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A method for quantifying the unstable and highly polar drug nafamostat mesilate in human plasma with optimized solid-phase extraction and ESI-MS detection: more accurate evaluation for pharmacokinetic study

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Abstract

An advanced quantification method was developed with solid-phase extraction (SPE) and mass spectrometry (MS) determination for nafamostat, an unstable and highly polar drug, in human plasma. For unstable drugs with an ester group, the main analytical challenge is how to avoid the ester hydrolysis, and strong acid or alkaline conditions should be excluded during sample preparation. Considering that, we developed a relatively mild method with SPE for sample preparation without strong acid and alkaline treatment, which was optimized with different pHs and salt concentrations in phosphate-buffered saline treatment. The results indicated that pH 5 gave the most efficient extraction and 0.1 M salt concentration enhanced the extraction the most, with a minor effect on MS monitoring. The extraction method effectively avoided drug hydrolysis and achieved good drug enrichment over 82.2%. The linear range of quantification was 1.25–160 ng mL−1. The stability of the drug in sample treatment was fully validated according to the sample processing procedure, including the stability in fresh blood, mobile phase, plasma and acidic methanol, and the results indicated that the drug remained stable during the whole sample preparation. Compared with a previous isotope-labeling method, more accurate and specific quantification of plasma concentration was achieved with liquid chromatography–electrospray ionization MS determination. With use of our method, nafamostat mesilate pharmacokinetics in 30 Chinese healthy volunteers was investigated with three doses via intravenous-drip infusion. The pharmacokinetic parameters were also estimated and compared with those of Japanese volunteers (slightly lower plasma concentration and longer terminal elimination half-life for Chinese volunteers). The difference in the pharmacokinetics may be ascribed to the quantification method, because previous isotope labeling may have overestimated the parent drug.

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References

  1. Dobosz M, Sledzinski Z, Juszkiewicz P, Babicki A, Stanek A, Wajda Z, Basinski A (1991) Hepatogastroenterology 38:139–142

    CAS  Google Scholar 

  2. Horiuchi H, Suzuki T, Taniguchi M, Magata S, Jin MB, Ishikawa H, Ogata K, Shimamura T, Furukawa H, Todo S (2001) Transplant Proc 33:848

    Article  CAS  Google Scholar 

  3. Kimura T, Fuchimoto S, Iwagaki H, Orita K (1993) Nippon Geka Gakkai Zasshi 94:66–70

    CAS  Google Scholar 

  4. Kotani K, Ichiba S, Andou M, Sano Y, Date H, Tedoriya T, Goto K, Shimizu N (2002) J Thorac Cardiovasc Surg 124:626–627

    Article  Google Scholar 

  5. Miyaso H, Morimoto Y, Ozaki M, Haga S, Shinoura S, Choda Y, Murata H, Katsuno G, Huda K, Takahashi H, Tanaka N, Iwagaki H (2006) Dig Dis Sci 51:2007–2012

    Article  CAS  Google Scholar 

  6. Ohtake Y, Hirasawa H, Sugai T, Oda S, Shiga H, Matsuda K, Kitamura N (1991) Contrib Nephrol 93:215–217

    CAS  Google Scholar 

  7. Tsukagoshi S (2001) Gan To Kagaku Ryoho 28:1237–1243

    CAS  Google Scholar 

  8. Yamashita Y, Ishiguro Y, Sano D, Kimura M, Fujita K, Yoshida T, Horiuchi C, Taguchi T, Matsuda H, Mikami Y, Tsukuda M (2007) Auris Nasus Larynx 34:487–491

    Article  Google Scholar 

  9. Yamaori S, Fujiyama N, Kushihara M, Funahashi T, Kimura T, Yamamoto I, Sone T, Isobe M, Ohshima T, Matsumura K, Oda M, Watanabe K (2006) Drug Metab Pharmacokinet 21:147–155

    Article  CAS  Google Scholar 

  10. Yang H, Henkin J, Kim KH, Greer J (1990) J Med Chem 33:2956–2961

    Article  CAS  Google Scholar 

  11. Aoyama T, Okutome T, Nakayama T, Yaegashi T, Matsui R, Nunomura S, Kurumi M, Sakurai Y, Fujii S (1985) Chem Pharm Bull (Tokyo) 33:1458–1471

    CAS  Google Scholar 

  12. Abe T, Kinoshita T, Matsuda J, Ogushi T, Kawasugi K, Yoshimura Y, Otromo M (1984) Jpn Pharmacol Ther 12:4941–4964

    Google Scholar 

  13. Aoyama T, Sasaki H, Shibuya M, Suzuki Y (1985) Chem Pharm Bull (Tokyo) 33:2142–2144

    CAS  Google Scholar 

  14. Yamaori S, Ukena E, Fujiyama N, Funahashi T, Kimura T, Yamamoto I, Ohshima T, Matsumura K, Oda M, Watanabe K (2007) Xenobiotica 37:260–270

    Article  CAS  Google Scholar 

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Acknowledgment

The authors gratefully acknowledge financial support from the National Natural Science Foundation of the People’s Republic of China (nos. 30572228, 30630076).

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Authors and Affiliations

  1. Key Laboratory of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China

    Yan-guang Cao, Ming Zhang, Dan Yu, Jing-ping Shao, Yuan-cheng Chen & Xiao-quan Liu

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  1. Yan-guang Cao
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  2. Ming Zhang
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  3. Dan Yu
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  4. Jing-ping Shao
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  5. Yuan-cheng Chen
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  6. Xiao-quan Liu
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Correspondence to Xiao-quan Liu.

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Cao, Yg., Zhang, M., Yu, D. et al. A method for quantifying the unstable and highly polar drug nafamostat mesilate in human plasma with optimized solid-phase extraction and ESI-MS detection: more accurate evaluation for pharmacokinetic study. Anal Bioanal Chem 391, 1063–1071 (2008). https://doi.org/10.1007/s00216-008-2054-4

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  • DOI: https://doi.org/10.1007/s00216-008-2054-4

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