Organic Anion Transporters (OATs) and pharmaconutrition

Role/function

OATs are primarily influx transporters albeit some are bidirectional, that with their multi-specific binding pockets are able to transport a wide variety of anionic and cationic substances into the kidney and then regulate their rate of excretion.

OATP Isoforms

There are 11 known human isoforms as summarised -

Transporter deficiencies

OAT deficiencies can be long term or short term, and are likely due to -

1. Polymorphisms (variants) – variations of a specific DNA sequence that can involve either a single nucleotide (aka single-nucleotide polymorphism, or SNP), or a longer DNA sequence.

There are many identified OAT-related polymorphisms, for example several OAT4 and URAT1 SNPs are associated with the urate handling anomalies of hyperuricaemia and hypouricemia;

2. Epigenetic - epigenetic regulatory mechanisms are dynamic, potentially inheritable, processes which alter transcriptional activity without affecting DNA sequence and represent a key mechanism for the response to environmental and other changes.

There is increasing evidence of epigenetic regulation of OAT transporter expression levels with potential functional consequences.

3. Environmental – likely to manifest at any age and is dependent upon the environmental insult -

Identified inhibitors include –

• cigarette smoke condensate (CSC) cis-inhibited OAT substrate uptake in OAT1- and OAT3-transfected HEK293 cells, in a concentration-dependent manner;
• EGCG (epigallocatechin-3-gallate) is an abundant, potent catechin representing 50−80% of the total catechins, is a component of green tea, and inhibits -
  • OAT1 - mixed-type inhibition,
  • OAT3 - competitive inhibition.

The low EGCG availability in usual tea drinking quantities is unlikely to cause harm, however the risk of harm is increased if there is consumption of high-dose EGCG supplements, and/or consumption of a green tea extract supplement containing multiple inhibitors, and/or decreased renal function such as in the elderly and chronic kidney disease.

Consequences of inhibition -

• OAT1 unavailability alters many metabolic pathways including fatty acid, carnitine, biotin, and many others;
• OAT3 unavailability alters many metabolic pathways including tryptophan, phenylalanine and tyrosine, pyridoxine, benzoate, and others;
• substrates being at risk of decreased renal elimination which means increased plasma exposure to xenobiotics and endogenous metabolites;
• OAT1/3 inhibition conferring protection against mercury-induced renal damage;
• increased plasma pCS concentrations (a uremic toxin) in diagnosed Chronic Kidney Disease even with only one OAT1/3 inhibitor prescribed;
• partial inhibition or competition for OAT1 may increase the risk of metabolic syndrome in part through altering lipid metabolism;
• uric acid-induced reduction in OAT1 membrane distribution which can be normalised with folic acid.
  

OAT1 and OAT3 inhibition can confer either harmful or beneficial impacts. For example, concurrent administration of the antiviral nucleoside analogue cidofovir and the strong OAT1 and OAT3 inhibitor probenecid prevents cidofovir-induced nephrotoxicity – proposed mechanism of action is inhibition of cidofovir uptake.

Can we use transporter inhibition as a strategy to increase nutrient uptake or improve nutritional health? There is now an increasing number of examples whereby drug inhibition of a transporter is a means for increasing cellular or organ uptake of a second drug. I suggest the precedent is established, and all we have to do is -

(a) try and find some evidence in the nutrition sphere,

(b) start discussions in team meetings and possibly with treating GPs about trialling this intervention option, and

(c) for those in a position to trial then monitor excessively, document and publish.

What actions will you initiate when you see someone prescribed some medicines that are transported by an OAT will you –

• clarify adequacy of dietary intake of folic acid, pantothenic acid, pyridoxine, niacin, vit C and carnitine, request blood tests, and then compare findings?
• question whether elevated creatinine and/or uric acid levels are related to the disease or the treatment?
• if there is disagreement between oral intake and blood test results, will you question altered expression of one or more OATs?
• recommend nutrient interventions be administered at different times from the prescribed medicines?

Conclusions

The primary function of OATs is to transport substances to organs and cells, and therefore are very important in the utilisation of a range of nutrients. As is now becoming increasingly common with pharmaceutical interventions, we need to be considering how to utilise transporter function to optimise nutritional health.

Medical History with Nutritional Aspect

Biochemistry with Nutritional Aspect

Medications That May Adversely Affect Nutritional Status

Comments – medication and nutrition effects only

Data summary

Biochemistry 

Relatively recent available biochemistry indicates elevated TSH + elevated T4 - thyroxine dose modified.

Glycaemia 

Currently prescribed 4 medications that alter glycaemia, being amlodipine, oxycodone, paracetamol, levothyroxine.

Pharmaconutrition

Currently prescribed -

   - 5 medications that include diarrhoea as a side effect.

  - 4 medications that include vomiting as a side effect.

  - 3 medications that include nausea, constipation sweating and tremor as side effects.

Chronic use of coloxyl + senna may promote excessive loss of water and electrolytes, especially potassium, and their regular monitoring recommended.

Amlodipine impairs zinc status.

Dietary levels of caffeine intake in conjunction with paracetamol inhibit antinocieception.

Concurrent ingestion of paracetamol and iron resulted increased rate of iron absorption and decreased extent of drug absorption; the authors advise drug and iron to be administered at different times from each other.

Thyroxine triples urinary excretion of carnitine.

Bowel management

   Regular aperient prescribed,

   No PRN interventions prescribed,

   No Nurse Initiated interventions administered.

Staff comments

Staff advise Mrs ACI is often drowsy at breakfast and midday meals and that the drowsiness impacts on her food intake. Staff also commented Mrs ACI wakes as the day progresses and that she eats well in the evenings - from these comments it seems Mrs ACI is an owl rather than a fowl.

Pharmaconutrition assessment

Mrs ACI is a small pale frail lady who was sitting in a fallout chair in the Day Room - she told me she eats well and that the food tastes as good as what she had at home - she refused to answer further questions as she does not know me.

As Mrs ACI is pale and is currently prescribed paracetamol, advisable to check iron levels and if low then short term intervention recommended.

Mrs ACI’s weights are unavailable as she broke her femur resulting in hospitalisation, and then was unable to be weighed for some time therefore adequacy of dietary intake and thyroxine intervention are unknown.

If weekly weighs identify a weight loss trend, then advisable to clarify thyroid function status.

Thyroxine dose is directly related to weight status and as weight status changes so does drug effectiveness therefore advisable to closely monitor thyroid function and weight status during the healing process.

Both vitamin D and amlodipine are P-gp substrates and inhibitors – vitamin D levels are well within acceptable range however is that due to the cholecalciferol intervention, or amlodipine inhibiting P-gp?

Wound healing

Nutritional factors that contribute to wound healing include -

   - weight gain of at least 2-3 kg - indicates adequate energy consumed to free protein for wound healing duties and some extra energy to store as fat for an emergency; weight loss delays the wound healing process and currently prescribed thyroxine therefore advisable to clarify adequacy of the thyroxine intervention, especially since an elevated TSH is noted.

Falls

Mrs ACI’s diagnoses include falls - nutritional factors that may be useful to consider in falls management include -

   - loss of weight – prescribed thyroxine which may alter thyroid function and therefore weight status, therefore advisable to clarify adequacy of the thyroxine intervention, especially since an elevated TSH is noted;

   - low iron – currently prescribed paracetamol therefore advisable to check status;

   - low carnitine - carnitine is both absorbed and produced de novo, and is important in a range of muscle functions; thyroxine decreases carnitine availability therefore advisable to clarify status.

What else would you include?

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