What tracers do you have in mind ?

Thanks for your answer. I currently work with 11C-donepezil and 18F-FEOBV, which targets acetylcholinesterase and the vesicular acetylcholine transporter, respectively. We are testing these tracers in various disease conditions, including imaging of the gastrointestinal tract. Both are to a certain extent excreted via the bile, but it would be nice to know if the tracers potentially also could be secreted directly from the mucosa itself to the gastrointestinal lumen.

In clinical Nuclear Medicine, we see a number of radiopharmaceuticals reaching the intestinal lumen through a variety of mechanisms.

Radiolabeled leucocytes are shedded to the lumen  at a low rate and in increased amounts at sites of inflammation.

Gallium reaches the lumen directly.

Lipophylic substances such as 99mTc-HIDA 99,Tc-sestaMIBI and 99mTc tetrofosmin are excreted via the bile.

Some 111In-somatostatin reaches the lumen especially in case of inflammatory disease.

Same for 123I-MIBG

99mTc-pertechnetate enter the lumen with the gastric juices and occasionally ectopic gastric mucosa excretes pertechnatate too. Same for iodides.

So: in case of Gallium / 123I-MIBG / 111In-somatostatine / radiolabeled leucocytes the tracer reaches the lumen through the mucosa. Whether secretion is the mechanism is often not known.

Dear Judocus, thank you very much for your comprehensive reply. I really appreciate it.

I am also a clinical nuclear medicine specialist, and have worked with all the tracers you mention - except gallium. My question is really what kind of mechanisms subserve the secretion we sometimes see. Obviously, biliary secretion is a well known and easy-to-spot phenomenon. Also, in the case of pertechnetate, 131-I, and (I guess also) gallium, the secretion is via well-known transporters. The slow excretion of leukocytes maybe a part of the normal shedding of the luminal layers of intestinal mucosa.

But I wonder which mechanisms are responsible for secretion of substances like MIBG and peptides like somatostatin. As mentioned I work with donepezil and FEOBV - both small molecules - and I have been searching for papers which describe the potential mechanisms and principles of which molecules get secreted in this way, and which that do not. Would you happen to know of any good papers or books, which describe this issue?

Dear Per,

I do understand your interest in specific mechanisms for transport of small molecules across the intestinal mucosa. However I am always suprised how little usually does leak into the lumen. Some reuptake may account for that, but the extent of aspecific 'leakage' is significant.

Given the very large effective surface area of the intestinal mucosa, measured in tens of square meters, even a relatively smal 'leakage' when expressed per square meter, adds up to a large amount.

On a daily basis, about 250 grams of mucosal cells, equivalent to 25 gram protein is shed into the lumen.

Most radiopharmaceuticals are [by design or selection] capable of leaving the vascular space and passing the basal membrane. It is often a requirement, else specific binding sites may not be reached.

In the villi the tissue 'outside'  the basal membrane lining the endothelial cells and underneath the mucosal cells are relatively loosely connected and all sorts of inflammatory cells migrate there freely. Also nerve endings can be found there. These inflammatory cells and nerve endings have a lot of receptors and small peptides exposed at their the outside. These cells, when dead,  and parts of the nerve endings are shedded from there too. Any radiopharmacon binding to these receptors will be shedded too.

At the mucosal cells themselves a number of more *and* less specific 'transport' processes take place, where a certain 'leakage' cannot be avoided.

I.e. given the mechanism by which  triglicerydes are taken up from the intestinal lumen, it is very difficult to believe that absolutely  no leakage from intracellular space to the lumen takes place.

The same is true at the other side of the mucosal cells.

Quantitatively such leaks are minor when compared to the amounts of metabolites transported, but on the scale of the entire intestines, the net effect can not be neglected.

This 'leakage' is, when expressed as a ratio is so little that it is neglected or left unmentioned in literature, or it is assumed that normal homeostatic mechanisms deal with the side effects.

So, given the abundancy of various bindingsites in the extravascular space, just behind the mucosal cells and given the various 'aspecific leaks' discussed, I wonder, if you have any evidence of SPECIFIC transport of any radiopharmaceutical  along the normal mucosal cells, from the blood stream towards the intestinal lumen ?

For me the primary suspects would be the various transporter proteins that internalize various ions / small molecules [often] in exchange for others. For each combination of radiopharmaceutical and transporter mechanism one should do specific tests, which is a major research project in it self.

I personally am not aware of any *specific* mechanism [for transport from the bloodstream to the intestinal lumen]. For transport 'inward' , the situation is quite different [i.e. strontium isotopes & calcium uptake mechanisms].

I am not aware of any radiopharmaceutical that has a faecal excretion beyond what could reasonably be expected from any of the mechanisms mentioned before [i.e. biliary excretion].

Dear Judocus, once again many thanks for your comprehensive reply. It has been very helpful and I will try to find some literature on your proposed mechanisms !

Dear Per,

This may not be directly relevant to you question, but donepezil is a potent sigma-1 receptor agonist and is not only an AChEI. There are sigma-1 receptors in the intestines and donepezil dose dependently binds there. Please see table 1 in the below publication.

http://www.ncbi.nlm.nih.gov/pubmed/24639047

Regards,

Nisha

Dear Nisha,

Thank you ! Yes, I am well aware of the sigma-1 binding. I know your paper :-) As well as papers by van Warde (JNM 2006) and Ishikawa (Int J Neuropsychpharm 2009), which demonstrates this. However, this still does no address whether there may or may not be secretion/excretion from the GI-tract to the GI-lumen.

Your study was very nice in that you measured biodistribution in organs post-mortem. As I recall you showed high binding (activity) in the intestine. Did you happen to measure the activity in the the bowel-lumen (i.e. content) !! This would to a certain extent answer the question, if there is substantial radioactivity in the contents? In this scenario you could probably only use data from the large intestine, since the small intestine contents would probably be confounded by radioactive contribution from bile-secretion, but the radioactive bile would probably not make it all the way to the large intestine in the short time span?

Thanks - Per

Dear Per,

Unfortunately we did not look at the lumen contents. We scraped the contents off. I believe this was because of previous observations of high variability due to weight of contents diluting the actual radioactivity in the organ.

I am glad that you know my paper!

Regards,

Nisha

@Nisha & Per, 

Re lumen contents:

In the past heparin was industrially produced from the intestines of pigs. A sort of simple mangling device, was used to press the mucus out of the intestinal lumen, leaving the intestines otherwise intact.

This may be a much more practical approach than opening the lumen and scraping. And it may be adapted to use for smaller animals.

From the radiation protection point of view this would also be preferable.

This approach was especially usable for the small intestines, to 'harvest' the polysacharid moiety from the small intestinal wall that was used as raw material for heparin production.

A large percentage of all intestines in slaughterhouses in Holland were used in this production. If I remember wel, the Organon company, formerly in Oss [city in The Netherlands] were the largest producer world wide.

If needed I can probably dig up some references on this technique, but these are all at least 15 years old.

A short "summary" about drug excretion, also mentioning drug weight and lipophilocity : http://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-excretion 

and for those who want to read more: http://classes.biology.ucsd.edu/bimm118.WI11/PPT%20Lecture%20Notes/Lecture%203.pdf

http://www.slideshare.net/mobile/homebwoi/drug-excretion-lecture-10

Interesting and good discussion!

Dear Jacek,

Thanks a lot for these references. I really appreciate it.

By the way - I found this paper on ivermectin. It is excreted 5-fold more from the intestinal mucosa than through biliary excretion.

http://dmd.aspetjournals.org/content/30/6/626.full.pdf

Best wishes - Per