Aluminum
hydroxide Al(OH)3 is a common ingredient in many over-the-counter (OTC)
oral antacid medications. It is also used in the short-term as an
oral phosphate binder in patients with hyperphosphatemia secondary to chronic
kidney disease. When using aluminum based products as an
antacid, the short duration of action requires frequent administration
throughout the day. Due to its availability OTC, the route, the frequency
of administration throughout the day, and the recognition that many people
prefer to take all of their medications at the same time, it is plausible that
the introduction of levofloxacin (Levaquin) for the treatment of a bacterial
infection could be met with the presence of a tri-valent cation, such as
aluminum. The coadministration of levofloxacin and aluminum hydroxide can
result in a reduction in the overall absorption and bioavailability of levofloxacin
thus increasing the risk of the patient either developing bacterial drug
resistance and/or treatment failure.(1)
How
does aluminum specifically interact with levofloxacin to cause a reduction in
absorption or bioavailability?
-
A basic evaluation of the chemical structure of levofloxacin reveals that each
levofloxacin molecule has one carboxyl group (R-COOH) as part of its structure.(2) The important thing to note about this carboxyl group as
it relates to an interaction with aluminum is its ionization state (i.e.,
whether it is charged or uncharged). The carboxyl group becomes
negatively charged when it releases its hydrogen (H+) ion. This process
is determined by its pKa.
- The pKa for carboxyl groups is approximately
1.8 to 2.4.(3) Therefore, a pH above this pKa would result in a greater
percentage of the carboxyl groups on levofloxacin being ionized (or in their
negatively charged state).
- Depending on other medications being taken by
the patient (such as antacids, H2 receptor antagonists or proton pump
inhibitors) and the type of food ingested, the pH of the stomach can easily
range from 1 to 6; thus, it is likely that the pKa of the carboxyl group will
be exceeded. However, even if the patient only takes the aluminum hydroxide
along with the levofloxacin on an empty stomach, the aluminum hydroxide itself
can interact with hydrochloric acid from the stomach to form aluminum chloride
and water which can cause an increase in the gastric pH.
- Therefore, the
magnitude of change in gastric pH (whether it is from aluminum hydroxide itself
or from the combination of aluminum hydroxide and other medications) will
influence the amount of ionized carboxyl groups found on levofloxacin.
Once this ionization has started to occur, the exposed and negatively charged
group on levofloxacin can then bind to the positively charged aluminum (Al3+)
ions that was present in the medication or supplement administered. This
final reaction is what most clinicians refer to when they say that aluminum or
a cation (positively charged molecule) can "chelate"
levofloxacin.
- The degree or significance of this interaction is, however,
dependent on the time of their exposure to one another and the pH of the
environment at the time. A 2 to 4 hour separation of the aluminum
containing product and the levofloxacin can avoid this interaction. Binding
or "chelation" of the levofloxacin and aluminum will result in
decreased absorption or bioavailability of levofloxacin and potentially
increase the risk for treatment failure of the infection. The risk of
failure to treat the infection will obviously also be influenced by the minimum
inhibitory concentration (MIC) of the bacteria and the tissue being targeted.
