Two problems that have hampered sigma receptor research are (i) a lack of high-affinity agents and (ii) the recent identification of multiple populations of sigma receptors (i.e., sigma 1 and sigma 2 sites). Recently, several high-affinity sigma ligands have been identified, and the term superpotent sigma ligands has been coined to describe agents with Ki values of < 1 nM. We have previously shown that appropriately N-substituted phenylalkylamines bind at sigma receptors with high affinity. In the present investigation, we examine the structure-affinity relationships of these phenylalkylamine derivatives for sigma 1 binding and describe some of the first superpotent sigma 1 ligands. A binding model was developed to account for the structural features of the phenylalkylamines that appear to be important for the interaction of these agents with sigma 1 sites.

The primary objective of this study was to determine the pharmacokinetic profile of firocoxib, a novel second generation coxib, in horses. Horses were administered either a single oral or intravenous dose of firocoxib at 0.1 mg/kg in a two-period crossover study with 12 animals. The dosage was based on previously determined pharmacodynamic parameters. Oral firocoxib was well absorbed with an average bioavailability (absolute) of 79% and a Cmax of 75 ng/mL at 3.9 h. The average elimination half-life was 30 h. Following intravenous administration the average Cmax was 210 ng/mL and the elimination half-life was 34 h. The area under the curve [AUC(0-tlast)] was 1.8 microg.h/mL for the oral dose and 2.3 microg.h/mL for the intravenous dose. Firocoxib was widely distributed with a volume of distribution value of 1.7 L/kg for the intravenous dose. Biotransformation of firocoxib was via dealkylation and glucuronidation to inactive metabolites, namely descyclopropylmethylfirocoxib and its glucuronide conjugate. Urinary excretion was the major route of elimination, and the clearance rate was 37 mL/h/kg.

No abstract

The pharmacokinetics of firocoxib during prolonged use were determined. Use of plasma or urine to ascertain drug concentrations in horses is scientifically valid because the plasma-to-urine ratio was consistent over time and among horses.

The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUC(inf)) was 4.28 +/- 0.536 microgxh/mL, and mean elimination half-life (t(1/2)) was 44.9 +/- 4.67 h, with a large volume of distribution (V(ss)) of 24.9 +/- 2.99 L/kg and a high clearance rate (Cl(obs)) of 712 +/- 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUC(inf) values were 4.55 +/- 0.690, 9.42 +/- 1.11 and 12.2 +/- 1.13 microgxh/mL, respectively, and the mean elimination half-lives (t(1/2)) were 51.2 +/- 6.10, 50.8 +/- 3.80 and 58.5 +/- 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6-112%) after s.c. administration. No statistically significant (alpha = 0.05) gender differences in the AUC(Inf) or elimination half-life values were observed. Dose proportionality was established based on AUC(Inf) over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day ( approximately 24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUC(inf) was 194 times higher than the corresponding plasma AUC(inf). The apparent elimination half-life for gamithromycin in lung was 90.4 h ( approximately 4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 +/- 0.60% bound over a range of 0.1-3.0 microg/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease.