Showing posts with label Dicaffeoylquinic acid. Show all posts
Showing posts with label Dicaffeoylquinic acid. Show all posts

Wednesday, 1 November 2017

OAT3 inhibitors for Bumetanide - Probenecid, but also Aspirin, Chlorogenic acid (Coffee), Epicatechin (Cocoa, Cinnamon) and more.

Today’s post is about OAT3, highlighted by the green lines.
The interventions reduce renal excretion and raise plasma
concentration rather than directly improving transport across the BBB

Today’s post is a collaboration. Our reader Ling pointed out research trying to boost the bioavailability of bumetanide using something clever called an OAT3 inhibitor.  This would reduce the rate at which the body excretes bumetanide and thus potentially improve its therapeutic effect.
Petra, our reader from Greece, pointed out that in her son Bumetanide seemed to work better when taken with Greek coffee and that that Greek Grandpas like to take their diuretics with a steaming Greek coffee.
Most people, me included, automatically think caffeine when someone mentions coffee.
So I assumed that caffeine might be an OAT3 inhibitor and I did make some experiments on that basis. There is no research data to support caffeine as an OAT3 inhibitor.
Recently I was again looking for other potential Bumetanide boosters.  The obvious one is called Probenecid.  Probenecid is used to treat gout because it lowers uric acid.
Aspirin has some odd effects; low dose aspirin will raise uric acid, but high dose aspirin will lower it. Aspirin is an OAT3 inhibitor.
OATs are a very niche subject, to add to the confusion sometimes you are better looking for SLC22A8, the gene that encodes the transporter. 
There was an earlier post on this subject, which showed that many NSAIDs inhibit OAT3, including Knut’s favourite Ponstan. They are not so well suited to continued use.

At the end of my little investigation I figured it out; there are many OAT3 inhibitors available, including some in your kitchen.  

Key points on OAT3 (Organic Anion Transporter 3)
If you want to increase the peak concentration and indeed the half-life of a drug that is excreted from the body by OAT3 (organic anion transporter 3), an OAT inhibitor is what you need.
The drug Probenecid is by far the best known OAT3 inhibitor and it is very potent. It has long been to boost the performance of penicillin type antibiotics to treat tough bacterial infections.
Probenecid, if available, may very well be the ideal bumetanide booster.
For adults a simple option is Greek/Turkish coffee. I see little downside as long as you can handle the caffeine. The Greeks live a long time and drink plenty of coffee.
For those who do not like caffeine you can go to active components within the coffee, which seem to be the chlorogenic acids (1,3- and 1,5-dicaffeoylquinic acid). They are sold as a weight loss supplement, the long established version is the French-made Svetol, but there are now others. They still contain 2- 3% caffeine.
Epicatechin, found in cinnamon, dark chocolate and high flavanol cocoa is another OAT3 inhibitor. Cocoavia, made by Mars, is used by some readers of this blog. Cocoa flavanols do clever things with nitric oxide (NO) and have been shown to improve mild cognitive impairment (MCI) and heart health by improving blood vessel elasticity.
Catechins are flavanols belonging to a family of closely related compounds, such as epicatechin, epigallocatechin, epicatechin gallate (EGC), and epigallocatechin gallate (EGCG). They are all slightly different. Catechin itself is not an OAT3 inhibitor; EGCG may or may not be.
Low dose aspirin is likely the cheapest OAT3 inhibitor. It also increases peripheral circulation, which could benefit some. Low dose aspirin has the downside of a small bleeding risk, mainly in old people, and there is a risk of Reye’s syndrome if given during/after a viral infection.
I think for adults a Greek coffee may be the best. For people who have a profound benefit from Bumetanide, I think they should look into Probenecid.
Personally I think Svetol is worth a try.
Coffee that has been extensively processed (just as we saw with cocoa) may not have the same chlorogenic acid content as the more gritty coffee used in the Balkans. Coffee consumption is actually associated with many neurological benefits, reducing the incidence of Parkinson’s and Alzheimer’s; the common mistake in research is the assumption that the effect must be from caffeine.

The health effects of decaffeinated Coffee
My eureka moment in this post was reading about gout and coffee and then decaffeinated coffee. 

So then it was a question of finding what in coffee could be the OAT3 inhibitor. At which point I found a very insightful paper that tells you everything, once you realise that:

Coffee = chlorogenic acids  = 1,3- and 1,5-dicaffeoylquinic acid

Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions

3.2. Inhibition of hOAT3 by Natural Anionic Compounds and Flavonoids

Human OAT3 expressing cells showed about 4-fold greater accumulation of ES as compared to background control cells ( versus  pmol mg 10  , resp.). Similar to hOAT1, hOAT3-mediated ES uptake was completely (>96% inhibition) blocked by probenecid (Figure 4). Five of the compounds, 1,3- and 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acids (15 : 1) and (17 : 1), significantly inhibited hOAT3-mediated transport at 50-fold excess (Figure 4). 1,3-Dicaffeoylquinic acid and ginkgolic acid (17 : 1) exhibited 41% inhibition, while 30–35% reduction of hOAT3-mediated ES uptake was observed for 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acid (15 : 1). Catechin, 18β-glycyrrhetinic acid, and ursolic acid failed to produce significant inhibition. Based on the level of inhibition observed, values for all of these compounds would be greater than 50 μM, much higher than clinically relevant concentrations (Table 1). Therefore, further dose-response studies were not performed.

