Impact of Concentrative Nucleoside Transporter 1 Gene Polymorphism on Oral Bioavailability of Mizoribine in Stable Kidney Transplant Recipients

Abstract

Mizoribine, an immunosuppressive anti-metabolite, is largely excreted into urine in its unchanged form, and its pharmacokinetics has been considered to be dependent on the glomerular filtration rate. However, the pharmacokinetic disposition of mizoribine has not been fully clarified. The aim of this study was to evaluate the pharmacokinetic disposition of mizoribine based on polymorphism of concentrative nucleoside transporter (CNT) 1 gene in kidney transplant recipients. Thirty-four Japanese stable recipients receiving an immunosuppressive regimen containing mizoribine for more than four months after transplantation were enrolled. Each recipient had been receiving a fixed dose of mizoribine for at least one month before enrolment. Oral bioavailability of mizoribine was obtained by dividing its amount in 24-hr urine by the daily dose. The median and interquartile range of the dose-normalized plasma concentration of mizoribine at 12 hr (C 12 ) were 6.11 and 3.47-10.9 ng ⁄ ml per mg, respectively. The median bioavailability of mizoribine was 44.8%, and interindividual variability was also observed (interquartile range, 37.8-61.5%). The correlation coefficient between creatinine clearance and substitute renal clearance (CL MZ ) estimated from the mizoribine C 12 was 0.65. The CNT1 G565A allele frequency was 51.5%. The mizoribine bioavailability was significantly lower in 565GA and AA than that in GG (median, 42.0%, 41.4% and 62.4%, respectively). No significant differences were observed in the dose-normalized C 12 of mizoribine and substitute CL MZ between the G565A genotypes. The mizoribine bioavailability was affected by CNT1 G565A in kidney transplant recipients. CNT1 G565A would contribute to interindividual differences in plasma disposition of mizoribine.Mizoribine has been used as an alternative immunosuppressive anti-metabolite of mycophenolate mofetil for the prevention of allograft rejection in kidney transplantation [1] and for the treatment of autoimmune diseases such as lupus nephritis [2], nephrotic syndrome [3] and rheumatoid arthritis [4]. Its pharmacological actions consist of selective inhibition of inosine monophosphate dehydrogenase and guanosine monophosphate synthetase, resulting in the inhibition of T and B cell proliferation [5]. Mizoribine is absorbed rapidly from intestine after oral administration and completely excreted into the urine in the unchanged form [6]. Mizoribine binds only slightly to plasma protein. Thus, its pharmacokinetic disposition is believed to be dependent on the glomerular filtration rate.Intestinal absorption of mizoribine requires some specific influx transport systems due to its hydrophilic property as a purine nucleoside derivative. Nucleoside transporters consist of two families: equilibrative nucleoside transporters (ENT) and concentrative nucleoside transporters (CNT) [7]. ENTs facilitate diffusion systems. CNTs are sodium-dependent transporters that mediate the active uphill transport of nucleosides, driven by sodium gradients. There are three human C...

Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters

“…Prior to our studies, the presence of the nucleo-pocket structure was unknown. Although our study with pyrrolo-gemcitabine serves merely as proof of concept, it is conceivable that the nucleo-pocket structure can be utilized in the design of nucleoside-derived drugs or prodrugs that can be specifically targeted only to cell types that express hCNT1 since expression levels of hCNT1 are closely related to the responsiveness of many different types of normal or cancer cells to chemotherapy treatment (Lane et al, 2010; Naito et al, 2010; Rabascio et al, 2010; Bhutia et al, 2011; Choi, 2012). …”

Population pharmacokinetics of mizoribine in adult recipients of renal transplantation

“…We previously evaluated the membrane transport of mizoribine using human intestinal epithelial LS180 cells, and reported that the cellular uptake of mizoribine was mediated not only by CNT but also by ENT [7,8]. In addition, Naito et al [14] evaluated the effect of the genetic polymorphism of CNT1 565G[A on the bioavailability of mizoribine in Japanese kidney transplant recipients. The bioavailability of mizoribine in patients with CNT1-G/A and -A/A alleles was significantly lower than that with the CNT1-G/G allele.…”

“…The bioavailability of mizoribine in patients with CNT1-G/A and -A/A alleles was significantly lower than that with the CNT1-G/G allele. The authors therefore thought that CNT1 565G[A was one of the factors causing the variation in the bioavailability (intestinal absorption) of mizoribine [14]. However, the mechanisms responsible for interindividual variability in bioavailability of mizoribine have not yet been fully assessed.…”

Nucleoside Transporters (SLC28 and SLC29) Family

“…Nevertheless, although particular polymorphisms may be relevant in terms of function, there still is a need for a better knowledge of their clinical relevance (Table 11.4). Combined genotype effect of CDA A-76C, dCK C-1205T, DCTD T-47C, hCNT3 1383 C<T, hENT1 T-549C and hENT1 C913T References: SLC28A1 (Gray et al, 2004a;Soo et al, 2009;Naito et al, 2010); SLC28A2 (Owen et al, 2005;Li et al, 2007Li et al, , 2009Soo et al, 2009;Yee et al, 2009); SLC28A3 (Badagnani et al, 2005;Errasti-Murugarren et al, 2008;Okazaki et al, 2010): SLC29A1 (Myers et al, 2006;Okazaki et al, 2010;Tanaka et al, 2010;Kim et al, 2011); SLC29A2 (Owen et al, 2006b); SLC29A3 (Molho-Pessach et al, 2008;Cliffe et al, 2009) …”

“…Presence of the hCNT1-Val189Ile is associated with increased thymidine uptake but also with a significantly lower affinity for the nucleoside analog gemcitabine (Gray et al, 2004a). This hCNT1 variant has also been linked to higher bioavailability of mizoribine in kidney transplant recipients (Naito et al, 2010) Another SLC28A1 variant, hCNT1-Asp521Asn, has been shown to be associated with the occurrence of neutropenia and thrombocytopenia in nonsmall cell lung cancer (NSCLC) patients receiving gemcitabine therapy, thus providing the first indication that the hCNT1 protein may be involved in the development of hematotoxicity and adverse drug reactions (ADRs) .…”