Pharmacokinetic and pharmacodynamic interactions of tolfenamic acid and marbofloxacin in goats.
Pharmacokinetic and pharmacodynamic properties in goats of the non-steroidal anti-inflammatory drug tolfenamic acid (TA), administered both alone and in combination with the fluoroquinolone marbofloxacin (MB), were established in a tissue cage model of acute inflammation. Both drugs were injected intramuscularly at a dose rate of 2 mg kg(-1). After administration of TA alone and TA+MB pharmacokinetic parameters of TA (mean values) were Cmax=1.635 and 1.125 microg ml(-1), AUC=6.451 and 3.967 microgh ml(-1), t1/2K10=2.618 and 2.291 h, Vdarea/F=1.390 and 1.725Lkg(-1), and ClB/F=0.386 and 0.552 L kg(-1) h(-1), respectively. These differences were not statistically significant. Tolfenamic acid inhibited prostaglandin (PG)E2 synthesis in vivo in inflammatory exudate by 53-86% for up to 48 h after both TA treatments. Inhibition of synthesis of serum thromboxane (Tx)B2 ex vivo ranged from 16% to 66% up to 12h after both TA and TA+MB, with no significant differences between the two treatments. From the pharmacokinetic and eicosanoid inhibition data for TA, pharmacodynamic parameters after dosing with TA alone for serum TxB2 and exudate PGE2 expressing efficacy (Emax=69.4 and 89.7%), potency (IC50=0.717 and 0.073 microg ml(-1)), sensitivity (N=3.413 and 1.180) and equilibration time (t1/2Ke0=0.702 and 16.52 h), respectively, were determined by PK-PD modeling using an effect compartment model. In this model TA was a preferential inhibitor of COX-2 (COX-1:COX-2 IC50 ratio=12:1). Tolfenamic acid, both alone and co-administered with MB, did not affect leucocyte numbers in exudate, transudate or blood. Compared to placebo significant attenuation of skin temperature rise over inflamed tissue cages was obtained after administration of TA and TA+MB with no significant differences between the two treatments. Marbofloxacin alone did not significantly affect serum TxB2 and exudate PGE2 concentrations or rise in skin temperature over exudate tissue cages. These data provide a basis for the rational use of TA in combination with MB in goat medicine.
Sidhu
P K
PK
Department of Epidemiology and Preventive Veterinary Medicine, College of Veterinary Science, Punjab Agricultural University, Ludhiana 141004, Punjab, India.
Landoni
M F
MF
Lees
P
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D015232:Dinoprostone / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D005122:Exudates and Transudates / Q000378:metabolism; D005260:Female; D024841:Fluoroquinolones / Q000097:blood / Q000493:pharmacokinetics*; D006041:Goats / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy; D007962:Leukocytes / Q000187:drug effects; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics*; D062367:ortho-Aminobenzoates / Q000097:blood / Q000493:pharmacokinetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D015363:Quinolones; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid; C080260:marbofloxacin; D015232:Dinoprostone