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A novel injection strategy of flurbiprofen axetil by inhibiting protein binding with 6-methoxy-2-naphthylacetic acid

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Abstract

Flurbiprofen axetil (FPA) is an injection product and a prodrug of a non-steroidal anti-inflammatory drug (NSAID). After injection, it is rapidly hydrolyzed to the active form, flurbiprofen (FP). Since frequent injections of FPA can lead to abnormal physiology, an administration strategy is necessary to ensure there is enhancement of the analgesic efficiency of FP after a single dose and to reduce the total number of doses. FP strongly binds to site II of albumin, and thus the free (unbound) FP concentration is low. This study focused on 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone (a prodrug of NSAID). We performed ultrafiltration experiments and pharmacokinetics analysis in rats to investigate whether the inhibitory effect of 6-MNA on FP binding to albumin increased the free FP concentration in vitro and in vivo. Results indicated that 6-MNA inhibited the binding of FP to albumin competitively. When 6-MNA was injected in rats, there was a significant increase in the free FP concentration and the area under concentration–time curve (AUC) calculated from the free FP concentration, while there was a significant decrease in the total (bound + free) FP concentration and the AUC calculated from the total FP concentration. These findings indicate that 6-MNA inhibits the protein binding of FP in vivo. This suggests that the frequency of FPA injections can be reduced when administered with nabumetone, as there is increase in the free FP concentration associated with pharmacological effect.

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Authors and Affiliations

  1. Second Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan

    Kenji Ogata, Norito Takamura & Jin Tokunaga

  2. Division of Neurobiology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, Miyazaki, 889-1692, Japan

    Tetsuya Ikeda

  3. Second Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan

    Nao Setoguchi

  4. Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan

    Kazuhiro Tanda

  5. Department of Pharmaceutical Chemistry, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan

    Tetsuo Yamasaki

  6. Shounan-Hiratuka Pharmacy, Kouei Inc., 6-2 Miyanomae, Hiratuka, Kanagawa, 254-0035, Japan

    Toyotaka Nishio

  7. School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 5-11-80 Kadatsuno, Kanazawa, Ishikawa, 920-0942, Japan

    Keiichi Kawai

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  1. Kenji Ogata
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  2. Norito Takamura
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  3. Jin Tokunaga
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  4. Tetsuya Ikeda
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  5. Nao Setoguchi
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  6. Kazuhiro Tanda
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  7. Tetsuo Yamasaki
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  8. Toyotaka Nishio
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  9. Keiichi Kawai
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Correspondence to Kenji Ogata.

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Ogata, K., Takamura, N., Tokunaga, J. et al. A novel injection strategy of flurbiprofen axetil by inhibiting protein binding with 6-methoxy-2-naphthylacetic acid. Eur J Drug Metab Pharmacokinet 41, 179–186 (2016). https://doi.org/10.1007/s13318-014-0248-z

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  • DOI: https://doi.org/10.1007/s13318-014-0248-z

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