Dissolution of the drug
After disintegration, a drug must become dissolved to be absorbed. This
dissolution process is affected by several variables, such as gastric
volume, gastric pH, and gastric transition time. After RYGB surgery,
there is limited exposure to acid, which is in contrast with a SG
procedure upon which the acid exposure time rises12,13. In any case, bariatric surgery patients are
generally prescribed prophylactic PPIs to reduce the risk of
gastro-intestinal complications after surgery, such as ulceration or
gastro-intestinal bleeding during the first months after surgery24,25. Due to this rise in pH, the solubility of more
basic drugs could decrease since they become less ionized, and the
solubility of acidic drugs could increase since they become more
ionized. Dissolution should, however, not be confused with absorption.
Ionized drugs have good solubility and show generally lower absorption
than unionized drugs, which are, in general less soluble. In healthy
subjects, the stomach is capable of absorbing most acidic drugs and the
very weakly basic drugs which are undissociated in the acidic gastric
environment 26. After surgery, the proposed rise in pH
could lead to reduced absorption of these drugs in the stomach. This
effect, however, should primarily affect the dissolution in the stomach,
where usually only a small degree of drug absorption takes place, and
the effect could, therefore, be small. In addition, there are other
factors of relevance for dissolution other than altered pH, like gastric
volume and transition time.
An example of a drug that is absorbed in the stomach is acetylsalicylic
acid, which is unionized in the acidic environment of the stomach upon
which it can be absorbed 26. Theoretically, because of
the higher pH, the absorption and exposure of acetylsalicylic acid (ASA)
could be reduced in patients after bariatric surgery. Mitrov-Winkelmolen
et al. studied the effect of RYGB on the pharmacokinetics of orally
administrated ASA before and six weeks after RYGB surgery27. Instead of a lower AUC, they found a significant
increase in AUC (14.1 vs. 11.4 mg h/l), an increased Cmax (4.6 vs. 3.5
mg/l) and a significantly decreased Tmax (0.7 vs. 1 hour) six weeks
after RYGB surgery. According to the authors, the higher AUC and Cmax
suggest that absorption of acetylsalicylic acid, even when occurring
mainly in ionized form because of the elevated pH, can also take place
in the jejunum where it may even exceed absorption in the stomach and
duodenum. Regarding these results, it is unknown what the contribution
of the higher pH and/or altered gastric emptying and transit time of the
GI tract is, as all of these changes occur simultaneously after
bariatric surgery.
The weak base posaconazole is another example of a drug where the
absorption is related to the residence time in the acidic environment of
the stomach. Several studies showed the dependence of posaconazole
absorption on the pH, resulting in the avoidance of PPI in patients
using posaconazole 28,29. As in bariatric surgery
patients, a higher pH and faster gastric emptying may be expected,
Gesquiere et al. performed a single-dose pharmacokinetic study in 12
RYGB surgery patients before and 6-9 months after surgery. After
surgery, the AUC0–∞ was significantly reduced (9.49 vs.
4.37 ug ml/h, p<0.05), which was explained by the low
solubility of posaconazole, of which the absorption is very sensitive to
intraluminal pH and residence time in the stomach 30.
As the decrease in AUC was more extensive than would be expected based
on pH-related changes in absorption alone, the authors suggest that the
reduced residence time after RYGB surgery contributes to their findings.
From these reports, it seems that the acidic drug acetylsalicylic acid
is absorbed after RYGB surgery even when the pH in the stomach is
decreased. However, the weak base posaconazole is, as expected, not
absorbed, resulting in a lower AUC0–∞ in RYGB surgery
patients.