Parecoxib (PX) is a injective pro-drug of Valdecoxib (VX), known to be a selective cyclo-oxygenase-2 (COX-2) inhibitor. The aim of the present study was to evaluate pharmacokinetics and pharmacodynamics in vitro/ex vivo cyclooxygenase selectivity of PX and VX in cats. In vitro evaluation of effects of PX and VX was performed using blood collected from 6 adult male cats (Ethic committee's protocol number 2473 - University of Pisa) in sodium citrate and anticoagulant free tubes for TXB2 (marker for COX-1 isoform) and PgE2 (marker for COX-2 isoform) measurements, respectively. For COX-1 evaluation, blood aliquots were mixed with dymethil sulfoxide (DMSO) containing VX or PX (0.0508-1,000 μM). Blood aliquots with only DMSO were used as controls. After incubation and centrifugation, supernatants were analyzed using a commercial TXB2 ELISA kit. Samples for COX-2 evaluation were incubated with VX or PX and with 5μl of lipopolysaccaride (LPS) solution to stimulate PgE2 synthesis. Supernatant was mixed with methanol (1:5) to allow protein precipitation. Supernatants were analyzed using a commercial PgE2 ELISA kit. In ex vivo study, the same method used in in vitro study was performed using samples collected by cats treated with 2.5 mg/kg of PX IM. For HPLC analysis, blood samples were collected into lithium-heparinized tubes and plasma samples were prepared according to a previous method (1) with some modifications. Pharmacokinetic analyses were described by a noncompartmental model (WinNonLin 5.3, Parsight). The IC50 values of VX for COX-2 and COX-1 were 0.45 and 38.6 μM, respectively. PX did not affect COX enzymes. HPLC analysis showed that PX is rapidly converted to VX with a relatively short half-life of 0.4 h. VX achieved peak plasma concentration (2.79 ± 1.59 μg/mL) at 7 h following PX injection. The mean residence times for PX and VX were 0.43 ± 0.15 and 5.94 ± 0.88 h, respectively. The ex vivo study showed a COX-2 inhibition rate of about 70% in samples taken at 1, 2, 4 and 10 h after injection of PX. COX-1 inhibition ranged from 0.7% to 9.7% compared to the control without any significant difference for 24 h after PX administration. Although PX has not been studied as extensively in veterinary medicine as it has been in humans, some preliminary studies reported that this drug might also be effective and safe (2, 3) in animal species. Results of the present study seem to encourage further experiments on feline species to investigate whether this drug could be successfully used in feline medicine.

PK/PD EVALUATION OF PARECOXIB AND ITS ACTIVE METABOLITE VALDECOXIB IN CATS.

BRIGANTI, ANGELA;GIORGI, MARIO
2014-01-01

Abstract

Parecoxib (PX) is a injective pro-drug of Valdecoxib (VX), known to be a selective cyclo-oxygenase-2 (COX-2) inhibitor. The aim of the present study was to evaluate pharmacokinetics and pharmacodynamics in vitro/ex vivo cyclooxygenase selectivity of PX and VX in cats. In vitro evaluation of effects of PX and VX was performed using blood collected from 6 adult male cats (Ethic committee's protocol number 2473 - University of Pisa) in sodium citrate and anticoagulant free tubes for TXB2 (marker for COX-1 isoform) and PgE2 (marker for COX-2 isoform) measurements, respectively. For COX-1 evaluation, blood aliquots were mixed with dymethil sulfoxide (DMSO) containing VX or PX (0.0508-1,000 μM). Blood aliquots with only DMSO were used as controls. After incubation and centrifugation, supernatants were analyzed using a commercial TXB2 ELISA kit. Samples for COX-2 evaluation were incubated with VX or PX and with 5μl of lipopolysaccaride (LPS) solution to stimulate PgE2 synthesis. Supernatant was mixed with methanol (1:5) to allow protein precipitation. Supernatants were analyzed using a commercial PgE2 ELISA kit. In ex vivo study, the same method used in in vitro study was performed using samples collected by cats treated with 2.5 mg/kg of PX IM. For HPLC analysis, blood samples were collected into lithium-heparinized tubes and plasma samples were prepared according to a previous method (1) with some modifications. Pharmacokinetic analyses were described by a noncompartmental model (WinNonLin 5.3, Parsight). The IC50 values of VX for COX-2 and COX-1 were 0.45 and 38.6 μM, respectively. PX did not affect COX enzymes. HPLC analysis showed that PX is rapidly converted to VX with a relatively short half-life of 0.4 h. VX achieved peak plasma concentration (2.79 ± 1.59 μg/mL) at 7 h following PX injection. The mean residence times for PX and VX were 0.43 ± 0.15 and 5.94 ± 0.88 h, respectively. The ex vivo study showed a COX-2 inhibition rate of about 70% in samples taken at 1, 2, 4 and 10 h after injection of PX. COX-1 inhibition ranged from 0.7% to 9.7% compared to the control without any significant difference for 24 h after PX administration. Although PX has not been studied as extensively in veterinary medicine as it has been in humans, some preliminary studies reported that this drug might also be effective and safe (2, 3) in animal species. Results of the present study seem to encourage further experiments on feline species to investigate whether this drug could be successfully used in feline medicine.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/535282
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact