Dosage plan of a flurbiprofen injection product using inhibition of protein binding by lipid emulsion in rats.
Flurbiprofen-axetil (FP-ax), a bolus injection product of a non-steroidal anti-inflammatory drug (NSAID), is a prodrug of flurbiprofen, an NSAID. As flurbiprofen strongly binds to site II of human serum albumin (HSA), the free (unbound) concentration of flurbiprofen after injection of FP-ax is low. We have examined the inhibitory effect of free fatty acid (FFA), a binding inhibitor for site II of HSA, on the binding of flurbiprofen in-vitro and in-vivo by ultrafiltration, to establish an effective dosage of FP-ax. In-vitro, fatty acid mixtures (FAs) inhibited the binding of flurbiprofen to rat serum albumin. The free fraction of flurbiprofen was remarkably increased by FAs in rat serum. In-vivo, FP-ax was injected into a control group (low FFA concentration in serum) and a lipid emulsion group (high FFA concentration in serum). The area under the curve of the free concentration of flurbiprofen during the alpha phase and the distribution volume of the central compartment of flurbiprofen were significantly higher in the lipid emulsion group than the control group (5.0- and 1.2-times, respectively). When FP-ax was administered at high FFA concentration, the free concentration of flurbiprofen and distribution of flurbiprofen to tissues increased transiently. This administration method may be useful for patients with cancer pain, having a potent analgesic effect.
Ogata
Kenji
K
Second Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
Takamura
Norito
N
Tokunaga
Jin
J
Kawai
Keiichi
K
Arimori
Kazuhiko
K
Higuchi
Shun
S
D000465:Algorithms; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004655:Emulsions; D005230:Fatty Acids, Nonesterified / Q000737:chemistry / Q000494:pharmacology; D005480:Flurbiprofen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D019787:Linoleic Acid / Q000737:chemistry / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D019301:Oleic Acid / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors; D014462:Ultrafiltration / Q000295:instrumentation / Q000379:methods
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D004655:Emulsions; D005230:Fatty Acids, Nonesterified; D008055:Lipids; D011355:Prodrugs; D012709:Serum Albumin; D019301:Oleic Acid; D005480:Flurbiprofen; D019787:Linoleic Acid; C504422:flurbiprofen axetil