Could the difference between absorption time of Diclofenac Sodium and Diclofenac Potassium be related to the cation?

Diclofenac is a common non-steroidal anti-inflammatory drugs (NSAID) that comes in a variety of formulations. Two of the most common forms are diclofenac sodium and diclofenac potassium (the links refer to the FDA prescribing information of both forms). I have heard several times that the Potassium salt starts to act faster than the sodium salt.

In the second page of both leaflets above there is a table with pharmacokinetic parameters:

1. For diclofenac potassium, Tmax (the time it takes to reach maximum concentration after one dose) is 1.0 hour, and the half-life (the time it takes the drug concentration to go down by 50%) is 1.9 hours.
2. For diclofenac sodium, Tmax is 2.3 hours, and the half-life (the time it takes the drug concentration to go down by 50%) is 2.3 hours too. This means that for the sodium salt is being "processed" (absorbed, metabolized, eliminated) by the body more slowly than the potassium salt.

One more important point of difference to note is that the sodium salt comes in enteric-coated tablets, while the potassium salt comes in immediate-release tablets.

My question is: Can the difference in "processing time" of both salts by the body stem from the different salts, or is it due to the pharmaceutical formulation (EC tablets compared to IR tablets)?

It might seem at first glance that the difference in formulation should be the answer, but if it is so, why is the cation different between formulations?

I hope anyone can shed light on the mechanism, I was unable to find any useful information that actually addressed this issue.

• I'd guess that the difference is due to different $\text{T}_\text{max}$ values. So the peak concentration of diclofenac itself would be greater for the potassium salt, and lower for the sodium enteric-coated salt. So at the peak of the sodium enteric-coated form some of the salt is still dissolving. – MaxW Jan 31 '17 at 20:16

Under physiological conditions, the counter-ion is almost entirely dissociated from the drug, meaning that the identity of the counter-ion isn't directly responsible for how well a drug performs. This has been looked at extensively by medicinal/formulation chemists, who often screen many salt forms looking for desirable properties.

From the graph below, you can see that the plasma concentration curves are essentially identical for sodium, potassium, and calcium salts (slight variation in Cmax and Tmax but within experimental error):

Source: Drug Like Properties: concepts, structure, design and methods, Chapter 7

One case in which the identify of the cation does matter is where there is a common ion in the body. This 'common ion' effect is most common when amine drugs are presented as their hydrochloride salts. The stomach is acidic (hydrochloric acid), and therefore the presence of a high concentration of chloride ions can prevent the salt from turning into the free drug.

What is likely to be different between different cations the form that the salt takes. Different salt forms have different packings (some might be amorphous, some might be highly crystalline and ordered). The formulation may also differ (powder coated tables vs gelatine capsules), which will change the time it takes for the drug to be released/absorbed.

• Can you link the reference for this graph? Particularly, was this a mouse study? – khaverim Jul 1 '17 at 14:54
• The reference is below the graph already, you'd need to look up the book – NotEvans. Jul 1 '17 at 14:55
• This is the original paper: onlinelibrary.wiley.com/doi/10.1002/jps.2600630512/full – khaverim Jul 1 '17 at 15:07

My guess is that this would due almost entirely to the formulation. The sodium and potassium are ions and bound ionically to the organic portion of the molecule. That is to say, these compound are "salts". When in the aqueous tissue of your body the Na and K ions likely dissociate to a large extent leaving identical anions which offer the physiological effect.