Skip to main content
SpringerLink
Log in

Population pharmacokinetics of mizoribine in adult recipients of renal transplantation

  • Original Article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

Background

The aim of the present study was to estimate the population pharmacokinetic parameters of mizoribine in adult recipients of renal transplantation using a nonlinear mixed effects model (NONMEM) program.

Methods

Pharmacokinetic data for population analysis were retrospectively collected from 114 recipients (66 males and 48 females) routinely treated with oral administration of mizoribine (25–450 mg/day). The range of creatinine clearance (CLcr) was 7.6−136.1 mL/min (mean 49.2 mL/min).

Results

The pharmacokinetics of mizoribine in adult recipients of renal transplantation was well described by a 1-compartment model with first-order absorption. The mean value of the absorption lag time (ALAG) and absorption rate constant (KA) was estimated to be 0.581 and 0.983 h−1, respectively. Apparent volume of distribution (V/F) was modeled as a function of body weight (WT), and the mean value was estimated to be 0.858 × WT L. Oral clearance (CL/F) was modeled as a function of creatinine clearance (CLcr), and the mean value was estimated to be 1.80 × CLcr × 60/1000 L/h. In addition, there was a strong correlation between CLcr-corrected CL/F and WT-corrected V/F in the adult recipients, indicating large interindividual variability in bioavailability (F) of mizoribine.

Conclusion

The present findings suggested that not only the rate of renal excretion but also the extent of intestinal absorption of mizoribine is responsible for the large interindividual pharmacokinetic variability of the drug.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Yokota S. Mizoribine: mode of action and effects in clinical use. Pediatr Int. 2002;44:196–8.

    Article  PubMed  CAS  Google Scholar 

  2. Morino T, Sano K, Hara H, Motoyama K, Iizuka K, Hara T, et al. A comparative, subacute toxicity study of mizoribine and azathioprine in dogs—with particular reference to hepatotoxicity, nephrotoxicity and hematotoxicity. Jpn J Transplant. 1982;17 Suppl:603–14.

    Google Scholar 

  3. Ihara H, Shinkuma D, Kubo M, Miyamoto I, Nojima M, Koike H, et al. Influence of bioavailability on blood level of mizoribine in kidney transplant recipients. Transplant Proc. 1996;1:1321–3.

    Google Scholar 

  4. Takada K, Asada S, Ichikawa Y, Sonoda T, Takahara S, Nagano S, et al. Pharmacokinetics of bredinin in renal transplant patients. Eur J Clin Pharmacol. 1983;24:457–61.

    Article  PubMed  CAS  Google Scholar 

  5. Honda M, Itoh H, Suzuki T, Hashimoto Y. Population pharmacokinetics of higher-dose mizoribine in healthy male volunteers. Biol Pharm Bull. 2006;29:2460–4.

    Article  PubMed  CAS  Google Scholar 

  6. Beal SL, Boeckmann AJ, Sheiner LB. NONMEM Users Guides: NONMEM Project Group: University of California, San Francisco; 1992.

  7. Ishida K, Takaai M, Yotsutani A, Taguchi M, Hashimoto Y. Membrane transport mechanisms of mizoribine in the rat intestine and human epithelial LS180 cells. Biol Pharm Bull. 2009;32:741–5.

    Article  PubMed  CAS  Google Scholar 

  8. Ishida K, Takaai M, Yotsutani A, Yokota A, Sakamoto T, Taguchi M, et al. Mechanisms responsible for different rates of uptake of mizoribine and ribavirin by human epithelial LS180 cells. Jpn J Pharm Health Care Sci. 2010;36:900–5.

    CAS  Google Scholar 

  9. Hosotsubo H, Takahara S, Taenaka N. Simplified high-performance liquid chromatographic method for determination of mizoribine in human serum. J Chromatogr. 1988;432:340–5.

    Article  PubMed  CAS  Google Scholar 

  10. Govindarajan R, Bakken AH, Hudkins KL, Lai Y, Casado FJ, Pastor-Anglada M, et al. In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta. Am J Physiol Regul Integr Comp Physiol. 2007;293:R1809–22.

    Article  PubMed  CAS  Google Scholar 

  11. Gray JH, Owen RP, Giacomini KM. The concentrative nucleoside transporter family, SLC28. Pflugers Arch. 2004;447:728–34.

    Article  PubMed  CAS  Google Scholar 

  12. Podgorska M, Kocbuch K, Pawelczyk T. Recent advances in studies on biochemical and structural properties of equilibrative and concentrative nucleoside transporters. Acta Biochim Pol. 2005;52:749–58.

    PubMed  CAS  Google Scholar 

  13. Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD. The equilibrative nucleoside transporter family, SLC29. Pflugers Arch. 2004;447:735–43.

    Article  PubMed  CAS  Google Scholar 

  14. Naito T, Tokashiki S, Mino Y, Otsuka A, Ozono S, Kagawa Y, et al. Impact of concentrative nucleoside transporter 1 gene polymorphism on oral bioavailability of mizoribine in stable kidney transplant recipients. Basic Clin Pharmacol Toxicol. 2010;106:310–6.

    PubMed  CAS  Google Scholar 

  15. Sugitani A, Kitada H, Ota M, Yoshida J, Doi A, Hirakata H, et al. Revival of effective and safe high-dose mizoribine for the kidney transplantation. Clin Transplant. 2005;20:590–5.

    Article  Google Scholar 

  16. Sonda K, Takahashi K, Tanabe K, Funchinoue S, Hayasaka Y, Kawaguchi H, et al. Clinical pharmacokinetic study of mizoribine in renal transplantation patients. Transplant Proc. 1996;28:3643–8.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The present study was executed as themes of secretaries of the study group of mizoribine on renal transplantation. The data in this study was collected by following 11 hospitals: Kyoto Prefectural University of Medicine, Osaka University, Hyogo College of Medicine, Ihara Clinic, Nara Medical University, Osaka City University, Sakai Hospital Kinki University faculty of Medicine, Kinki University Hospital, Hyogo Prefectural Nishinomiya Hospital, Yamaguchi-ken Saiseikai Shimonoseki General Hospital, and Hiroshima Prefectural Hospital. We are grateful to the doctors in these hospitals.

Author information

Authors and Affiliations

  1. Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Kazuya Ishida & Yukiya Hashimoto

  2. Department of Organ Interaction Research Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Masahiko Okamoto

  3. Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan

    Michio Ishibashi

Authors
  1. Kazuya Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masahiko Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michio Ishibashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yukiya Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yukiya Hashimoto.

About this article

Cite this article

Ishida, K., Okamoto, M., Ishibashi, M. et al. Population pharmacokinetics of mizoribine in adult recipients of renal transplantation. Clin Exp Nephrol 15, 900–906 (2011). https://doi.org/10.1007/s10157-011-0487-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-011-0487-0

Keywords

Search

Navigation