Biodisponibilidade plasmática de tacrolimo em ratos pré-tratados com omeprazol: sua prescrição é realmente necessária?

Abstract

Cytochrome P450 3A (CYP3A) and the drug transporter P-glycoprotein (P-gp) affect the bioavailability of tacrolimus, the most commonly used immunosuppressive agent in organ transplant recipients. We tested if changes in gastric acidity, induced by omeprazole, increase tacrolimus serum concentrations in the short term. We also evaluated the anti-ulcer and healing activities of tacrolimus. The serum concentration of tacrolimus was verified in Wistar rats pretreated with omeprazole two hours after tacrolimus treatment. Biochemical parameters of gastric secretions were determined after ligature of the pylorus. Additionally, the anti-ulcer and healing activities of tacrolimus were evaluated using in vivo experimental models. In gastric ulcer models (ethanol and non-steroidal anti-inflammatory drugs), tacrolimus significantly reduced the ulcerative area at all doses tested. In the acetic acid-induced ulcer model, tacrolimus did not modify the healing of gastric ulcers in rats. Animals that underwent tacrolimus-treated pyloricligation (3 mg/kg) had increased gastric juice pH compared to controls. The alkalinization promoted by five-day pretreatment with omeprazole was found to increase serum tacrolimus levels (p<0.01). Tacrolimus administration requires specific care by the narrow therapeutic range, the need to monitor dose adjustments, and the need to check for ulcers. The alkalinization of stomach contents increases plasma tacrolimus levels. Because it has anti-ulcerogenic activity, it is not necessary to prescribe omeprazole in patients without a history of gastriculcers, although this does not apply for those with peptic ulcers.