title: A novel injection strategy of flurbiprofen axetil by inhibiting protein binding with 6-methoxy-2-naphthylacetic acid.
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.
authors.affiliation: Second Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan. k-ogata@phoenix.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Second Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Norito
authors.initials: N
authors.lastname: Takamura
authors.affiliation: Second Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Tokunaga
authors.affiliation: Division of Neurobiology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Second Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Setoguchi
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tanda
authors.affiliation: Department of Pharmaceutical Chemistry, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Shounan-Hiratuka Pharmacy, Kouei Inc., 6-2 Miyanomae, Hiratuka, Kanagawa, 254-0035, Japan.
authors.forename: Toyotaka
authors.initials: T
authors.lastname: Nishio
authors.affiliation: School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 5-11-80 Kadatsuno, Kanazawa, Ishikawa, 920-0942, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawai
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000378:metabolism; D019540:Area Under Curve; D002074:Butanones / Q000008:administration & dosage / Q000378:metabolism; D005480:Flurbiprofen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007267:Injections; D008297:Male; D000077430:Nabumetone; D009280:Naphthaleneacetic Acids / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000418:Albumins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D009280:Naphthaleneacetic Acids; D011355:Prodrugs; D005480:Flurbiprofen; C044612:6-methoxy-2-naphthylacetic acid; C504422:flurbiprofen axetil; D000077430:Nabumetone
keywords: 6-Methoxy-2-naphthylacetic acid; Flurbiprofen; Free concentration; Protein binding inhibition