The Importance of the Use of Omeprazole and Famotidine in the Development of Chronic Dysfunction of the Transplanted Kidney

1. Scientific aim of the project Tacrolimus is an immunosuppressive calcineurin inhibitor used to prevent rejection in allogeneic organ transplant recipients such as kidney, liver, heart or lungs. It is metabolized in the liver with the participation of the cytochrome P450 isoform CYP3A4 (CYP3A4), it is characterized by a narrow therapeutic window, dose-dependent toxicity and high inter-individual and intra-individual variability. Increased serum concentration of tacrolimus may be caused by substrates and inhibitors of CYP3A4, revealing adverse effects of this drug, especially nephrotoxicity. Proton pump inhibitors (PPIs) are used as standard in kidney transplant patients to prevent duodenal and gastric ulcer disease in connection with the use of glucocorticoids. One of the PPIs is omeprazole, which is a substrate and inhibitor of the enzyme CYP2C19 and CYP3A4 and also an inhibitor of P-glycoprotein. The enzyme CYP2C19 is mainly responsible for the metabolism of omeprazole, however, upon saturation or in the event of a mutation in the CYP2C19 gene (a poor metabolizer), CYP3A4 becomes the major enzyme involved in the elimination of omeprazole and thus may interact with tacrolimus. Therefore, it seems important to use drugs with a similar prophylactic effect on the gastrointestinal tract, which, unlike omeprazole, are not substrates or inhibitors of the CYP3A4 enzyme, such as famotidine - an antagonist of H2 receptors.

Due to the potential influence of omeprazole on the pharmacokinetics of tacrolimus, which may influence the process of chronic rejection of the transplanted kidney and drug toxicity, it seems important to study this hypothesis, as well as researching for therapeutic substances neutral to the above process. The use of famotidine in place of omeprazole may turn out more beneficial and safer for renal transplant patients. The aim of the study is to compare the effect of omeprazole and famotidine on the risk of developing chronic renal transplant dysfunction. 2. Project meaning No study has been found in the available scientific literature to assess the effect of omeprazole administration on the development of chronic renal transplant rejection. However, studies have been found to assess the effect of omeprazole on the change in tacrolimus plasma levels. The search strategy consisted of controlled vocabulary and keywords. The following databases were searched: MEDLINE (Pubmed), Scopus, Web of Science and Cochrane. The main search concept was to combine "tacrolimus", "omeprazole" and "kidney". 74 studies were found, of which only 7 were related to the topic searched.

In one of the studies, the authors presented a case of a patient and observed a change in the concentration of tacrolimus in the blood plasma after switching from ranitidine to omeprazole. Since informed consent could not be obtained from this patient, authors were unable to access the genetic information. It was not known if the patient had a mutation in the gene encoding CYP2C19. Other authors observed an over fourfold increase in the concentration of tacrolimus after the administration of omeprazole. Patient was homozygous mutated (*2/*2) for CYP2C19, carrying an aberrant splicing site that reduces significantly or inactivates the encoded protein's activity of CYP2C19, classified as CYP2C19 poor metabolizer. The CYP2C19 gene, which includes nine exons and eight introns, is located at the 10q24.1-10q24.3 locus of chromosome 10, where coding sequences is 1,473 bp and resulting in a protein of 490 amino acid residues. Approximately 25 genetic variants in the exonic region of the CYP2C19 have been identified. CYP2C19 is involved in metabolizing several important therapeutic drugs, including omeprazole. Common variants of the CYP2C19 gene are associated with impaired drug metabolism. CYP2C19*2 and CYP2C19*3 were identified in individuals who exhibited a reduced capability for metabolizing the probe drugs, and variant CYP2C19*17 is associated with ultra-rapid metabolism of CYP2C19 substrates. The principal detrimental allele, CYP2C19*2, results from a guanine (G) to adenine (A) transition at position 681 in exon 5 (rs4244285), producing an aberrant splice site and it represents the most frequent CYP2C19 defect in all populations. CYP2C19*2 and CYP2C19*3 are the most common alleles, encoding enzymes with decreased activity. CYP2C19*3 (636G>A) is considered the most important allele, in which a point mutation in exon 4 results in a premature stop codon, and therefore nonfunctional protein. The prevalence of the CYP2C19 poor metabolizer (PM) phenotype is 2-5% among Caucasians and Africans, and ~15% in Asians, while CYP2C19*3 is considered to be an Asian mutation. CYP2C19*2 and *3 alleles have been proposed to explain <50%, to >90%, of the PM phenotype. The enzyme CYP2C19 is mainly responsible for the metabolism of omeprazole, however, in the event of a mutation in the CYP2C19 gene (poor metaboliser), CYP3A4 becomes the major enzyme involved in the elimination of omeprazole. Tacrolimus is also metabolised by CYP3A4, so in the above situation there is a competitive competition for the CYP3A4 enzyme, as a result, the metabolism of tacrolimus may be insufficient, and this may result in an increase in plasma tacrolimus concentrations, which may be a factor in the process of chronic renal rejection. In one of the studies, the authors demonstrated during study of 75 patients that recipients with CYP2C19*2/*2 genotype showed allograft delayed function (acute tubular necrosis in 3 patients) during treating with tacrolimus and omeprazole. It should be noted that other authors in clinical-analytical study (n = 51) conclused that an omeprazole- tacrolimus interaction is not clinically relevant. Despite possible competition or interaction at the molecular level, clinical management was not significantly affected in renal allograft recipients. However, the study lasted 6 months. The duration of the study was too short to provide an answer regarding the effect of tacrolimus on chronic renal rejection. In one of the works, the authors suggest in their study (n=27) that omeprazole may increase the serum tacrolimus concentration if ingested 2 hr before tacrolimus ingestion, likely through alkalization of the intestinal contents. Famotidine does not interact with the cytochrome P450-linked drug metabolizing enzyme system, therefore it is a good candidate for use in place of omeprazole.

It is known that there may be an interaction between omeprazole and tacrolimus. There have been several cases of such an interaction in history. It is not known whether the use of omeprazole has an impact on the chronic rejection of a transplanted kidney. The scheduled study is a new issue. Conducting the above study will allow to assess whether the use of omeprazole has an impact on the process of chronic rejection of the transplanted kidney.

Due to the timing of kidney rejection, there are three phases: hyperacute, acute and chronic phase. Hyperacute rejection occurs immediately after transplantation and is associated with the presence in the blood of the recipient of antibodies that react with antigens on the organ donor endothelial cells. They are mainly antibodies against HLA antigens and against AB0 blood group antigens. Acute rejection occurs within a few days to several months after transplantation. It can be cellular, humoral or mixed. Cellular response mechanisms (cellular rejection) dominate the pathogenesis of acute rejection. Chronic rejection occurs one year after transplantation. Due to the type of reaction, it may be cellular, humoral or mixed with a predominance of cellular or antibody-dependent mechanisms. To the current knowledge, donor-specific antibodies are mainly responsible for late graft loss.