-sensitive coatings that are meant to allow the tablet to dissolve in the supposedly alkaline pH (pH greater than 7, which is the pH of water) of the duodenum and jejunum (the upper intestine, just past the stomach). The coatings are substances whose solubility is pH-sensitive, meaning that they would dissolve in a weak sodium bicarbonate solution, such as in the upper intestine (ideally), but not in an acidic solution (as in the stomach, in which the pH is 1-2 or 3, usually). The problem is that, in some people (if not many people), the pH never exceeds about 6 in the upper intestine. I don't have time to cite the article, but one article discusses the fact that the pH in the jejunum tends to range from something like 4.5 to 6.2 or something. The jejunal pH also decreases progressively throughout the day, with each meal, essentially, and may not reach a maximum again until the morning of the next day (in the "fasted" state). I'm surprised that some of the enteric coated SAM-e preparations have any bioavailability, but that's just my opinion or impression. Even assuming the enteric coating dissolves, the counterions of some SAM-e salts have pKa's of less than -2. I don't want to go into the details. This makes the enteric coating necessary, because the counterion would be protonated in a slightly acidic solution (esp. in the acidic environment of the stomach) and would be "outside" of the acid-base buffers. Something with a pKa of less than -2 is highly acidic. In the absence of an enteric coating, there would be the potential for acid-mediated damage to the stomach. But some of the counterions are protonated in crystalline form, as ion pairs with S-adenosylmethionine, and acidic drugs tend to slow tablet dissolution. There's some kind of "shell," or localized pH gradient, of acidity or something that exists around the dissolving tablet. I forget the term and the mechanism. This would be another concern, in my opinion. When one adds the additional facts that tablets in over-the-counter supplements can be rock hard and that there is no regulatory mechanism to impose dissolution standards on the supplement industry (discussed briefly here: http://hardcorephysiologyfun.blogspot.com/2009/01/copper-and-zinc-complexities-and.html), there is the potential for some real problems with bioavailability, in my opinion.
The problem is that the very slow release of a purine from a dosage form will tend to allow most or all of it to be converted into uric acid by intestinal epithelial cells, and this will prevent most of it from entering the portal venous blood and, following the uptake of a significant percentage of the purine, from the portal vein, by the liver, entering the systemic circulation. To enter the brain or another target tissue, a compound has to enter the systemic circulation at some point. Bioavailability essentially means availability to tissues in the "body" other than the liver or intestinal tract. Absorption is not the same thing as bioavailability. Something can be absorbed very slowly into the portal vein and be entirely taken up by the liver, before it reaches the systemic circulation. In an extreme case, something can have 100 percent absorption and zero bioavailability. This doesn't usually occur and doesn't occur, to that extreme extent, with some of the enteric-coated SAM-e preparations, given that there have been the positive results in all the trials. But researchers have expressed concerns in the literature, on many occasions, about the bioavailability of some dosage forms. As purines go, the preponderance of evidence, in my opinion, indicates that free purine nucleotide monophosphates or other purines that are not enteric-coated have relatively high and "desirable" degrees of bioavailability.
Some oral adenosine triphosphate disodium formulations are now enteric-coated as well, however, and, in contrast to the situation involving some of those counterions in some SAM-e preparations, this makes no sense at all, in my opinion. Supposedly the intent, as I understand it, is to protect the ATP from presystemic or pre-absorptive dephosphorylation or from some vague degradative process in the stomach (?), but the animal studies that have used non-enteric-coated infusions into the jejunum have shown more than adequate bioavailability (1,000-fold elevations in adenosine nucleotide levels in the portal vein, post-infusion, for example, implying availability to the systemic circulation) [here's one of the animal studies: Kichenin et al., 2000: (http://jpet.aspetjournals.org/cgi/content/full/294/1/126) (http://www.ncbi.nlm.nih.gov/pubmed/10871303); (http://hardcorephysiologyfun.blogspot.com/2009/01/purines-and-orotic-acid-in-porphyrias.html)]. Acid in the stomach protonates functional groups on organic molecules and does not produce random, degradative reactions. Even S-adenosylmethionine, which is very labile, only degrades to a meaningful degree (there are many more possible intramolecular degradative reactions with S-adenosylmethionine than with ATP) after about 8-14 hours in aqueous solutions (and the rate is actually slowest in acidic solutions). I have those old articles, and I'll try to cite them sometime. But, in my opinion, the rate of degradation of purines by acidic, intramolecular degradative reactions, to the extent that they would occur at all, would be extremely slow. Once a nucleotide is dissolved in water, either before ingestion or in the luminal fluid of the stomach, the solution of water and its solutes can enter the upper intestine almost instantly upon ingestion or, relatively quickly but not necessarily as quickly, upon entry into solution in the intraluminal fluid (which may, along any given portion of the stomach or upper intestine, be, as discussed in articles in pharmacology journals, as little as 10-15 mL). This entry of predissolved solutes into the upper intestine is the same way glucose or fructose from a soft drink or "orange juice" or whatever other substance is absorbed into the body, such as when a person with diabetes drinks a soft drink to elevate his or her blood sugar. Some of the solution enters the upper intestine almost immediately upon ingestion. Solid food moves much more slowly out of the stomach and may remain there for up to 12-14 hours (I don't have time to cite the long article I have on this). But water-soluble, dissolved solutes are subject to no such temporal barrier to entry into the duodenum and jejunum.
