Ion trapping

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The build up of a higher concentration of a drug across a cell membrane due to the pKa value of the drug and difference of pH across the cell membrane is known as ion trapping.

Many cells have other mechanisms to pump a drug molecule inside or outside the cell against the concentration gradient, but these processes are active ones, meaning that they require enzymes and consume cellular energy. In contrast, ion trapping does not require any enzyme or energy. It is similar to osmosis in that they both involve the semipermeable nature of the cell membrane.

Life is an acidogenic process, so most of the cells have a more acidic pH inside the cell than outside (gastric mucosal cells being an exception). Therefore basic drugs (like bupivacaine, pyrimethamine) are more ionized inside the cell than outside. Cell membrane is permeable to non-ionized (fat soluble) molecules, ionized (water soluble) molecules cannot cross it easily. Once a non-ionized molecule of a basic drug crosses the cell membrane to enter the cell, it becomes ionized due to the lower pH inside the cell, and thus becomes unable to cross back. Because transmembrane equilibrium must be maintained, another unionized molecule must diffuse into the cell to repeat the process. Thus its concentration inside the cell increases many times that of the outside. The non-ionized molecules of the drug remain in equal concentration on either side of the cell membrane.

The ionization of a molecule depends upon the pH of its solution. In acidic medium, basic drugs are more ionized and acidic drugs are less ionized. The converse is true for acidic drugs. For example, Naproxen is a non-steroidal anti-inflammatory drug that is a weak acid (its pKa value is 5.0). The gastric juice has a pH of 2.0. It is a 3-fold difference (due to log scale) between its pH and its pKa; therefore there is a 1000x difference between the ionized and unionized concentrations. So, in this case for every one molecule of ionized Naproxen, there are 1000 molecules of unionized Naproxen at a pH of 2.^[1] This is why weak acids are better absorbed from the stomach, weak bases from intestine where pH is alkaline. When pH of a solution is equal to pKa of dissolved drug, then 50% of the drug is ionized, another 50% is unionized.

Ion trapping is the reason why basic (alkaline) drugs are secreted into the stomach (for example morphine)^[2] where pH is acidic, and acidic drugs are excreted in urine when it is alkaline. Similarly, ingesting sodium bicarbonate with amphetamine, a weak base, causes better absorption of amphetamine (in stomach) and its lesser excretion (in urine), thus prolonging its actions. Ion trapping can cause partial failure of certain anti-cancer chemotherapies.^[3]

See also

• Osmosis
• Biophysics
• Forced diuresis
• Henderson-Hasselbalch equation

References

1. ^ www.angelfire.com/tx5/scribe2003/scribe/august/F081709.doc
2. ^ http://www.1911encyclopedia.org/Opium
3. ^ Mahoney BP, Raghunand N, Baggett B, Gillies RJ. (2003 Oct). "Tumor acidity, ion trapping and chemotherapeutics.I Acid pH affects the distribution of chemotherapeutic agents in vitro". Biochem Pharmacol 1;66(7):1207-18. PMID 14505800.