Interaction between Tacrolimus and Omeprazole in a Pediatric Liver Transplant Recipient (2006)

Omeprazole, a proton-pump inhibitor (PPI) is used to prevent stress-related gastric bleeding or gastrointestinal ulceration in patients after organ transplantation (1). It is metabolized into the major primary metabolites of 5′:-hydroxyomeprazole which is mediated by CYP2C19 with a minor contribution of CYP3A4 (2–4). We report here an interaction between tacrolimus and omeprazole. A 13 year-old child weighing 43 kg received a liver transplant for progressive familial intrahepatic cholestasis. Primary immunosuppression consisted of an association of tacrolimus (12 mg/day) with methylprednisolone (40 mg/day). Other coadministered drugs were valaciclovir, cotrimoxazole, nifedipine, acebutolol, and acetylsalicylate acid. Nine days after transplantation, omeprazole (20 mg/day) was introduced for gastroesophageal reflux while the dose of tacrolimus remained unchanged. Trough blood tacrolimus concentration was assayed using an IMx autoanalyzer (5). Tacrolimus dosages were adjusted to reach a trough blood concentration ranging from 5 to 15 ng/ml. Calculated omeprazole-tacrolimus concentration molar ratio was 40. Biologic parameters and adverse events were recorded. CYP 2C19 (exon 5) genotyping was performed by polymerase chain reaction analysis. Before omeprazole was introduced, trough blood tacrolimus concentrations remained stable around 10 ng/ml. The addition of omeprazole led to an increase in trough tacrolimus concentrations, which peaked at 28 ng/ml associated with a rise in serum creatinine level, reaching 244 μM (Fig. 1). When omeprazole was discontinued, the blood concentration of tacrolimus fell to 6 ng/ml while serum creatinine levels returned progressively to normal. No alteration of liver function tests was noted. No mutation of CYP 2C19 was detected. No other medication or clinical events such as diarrhea affecting the level of tacrolimus was reported.FIGURE 1.: Tacrolimus blood concentration and serum creatinine before and after introduction of omeprazole in a pediatric liver recipient.The CYP3A4 involved in tacrolimus metabolism, is particularly sensitive to inhibition by numerous agents (6). To date, no interactions between omeprazole and tacrolimus has been clearly demonstrated. In vitro studies using human liver microsomes have shown that omeprazole inhibits the metabolism of tacrolimus mediated through the CYP3A4 and that such an inhibition by omeprazole (Ki: 34±5 μM) was competitive and not negligeable compared to the specific inhibition of tacrolimus metabolism by ketoconazole (Ki: 11±1 μM) (7, 8). In the liver, the CYP2C19 is predominantly involved in 5-hydroxylation of omeprazole (9). However, once CYP2C19 enzyme is saturated when high doses of omeprazole (40 mg) are given to extensive metabolizers or in case of CYP2C19 gene mutation (poor metabolizers), the CYP3A4 becomes the main enzyme involved in omeprazole elimination (10). These data were confirmed by an in vitro study on human liver microsomes which suggests that at higher substrate concentration, 5-hydroxylation and sulfoxidation of omeprazole are catalyzed principally by CYP3A4 (11). Therefore, these individuals are at risk of interaction with drugs inhibiting CYP3A4 activity, such as tacrolimus. Interactions between tacrolimus and other PPI have been only described in subjects with CYP2C19 polymorphism (12, 13), which was not found in the studied patient. The interaction seems not to be only due to inhibition on hepatic CYP3A4. A highly abundant intestinal CYP3A4 probably plays also a role in tacrolimus and omeprazole interaction (14, 15), because it is predominantly involved in the 5-hydroxylation of omeprazole. Esomeprazole which is the S-enantiomer of omeprazole is an inhibitor of intestinal P-glycoprotein (PgP). In clinical studies, PgP inhibitors affect oral bioavailability of tacrolimus rather than its clearance, indicating a key role of intestinal PgP (16, 17). Therefore, the high molar ratio of omeprazole / tacrolimus concentration observed in this patient, greater than that previously observed in vitro studies (8) may result from inhibition by omeprazole of gut and hepatic CYP3A4 tacrolimus metabolism and inhibition of the intestinal PgP activity (8, 16). In conclusion, interaction of omeprazole with tacrolimus may involve inhibition of the hepatic and intestinal CYP3A4, of the intestinal PgP and pharmacokinetic characteristics of omeprazole. Close monitoring is required when tacrolimus and omeprazole are combined. Céline Moreau Anne Marie Taburet Valérie Furlan Department of Clinical Pharmacy, CHU de BicêtreKremlin, Bicêtre, France Dominique Debray Department of Pediatric, Liver Transplantation, Hepatology Unit, CHU de BicêtreKremlin, Bicêtre, France Marie Anne Loriot Department of Molecular Toxicology, INSERM U490, Medical University, School of Saints Pères, Paris, France