Pharmacokinetics of flunixin in the cat: enterohepatic circulation and active transport mechanism in the liver.
The plasma and urine pharmacokinetics of flunixin-meglumine (FNX) in cats were examined using a total of 12 adult animals. After an intravenous injection of FNX (2 mg/kg), the plasma concentration time curves showed a profile of a two-compartment open model with an elimination half-life of 6.6 h. In spite of high plasma protein binding (>99%), the V(d)beta was unusually large, 0.7 L/kg. Although the recovery of FNX from urine was only 0.4% of the dose, the estimated inherent renal clearance closely corresponded to the renal plasma flow rate, indicating that a renal active tubular secretion was involved in the pharmacokinetics of FNX. Cholestyramine (ChSA), an anion exchanger, was orally administered immediately before the FNX injection in order to determine the involvement of enterohepatic circulation in FNX pharmacokinetics. The elimination phase of the profile of FNX was prevented by the concomitant administration of ChSA, so it was concluded that the drug undergoes enterohepatic circulation in cats. Pravastatin (PV) is a specific substrate of the type-2 organic anion transporting polypeptide transporter (OATP-2) in human liver cells. The effect of a concomitant intravenous injection of PV with FNX was examined in order to determine the involvement of OATP-2 like transporter in the pharmacokinetics. The V1 and total body clearance were decreased after the injection of PV. In conclusion, at least two active transport mechanisms are involved in the pharmacokinetics of FNX in cats. One pathway is renal tubular secretion and the other is sinusoidal active uptake by liver cells. The latter may be responsible for the enterohepatic circulation of FNX in cats.
Horii
Y
Y
Laboratory of Veterinary Pharmacology, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan.
Ikenaga
M
M
Shimoda
M
M
Kokue
E
E
D000818:Animals; D000837:Anion Exchange Resins / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001693:Biological Transport, Active; D001798:Blood Proteins / Q000378:metabolism; D002415:Cats; D002792:Cholestyramine Resin / Q000494:pharmacology*; D003002:Clonixin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D004764:Enterohepatic Circulation / Q000187:drug effects*; D006207:Half-Life
D000837:Anion Exchange Resins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D002792:Cholestyramine Resin; C014558:flunixin meglumine; D003002:Clonixin