Determination of Mizoribine in Human Plasma Using High-performance Liquid Chromatography: Application to a Pharmacokinetic Study in Chinese Renal Transplant Recipients

Abstract

A rapid, simple, and reproducible high-performance liquid chromatographic method (HPLC) was developed and validated for the determination of mizoribine in human plasma using cytarabine as internal standard (IS). The plasma samples of mizoribine were precipitated with 6% perchloric acid. The supernatant was separated on a reversed phase C₁₈ column with a mobile phase of 10 mM KH₂PO₄ buffer solution (pH 6.3) containing 10 mM perchloric acid using isocratic elution (at flow rate 1.5 mL/min), and detected using an ultraviolet detector at 280 nm. The assay exhibited a linear range of 0.02–10.0 μg/mL for mizoribine in human plasma and the lower limit of quantification was 0.02 μg/mL. The method was statistically validated for linearity, accuracy, precision and selectivity. In addition, the method was successfully applied to estimate the pharmacokinetic parameters of mizoribine in Chinese kidney transplant patients following an oral administration of 100 mg mizoribine (2 Bredinin^® 50 mg tablets).

Key words

mizoribine - HPLC - human plasma - pharmacokinetics

• References

• 1 Mizuno K, Tsujino M, Takada M et al. Studies on bredinin. I. Isolation, characterization and biological properties. J Antibiot (Tokyo) 1974; 27: 775-782
• 2 Koyama H, Tsuji M. Genetic and biochemical studies on the activation and cytotoxic mechanism of bredinin, a potent inhibitor of purine biosynthesis in mammalian cells. Biochem Pharmacol 1983; 32: 3547-3553
• 3 Kusumi T, Tsuda M, Katsunuma T et al. Dual inhibitory effect of bredinin. Cell Biochem Funct 1989; 7: 201-204
• 4 Inou T, Kusaba R, Takahashi I et al. Clinical trial of bredinin in renal transplantation. Transplant Proc 1981; 13: 315-318
• 5 Hughes SE, Gruber SA. New immunosuppressive drugs in organ transplantation. J Clin Pharmacol 1996; 36: 1081-1092
• 6 Aihara Y, Miyamae T, Ito S et al. Mizoribine as an effective combined maintenance therapy with prednisolone in child-onset systemic lupus erythematosus. Pediatr Int 2002; 44: 199-204
• 7 Ichinose K, Origuchi T, Kawashiri SY et al. Efficacy and safety of mizoribine by one single dose administration for patients with rheumatoid arthritis. Intern Med 2010; 49: 2211-2218
• 8 Takei S. Mizoribine in the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Pediatr Int 2002; 44: 205-209
• 9 Suzuki D, Kimoto O, Sawada J et al. The efficacy and safety of combination therapy with mizoribine and methotrexate for rheumatoid arthritis resistant with methotrexate. Nihon Rinsho Meneki Gakkai Kaishi 2011; 34: 149-153
• 10 Yoshioka K, Ohashi Y, Sakai T et al. A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. Kidney Int 2000; 58: 317-324
• 11 Kaneko K, Nagaoka R, Ohtomo Y et al. Mizoribine for childhood IgA nephropathy. Nephron 1999; 83: 376-377
• 12 Kaneko T, Hirama A, Ueda K et al. Methylprednisolone pulse therapy combined with mizoribine following tonsillectomy for immunoglobulin A nephropathy: clinical remission rate, steroid sparing effect, and maintenance of renal function. Clin Exp Nephrol 2011; 15: 73-78
• 13 Stypinski D, Obaidi M, Combs M et al. Safety, tolerability and pharmacokinetics of higher-dose mizoribine in healthy male volunteers. Br J Clin Pharmacol 2007; 63: 459-468
• 14 Sonda K, Takahashi K, Tanabe K et al. Clinical pharmacokinetic study of mizoribine in renal transplantation patients. Transplant Proc 1996; 28: 3643-3648
• 15 Takada K, Nakae H, Asada S et al. Rapid method for the high-performance liquid chromatography determination of bredinin in human serum. J Chromatogr 1981; 222: 156-159
• 16 Hosotsubo H, Takahara S, Taenaka N. Simplified high-performance liquid chromatographic method for determination of mizoribine in human serum. J Chromatogr 1988; 432: 340-345
• 17 Erdmann GR, Gruber SA, McGuiggan MM et al. Determination of mizoribine in plasma using ion-pair high-performance liquid chromatography. J Chromatogr 1989; 494: 354-360
• 18 Kaji H, Maiguma T, Inukai Y et al. A simple determination of mizoribine in human plasma by liquid chromatography with UV detection. J AOAC Int 2005; 88: 1114-1117
• 19 Choi SJ, Hur HJ, Lee SB et al. A simple HPLC method for the quantification of mizoribine in human serum: pharmacokinetic applications. Biomed Chromatogr 2008; 22: 1259-1264
• 20 Zhao YN, Yang JJ, Li XH et al. A sensitive and practical LC-MS/MS method for the determination of mizoribine in human serum and its bioequivalence study on Chinese healthy volunteers. Yao Xue Xue Bao 2010; 45: 1149-1154
• 21 Ishida K, Okamoto M, Ishibashi M et al. Population pharmacokinetics of mizoribine in adult recipients of renal transplantation. Clin Exp Nephrol 2011; 15: 900-906
• 22 Ishida K, Motoyama O, Shishido S et al. Population pharmacokinetics of mizoribine in pediatric recipients of renal transplantation. Clin Exp Nephrol 2012; 16: 799-804