Lay off the Lycopene?
Lycopene does the opposite of what we want. Too much lycopene may lower the effectiveness of a drug that is excreted via OAT3. 

2.29. Lycopene

Lycopene is a carotenoid pigment found in tomato [94]. Lycopene from dietary sources has been shown to reduce the risk of some chronic diseases including cancer and cardiovascular disorders [95]. The administration of lycopene significantly normalized the kidney function and antioxidant status of CSP-treated animals. Furthermore, lycopene also increased the expression of the organic anion and cation transporters (OAT and OCT, resp.) including OAT1, OAT3, OCT1, and OCT2 in the renal tissues [9698]. In addition, lycopene also decreased the renal efflux transporters (multidrug resistance-associated protein [MRP]-2 and MRP4) levels and induced Nrf2 activation, which activated the antioxidant defense system [99]. Furthermore, lycopene protected against CSP-induced renal injury by modulating proapoptotic Bax and antiapoptotic Bcl-2 expressions and enhancing heat shock protein (HSP) expression [97].                                                                                                                  

I actually started out this post by looking at what dose of aspirin might be effective in inhibiting OAT3.  We do know that Aspirin is indeed an OAT3 inhibitor.  

I did find the answer, but along the way you do end up having to look at uric acid. 
Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1 Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1. 
Uricosuric drugs increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. 
In general, uricosuric drugs act on as urate transporter 1 (URAT1). URAT1 is the central mediator in the transport of uric acid from the kidney into the blood.  By their mechanism of action, some uricosurics (such as  probenecid) increase the blood plasma concentration of certain other drugs and their metabolic products  – this is their effect on OAT3.
Probenecid is a medication that increases uric acid excretion in the urine.
Atorvastatin is a so-called secondary uricosuric. High dose aspirin should also be called a secondary uricosuric.
Antiuricosuric drugs raise serum uric acid levels and lower urine uric acid levels. These drugs include all diuretics and low dose aspirin. 
Low dose aspirin inhibits OAT1 and OAT3 which reduces urate secretion, but high dose aspirin inhibits URAT1 and reduces urate re absorption. This is sometimes known as the biphasic effect.
So low dose aspirin will increase plasma uric acid, but high dose aspirin has the same effect as Probenecid, it lowers plasma uric acid levels.
So Aspirin and Probenecid both affect URAT1 and OAT3. 

At what dose is Aspirin an OAT3 inhibitor?
If we just want aspirin to inhibit OAT3 and not inhibit URAT1, what dose is effective? Fortunately this has been answered in the research. The typical low dose of aspirin (75mg) used preventatively in older people is OAT3 inhibiting, it raises plasma uric acid.  


Salicylic acid and its derivatives are the most prescribed analgesic, antipyretic, and anti-inflammatory agents. Salicylates have a “paradoxical effect” on the handling of uric acid by the kidney. The action of salicylates on uric acid excretion depends on the dose of salicylates. At doses of less than 2.5 g/day, salicylates cause the retention of uric acid by blocking the tubular secretion of uric acid, while at dose of higher than 3 g/day, they cause increased urinary excretion of uric acid [70]. Mini-dose aspirin, even at a dosage of 75 mg/day, caused a decrease in uric acid excretion and raised serum uric acid level [71]. It has been suggested that the “paradoxical effect” of salicylate can be explained by two modes of salicylate interaction with URAT1: (1) acting as an exchange substrate to facilitate uric acid reabsorption, and (2) acting as an inhibitor for uric acid reabsorption [72]. Low dose of salicylate interact with OAT1/OAT3, the uric acid secreters [73].

Low dose aspirin leads to decreased renal excretion of uric acid and raised serum uric acid levels, which can cause a gout attack in those predisposed to this condition.
High doses of aspirin lower serum uric acid concentration.

Reye’s Syndrome
In children aspirin is very rarely used because of the risk of Reye’s syndrome. Reye’s syndrome causes severe liver and brain damage. It is a type of severe mitochondrial failure that can occur after a viral infection like flu or chickenpox, but it almost only occurs when aspirin has been prescribed. Nobody knows for sure the exact mechanism of the disease.
So do not give aspirin to children with a viral infection.  We already know to avoid paracetamol/acetaminophen (Tylenol in the US) in babies/children and people with autism. Paracetamol/acetaminophen depletes the body’s key antioxidant GSH. 
If someone overdoses on Paracetamol/acetaminophen you give them a high dose of NAC to prevent death. 

Given how long it takes to develop new drugs, I think that improving the pharmokinetics of bumetanide is a pretty obvious thing to do. 
Diamox is an OAT3 inhibitor and our reader Agnieszka found it beneficial only when administered along with Bumetanide.
Strong coffee is an OAT3 inhibitor and this was found to enhance bumetanide by Petra’s son with Asperger’s.
Cinnamon which contains epicatechin, another OAT3 inhibitor, did seem to be helpful in Monty who also takes bumetanide.
I suspect Diamox may be the most potent OAT3 inhibitor of those three
The interesting OAT3 inhibitors seem to be:-

·        Probenecid

·        Low dose aspirin

·        Epicatechin (cocoa, cinnamon ..)

·        Chlorogenic acids (coffee and decaffeinated green coffee extracts) 

Cinnamon, high flavanol cocoa and indeed coffee (minus the caffeine) have numerous health benefits.
Note that Catechin has no effect on OAT3. EGCG was not tested but in other studies has been shown it does affect.

The logical next step would be to improve bumetanide transport across the blood brain barrier.