Is the absorption of meclozine (Postafen), tramadol (Tradolan), fluconazole (Flukonazol), capecitab

Fråga: Is the absorption of meclozine (Postafen), tramadol (Tradolan), fluconazole (Flukonazol), capecitabine (Xeloda) or acetylsalicylic acid (Trombyl) significantly reduced after gastrectomy? A 55-year-old man cared for by ASIH (advanced health-care in the home) has undergone a total gastrectomy because of cancer. He has had a bypass operation for impaired circulation in his lower extremities. The patient is currently treated with the drugs listed above.

Sammanfattning: The documentation on how the absorption of different substances is affected by gastrectomy is limited. For fluconazole, capecitabine and acetylsalicylic acid only limited conclusions can be drawn from the literature on the consequences of gastrectomy. Fluconazole might not be affected according to a case report. Capecitabine seems not to be affected but the safety profile after gastrectomy is not sufficiently defined. Acetylsalicylic acid may be affected but in a study comparing gastrectomy patients with healthy volunteers no statistically significant difference in absorption was seen. For meclozine and tramadol no specific information was found.

Svar: The stomach has its primary function as an organ of digestion, some pharmaceuticals are however absorbed. At a normal gastric pH weak acids, such as acetylsalicylic acid, as well as non-ionized drugs and lipophilic substances are absorbed from the stomach (1). Absorption is limited in the stomach though, because of the limited epithelial surface and the short time that substances are in contact with the epithelium compared to the rest of the gastrointestinal tract (2). Since the epithelium is covered with a thick mucous layer and its surface is small compared to the small intestine, factors that increase the rate of gastric emptying will probably increase the rate of absorption irrespective of the characteristics of the drug (1). Drugs that are more soluble at low pH could be affected by a reduced production of gastric acid. A reduced intestinal length and surface can possibly reduce absorption of oral depot drugs. Theoretically these drugs could pass through and leave the gastrointestinal tract faster than they are absorbed (3).

The bioavailability of fluconazole in contrast to other azole drugs is not affected by gastric pH (4). A case report describes a man who had gone through a Billroth II gastrectomy (gastro-jejunostomy) and who was treated with oral fluconazole. His serum concentrations of fluconazole were comparable to steady-state levels in healthy volunteers (5).

No studies were found on absorption of capecitabine in patients who had undergone gastrectomy. In one study the effect of combination therapy with capecitabine and cisplatin is described. 51 % of 223 included patients had undergone gastrectomy. No difference was seen among the different groups in response to treatment. Differences in frequency of adverse events are not described (6). In a letter to the editor Fornaro et al discusses the lack of a clear definition of the safety profile of capecitabine and the possible risk of a reduced tolerability of capecitabine after total gastrectomy (7). A number of studies describes successful treatment with capecitabine where all or a subset of the patients has gone through gastrectomy (6,8,9).

The absorption of acetylsalicylic acid mainly occurs in the small intestine but to some extent in the stomach (10). When comparing serum concentrations of salicylic acid in five patients who had gone through Billroth I (simple gastrectomy), four who had gone through Billroth II, five who had gone through total gastrectomy and 14 healthy volunteers no statistically significant differences was seen between the groups in Tmax, Cmac or AUC. In this study the acetylsalicylic acid pills were crushed before administration and all subjects were fasting prior to administration which could have resulted in a higher rate of gastric emptying in the control group and could have masked a possible difference in absorption according to the authors (11).

In our literature search meclozine and tramadol was also included but no specific information was identified for those substances.

With the purpose of speculation on the effects of a reduced exposure of drugs to the gastric environment with low pH, and in want of studies describing the effects on this of gastrectomy, we conducted a literature search on interactions between the different drugs of the patient and proton pump inhibitors and histamine-2 receptor antagonists. Only one relevant article was identified that describes the reduced effect of acetylsalicylic acid on concurrent administration of ranitidine to healthy volunteers. According to the authors an explanation to this could be an increase in gastric pH and a possible induction of gastric emptying rate. These effects could reduce the relative amount of acetylsalicylic acid absorbed in the stomach. The study has several limitations and the authors conclude that more investigations are needed (12). Apart from this one study no other documentation was found on reduced absorption of the reported drugs under those circumstances.

Tramadol- and fluconazoleconcentrations in plasma can be measured at the Karolinska laboratory for pharmacology and a measure of plasma concentrations could contribute to the information on the patients absorption of these substances. Apart from the above it should also be mentioned that there is a potential interaction between acetylsalicylic acid and tramadol since tramadol inhibits reuptake of serotonin which affects the aggregating capability of platelets.