Potency and selectivity of carprofen enantiomers for inhibition of bovine cyclooxygenase in whole blood assays.
Whole blood in vitro assays were used to determine the potency and selectivity of carprofen enantiomers for inhibition of the isoforms of cyclooxygenase (COX), COX-1 and COX-2, in the calf. S(+)-carprofen possessed preferential activity for COX-2 inhibition but, because the slopes of inhibition curves differed, the COX-1:COX-2 inhibition ratio decreased from 9.04:1 for inhibitory concentration (IC)10 to 1.84:1 for IC95. R(-) carprofen inhibited COX-2 preferentially only for low inhibition of the COX isoforms (IC10 COX-1:COX-2=6.63:1), whereas inhibition was preferential for COX-1 for a high level of inhibition (IC95 COX-1:COX-2=0.20:1). S(+) carprofen was the more potent inhibitor of COX isoforms; potency ratios S(+):R(-) carprofen were 11.6:1 for IC10 and 218:1 for IC90. Based on serum concentrations of carprofen enantiomers obtained after administration of a therapeutic dose of 1.4 mg/kg to calves subcutaneously, S(+)-carprofen concentrations exceeded the in vitro IC80 COX-2 value for 32 h and the IC20 for COX-1 for 33 h. The findings are discussed in relation to efficacy and safety of carprofen in calves.
The Royal Veterinary College, Hawkshead Lane, Hatfield, Hertfordshire AL9 7TA, United Kingdom.
Claire
C
Brentnall
Zhangrui
Z
Cheng
Quintin A
QA
McKellar
Peter
P
Lees
D000818:Animals; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle / Q000097:blood*; D051545:Cyclooxygenase 1 / Q000097:blood* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000097:blood* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013929:Thromboxane B2
D002227:Carbazoles; D016861:Cyclooxygenase Inhibitors; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C007005:carprofen