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.