Influence of oxytetracycline on carprofen pharmacodynamics and pharmacokinetics in calves

Abstract

A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four-period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(-) and S(+) carprofen enantiomers, except for a lower maximum concentration (Cmax ) of S(+) carprofen in serum after co-administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration-time curve (AUC0-96 h were 136.9 and 128.3 μg·h/mL and means for the terminal half-life (T(1/2) k10 ) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC0-96 h in both carprofen treatments and T(1/2) k10 for carprofen alone were lower (P < 0.05) than R(-) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B2 ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E2 synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE2 correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(-) and S(+) enantiomers, respectively. Carprofen reduction of zymosan-induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co-administered.

Impact of carprofen administration on stress and nociception responses of calves to cautery dehorning1

“…Pharmacokinetic parameters following a noncompartmental analysis for carprofen (RS±; Vedco, Inc., St. Joseph, MO) orally administered before cautery dehorning (mean dose, 1.4 mg/kg; range, 1.13 to 1.63 mg/kg) be a result of using a younger population of animals in the present study. Age-dependent pharmacokinetics of carprofen has been reported in calves, with concentrations persisting longer in younger animals Brentnall et al, 2013). Longer half-lives in younger calves are suggested to be a result of a reduction in clearance, which is consistent with our findings .…”

“…Oral administration did not achieve this target mean concentration throughout the course of the study. These data would potentially support the current daily regimen of SQ administration to achieve the previously reported IC 80 ; however, the duration above the IC 80 observed in this study is shorter than that previously reported using the S(+) enantiomer alone (Brentnall et al, 2013). This may due to the interaction of the R(-) enantiomer given the enantioselectivity observed following administration of the racemic mixture in calves as reported by Miciletta et al (2014).…”

“…Although carprofen is administered as a racemic mixture, the S(+) enantiomer has been reported to be primarily responsible for the observed PG inhibition (Brentnall et al, 2013). Using AUC0-∞, the observed enantiomer ratio, R:S, was 57:43 for both oral and subcutaneous administration.…”

“…As such, the mechanism of action of this NSAID is thought to be both COX dependent and COX independent. In addition to inhibition of PG (Brentnall et al, 2013;Miciletta et al, 2013Miciletta et al, , 2014, the effect of carprofen may be mediated through reductions in proinflammatory IL-6, observed in an equine in vitro study (Armstrong and Lees, 2002). In our study, ex vivo PGE concentrations were persistently decreased for the duration of the study in carprofen-treated calves compared with placebo-treated controls; however, only a moderate overall reduction was observed in comparison with other NSAID demonstrating up to 100% PG inhibition using tissue cage models evaluating PGE 2 inhibition in exudate (Lees et al, 2004).…”

“…Carprofen is an NSAID with a prolonged half-life in cattle that is administered as a racemic (RS±) mixture (Brentnall et al, 2013). Currently, it is approved in countries in Europe as an adjunctive treatment for inflammation associated with pneumonia in young calves.…”