All or most of the ATP could be dephosphorylated by intestinal epithelial cells, anyway, and this would still probably not limit the bioavailability, in my opinion. If ATP or a nucleoside monophosphate (a nucleotide is a nucleoside that has been phosphorylated and is a monophosphate, diphosphate, or triphosphate) were dephosphorylated before it either had diffused, by paracellular diffusion, between jejunal epithelial cells, or entered the cytosol of a jejunal epithelial cell, this "early dephosphorylation" could, in fact, limit its solubility, in my opinion. But I think the rate of absorption would be so rapid as to preclude that effect. I don't have time to link to the many websites on the internet that provide solubility data for nucleosides, but adenosine and guanosine, for example, are much less soluble than adenosine monophosphate disodium and guanosine monophosphate disodium are, for example. Again, I don't see how the dephosphorylation could occur before the rapid absorption of a nucleotide in a capsule or solution. There are alkaline phosphatase enzymes that, I think, may be able to dephosphorylate triphosphorylated nucleosides (such as ATP) prior to carrier-mediated transport or paracellular diffusion, but I think those "digestive, enzymatic dephosphorylation" reactions are slow in comparison to the rate of passive diffusion, intercellularly, of small molecules across the intestinal barrier. People tend to overestimate the "strictness" of the intestinal absorption barrier, as I've discussed in recent postings. I've seen many articles refer to the fact that nucleotides probably are absorbed en masse by paracellular, passive diffusion, and the fact that the nucleotides have a net charge, on the phosphate groups, is, in my opinion, of little consequence or concern.
A separate issue is the rate of degradation of guanosine to guanine and xanthine and uric acid (urate), by guanine deaminase and xanthine oxidoreductase/xanthine oxidase, and of adenosine to inosine, xanthine, and urate in either the intestinal tract or elsewhere. The authors of one article I have cite evidence that xanthine oxidase activity is lower in the fasting state (meaning before breakfast, not between meals), and that might suggest that some small bioavailability enhancement could occur in the fasting state. Incidentally, the authors of several articles refer to guanosine as being, perhaps, more absorbable than other free nucleosides, and it's interesting that its plasma concentration is normally extremely low. The CSF concentration is something like 500 nM, I think, though, in rodents, and guanosine nucleotides are exported from the liver or kidneys following fructose loads, etc. Guanase (guanine deaminase) is widely distributed throughout the body. The reason bioavailability is so important with purines is that purines are metabolized extremely rapidly by every cell in the body, including red blood cells.
There are many articles showing that oral guanosine, dissolved in the drinking water of rats, is bioavailable enough to enter the brain and produce neuroprotection against otherwise-lethal experimental treatments with neurotoxins (glutamatergic drugs, such as kainate and quinolinic acid, that exert convulsant effects, etc.) (see here for some of the references: http://hardcorephysiologyfun.blogspot.com/2009/01/anticonvulsant-effects-of-oral.html). But the researchers ultimately had to switch to using guanosine monophosphate disodium, which is much more soluble than guanosine. But those and other articles suggest to me that free adenosine and guanosine nucleotides have significant bioavailability. I don't like to do this, but it's just potentially a really complicated issue for people. There are large numbers of pitfalls, etc. For example, nucleotides that are not in free form, such as in RNA or DNA chains, would also not be expected to be bioavailable, in my opinion. The rate of phosphorolysis of the nucleotides would, in my opinion, be too slow to make up for the rapid degradation of the nucleotides into uric acid in the intestinal tract. I'd suggest that anyone who reads this consult with his or her doctor before using any products, obviously. I have no idea what the percentage of the individual nucleotides is, but the molar masses might be expected, in an equimolar mixture, to make the contents or percentages "weigh" in favor of the purines [meaning that more than 1/2 of a mixture would be purines (guanosine monophosphate + adenosine monophosphate)]. I might be getting that backwards, though, because I don't have time to do the math. Inosine is fairly widely available, as far as I know. Anyone using purines should really have his or her uric acid levels monitored at some times, even though the uric acid production from adenosine tends to be lower than the production from inosine and guanosine. I have an article that compares the different purines in those terms, but it's not the only way to compare them. An over-the-counter source of uridine has been used in some clinical trials in people with HIV-associated lipoatrophy/lipodystrophy.
I don't know if anyone is reading this, but I'm just trying to provide this information and am not trying to make any other types of assessments, etc. There are many articles on the use of nucleotides in animal research (http://scholar.google.com/scholar?q=dietary+nucleotides&hl=en&lr=), but it's important to note that, in my view, the amounts of nucleotides and nucleosides that exist in foods and that are likely to be able to reach the brain, after one ingests the foods, are likely to be very small. I talked about it in the link to my past posting, below, but there's, arguably, a limit to the dosage of purines that a human can reasonably consume, given the production of uric acid from the purines.
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