Absence of Influence of Concomitant Administration of Rabeprazole on the Pharmacokinetics of Tacrolimus in Adult Living-donor Liver Transplant Patients: A Case–control Study

Abstract

This study assesses the effects of rabeprazole on the pharmacokinetics of tacrolimus, considering the cytochrome P450 (CYP) 2C19 and CYP3A5 genotypes of living-donor liver transplant patients (native intestine) and their corresponding donors (graft liver). We examined the concentration/dose ratio of tacrolimus in transplant patients treated with (n=17) or without (n=38) rabeprazole at 10 mg/day on postoperative days 22-28. A stratified analysis revealed no significant differences between the control and rabeprazole groups in the median (range) concentration/dose ratio of tacrolimus [(ng/mL)/(mg/day)] for CYP2C19 extensive/intermediate metabolizers [2.71 (1.00-6.15) versus 2.55 (0.96-9.25); P=0.85] and for poor metabolizers [4.92 (2.44-7.00) versus 3.82 (2.00-7.31); P=0.68], respectively. Even based on the classification of CYP2C19 genotypes of donors, no significant difference in the concentration/dose ratio of tacrolimus was found for the two groups (CYP2C19 extensive/intermediate metabolizers, P=0.52; poor metabolizers, P=0.51). The same was observed for CYP3A5(*)1 carriers (P=0.97 for native intestine; P=0.87 for graft liver) and CYP3A5(*)3/(*)3 carriers (P=0.89 for native intestine; P=0.56 for graft liver). These findings suggest a safer dosing and monitoring of tacrolimus coadministered with rabeprazole early on after liver transplantation regardless of the CYP2C19 and CYP3A5 genotypes of transplant patients and their donors.

Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

“…In this respect, the elevation of tacrolimus levels when it is administered concomitantly with omeprazole in patients with CYP2C19*2/*2 had previously been described in liver recipients (Hosohata et al, 2008;Hosohata et al, 2009a;Hosohata et al, 2009b) and in healthy volunteers and renal recipients Takahashi et al, 2007;Maguire et al, 2012). However, no clinical relevance of this elevation has been reported to our knowledge.…”

“…The decreasing effects of CYP3A5 expressers could hide the hypothetical increasing effect of CYP2C19*2/*2 genotype because of the described omeprazole-tacrolimus interaction. This is the reason why we decided to plot tacrolimus levels with regard to CYP2C19 only in the subset of patients with CYP3A5*3/*3s, as other authors have previously done (Hosohata et al, 2009a;Hosohata et al, 2009b). There is a work (Katsakiori et al, 2010) in which no elevation of tacrolimus levels was found in patients cotreated with omeprazole, but this was probably because the authors only considered CYP3A5 genotype and not CYP2C19; thus, they could not see the interaction.…”

“…Most of the time, the relevance of the interaction is also determined by genetic polymorphisms, which modulate the expression or function of the metabolizing enzyme. In this sense, the interaction between proton pump inhibitors (PPI) and tacrolimus has been described previously in liver transplant recipients (Hosohata et al, 2008;Hosohata et al, 2009a;Hosohata et al, 2009b) with CYP2C19 variant genotype in the polymorphism rs4244285 (CYP2C19*2) leading to elevated blood concentrations.…”

Successful Telaprevir Treatment in Combination of Cyclosporine against Recurrence of Hepatitis C in the Japanese Liver Transplant Patients

“…[22][23][24] Uesugi et al showed that the CYP3A5 genotype in the graft liver and native intestine had an effect on the blood concentration of tacrolimus. 25) TVR inhibits not only CYP3A4 but also CYP3A5.…”

Vascular Endothelial Growth Factor Improves Liver Regeneration and Survival after 90% Hepatectomy in a Rat Model of Diet-Induced Steatosis

“…Here, in many cases extended resections, which are substantially affected by the risk of postoperative liver failure, are needed to improve the curative rates. Therefore, optimization of postoperative outcome could increase the donor pool in LDLT and enable more extended anatomic and nonanatomic resections [24,25]. …”