Toxic metals and drug transporters – is there a concern?

Membrane transporters

Membrane transporters are euphemistically called “drug transporters” however their primary role is to move physiological substances to sites requiring their presence. There is a lot of drug company interest in transporters for 2 reasons, being -

•  US FDA now requires this information to be included in drug discovery submissions, and
•  drug companies consider they may be the vehicles to provide access to the bits of the body their drugs currently can’t currently access, or find it difficult to access such as crossing the blood-brain barrier.

Transporters have 3 mechanisms of action, being -

 - Inducer – enhances the effectiveness of the substance being transported. A well-known example is grapefruit juice and cytochrome P450 isoform 3A4 whereby grapefruit increases the effectiveness of some drugs such as felodipine/nifedipine;

 - Inhibitor – blocks the effectiveness of the transporter for a period of time – seemingly typically about 1 hour. For example, metformin inhibits THTR2 (Thiamine Transporter 2) ie the transporter of thiamine from the intestines;

 - Substrate – can be carried by the substance. For example, metformin is a substrate for OCT 2 (Organic Cation Transporter 2) which transports thiamine to the kidneys.

Toxic metals

Toxic metals have a capacity for molecular mimicry and can be carried by the same transporters as nutrients however are not regulated by physiological processes in the same way as the essential elements and therefore can cause harm. It also means that once absorbed, toxic metals can be transported throughout the body to many of the same sites available to the essential elements.

Toxic metals and transporters

Examples of “shared” transporters include -

• arsenic can travel on glucose transporters, water channels, thiamine and phosphate transporters;
• cadmium (Cd) can be transported on thiamine, zinc, iron, magnesium and calcium transporters, and albumin;
• lead can travel on calcium and zinc transporters;
• mercury can be transported by albumin, homocysteine, and a range of other substances, inhibits aquaporins (water channels), and is a substrate for some transporters.

Toxic metals hidden harm

What makes many of the toxic metals even more harmful is that they are stored in the body in organs such as the liver and bone. Using bone as an example, continuous bone remodelling means the bone is constantly releasing and taking up toxic metals.

A hidden form of harm is the competition between toxic metals, prescribed medicines and nutritional factors for access to relevant transporters, and seemingly it all depends upon which one gets to the transporter first. Using thiamine, metformin and cadmium as an example:

 - thiamine is typically absorbed during the meal, and so if there is no competition, will be first on the transporter,

 - metformin is a substrate for many of the thiamine transporters, and is typically administered before meals therefore is likely to have first access to the transporters and so will fill the transporter slots and therefore the thiamine in that meal will not be transported,

 - cadmium is also a substrate for some of the thiamine transporters, is typically in a state of flux ie being released and taken up by various body processes, and is therefore more likely to be available to fill the transporter slots first and so neither metformin nor thiamine will be transported. In this example the long term consequences are altered therapeutic benefit from the metformin and hidden malnutrition due to sustained chronic inadequate thiamine uptake.

The utilisation of transporters by toxic metals via molecular mimicry is in the early stages of research, however the early findings are pointing to areas of harm not previously considered ie the alteration to therapeutic benefits conferred by prescribed medicines, and the mal-nutrition impacts.

Clinical Question 

Do you consider environmental impacts in your daily clinical practice?

Case study

The comments refer to the drug-nutrient, drug-food, and PharmacoNutrition effects only.

Data summary

Medical History with Nutritional Aspect

Biochemistry with Pharmaconutritional Consequences

Medications That May Adversely Affect Nutritional Status

Biochemistry

Although recent relevant biochemistry indicates markers of concern, none seem to be related to the currently prescribed medicines.

Glycaemia

Mr AAP is at increased risk of diabetes as a consequence of some of his prescribed medicines include altered glycaemia as a side effect in conjunction with likely dysfunctional mitochondria.

Pharmaconutrition comments

There is some evidence that concurrent administration of magnesium with epilim (Sodium valproate) enhances epilim's anticonvulsant effect.

Ferrograd+C (Ferrous sulfate + ascorbic acid) comprises ferrous sulfate + vitamin C. Iron is available in two forms being ferrous and ferric - ferrous is the absorbable form whilst ferric requires vitamin C to convert it to ferrous in order to be absorbed. The combination of iron in a ferrous form plus vitamin C is unnecessary and implies the drug company is being disingenuous. Ferrograd+C has a very slow rate of dissolution and poor rate of absorption ie less than 30%. Both ferrous sulfate and ferrous fumarate have rapid rates of dissolution and higher rates of absorption. Advisable to review iron intervention and consider alternative, more effective products as outlined.

Chronic use of lactulose may decrease water and electrolytes, especially potassium, and their regular monitoring recommended.

Regular monitoring sodium levels recommended whilst sertraline prescribed as there is increased risk of hyponatraemia - hyponatraemia is associated with increased risk of falls and poor appetite.

Thiamine

At increased risk of thiamine deficiency as lamictal (lamotrigine) is both an inhibitor and substrate for some of the thiamine transporters therefore advisable to consider a thiamine intervention. Advisable to administer thiamine intervention at a time when none of the inhibitors and substrates are administered. Very early evidence indicates nutrient interventions are effective if administered either one hour before or two hours after drug administration.

If a thiamine intervention is initiated then advisable to consider a magnesium intervention (to provide ~ 300 mg elemental magnesium/day) as adequate magnesium status is essential for activation of thiamine, vitamin D and iodine. 

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The information in this article is provided to support Health Professionals. It is not an exhaustive protocol and Health Professionals are advised that adequate professional supervision is accessed to ensure that Duty of Care obligations with respect to safe administration of medicines is met for each consumer.