In vivo and in vitro metabolism of dexamethasone in the camel.

The metabolism of dexamethasone (DXM) in the camel was assessed by in vivo and in vitro techniques. Liver samples were collected at the abattoir from camels of either sex, and microsomes were isolated and characterized as to their protein and haemoprotein content as well as for their ability to metabolise several cytochrome P450 model substrates. The expression of different P450 enzymes was evaluated by means of immunoblotting, and the glucuronidating capacity was assessed with 1-naphthol as the substrate. The activity of 11 beta-hydroxysteroid dehydrogenase type 1 was assayed using metyrapone as a model substrate. To examine the in vitro metabolism of DXM, microsomes were incubated with the corticoid in the presence of either a NADPH-generating system or of uridindiphosphoglucuronic acid. In vivo metabolism of DXM was studied in two male camels, injected with a bolus intravenous dose of DXM (0.2 mg/kg body weight) and DXM metabolites were evaluated in urine samples collected at different times after the administration. DXM and metabolites were extracted using solid phase and liquid-liquid extraction, and analysed by liquid chromatography mass spectrometry (LC/MS) and by LC/MS/MS. Comparative results were obtained by in vitro and in vivo studies. Two phase I metabolites were detected: the major one resulted from reduction of the 3-carbonyl group in ring A and the minor metabolite from ring hydroxylation of ring A. Glucuronidation involved both phase I metabolites as well as the parent compound.

Pharmacokinetics and pharmacodynamics of dexamethasone after intravenous administration in camels: effect of dose.

The pharmacokinetics and pharmacodynamics of dexamethasone were evaluated in healthy camels after single intravenous bolus doses of 0.05, 0.1 and 0.2 mg/kg body weight. Dexamethasone showed dose-independent pharmacokinetics. The pharmacokinetic parameters of the two-compartment pharmacokinetic model for the lowest intravenous dose (mean+/-SD) were as follows: terminal elimination half-life 8.17 +/- 1.79 h; total body clearance 100.7 +/- 52.1 (ml/h)/kg; volume of distribution at steady state 0.95 +/- 0.23 L/kg; and volume of the central compartment 0.22 +/- 0.07 L/kg. The extent of plasma protein binding was linear over the concentration range 5-100 ng/ml and averaged 75% +/- 2%. Pharmacodynamic effects were evaluated by measuring endogenous plasma cortisol concentrations, numbers of circulating lymphocytes and neutrophils and plasma glucose concentrations and were analysed using indirect pharmacokinetic/pharmacodynamic models. The cumulative systemic effect increased with dose for markers of pharmacodynamic activity. The estimated IC50 of dexamethasone for cortisol and lymphocytes for the lowest dose were 3.74 +/- 2.44 and 5.58 +/- 8.37 ng/ml, respectively and the EC50 values for neutrophils and glucose were 45.8 +/- 36.9 and 1.17 +/- 0.71 ng/ml, respectively.

The pharmacokinetics, metabolism and urinary detection time of etamiphylline in camels after intramuscular administration.

The pharmacokinetics of etamiphylline were determined after an intramuscular (i.m.) dose of 3.5 mg/kg body weight in six healthy camels. Furthermore, the metabolites and drug detection time were evaluated. The data obtained median and (range) were as follows: the terminal elimination half-life (t(1/2 beta), h) was 3.04 (2.03-3.62); apparent total body clearance (Cl/F, L/h/kg) was 1.27 (0.74-2.99); the apparent volume of distribution at steady state (V(ss)/F, L/kg) was 4.94 (3.57-12.54); and renal clearance (Cl(r), L/h/kg) determined in two camels was 0.005 and 0.004, respectively. The detection time of etamiphylline in urine after an i.m. dose of 3.5 mg/kg body weight ranged between 12 and 13 days. Three etamiphylline metabolites were tentatively identified in camels urine: The first one desethyletamiphylline was the main metabolite and resulted from N-deethylation of etamiphylline had a molecular weight of 251, and was detected in urine for about 13-14 days. Theophylline (molecular weight 180) was the second metabolite and resulted from ring N-dealkylation of etamiphylline. It was present in small amounts and was detected for about 5 h after drug administration in urine. The third metabolite, possibly resulted from demethylation of etamiphylline, had a molecular weight of m/z 265, and was present in small amounts and was detected in urine for about 5 h after drug administration.

Pharmacokinetics of ketoprofen enantiomers after intravenous administration of racemate in camels: effect of gender.

The pharmacokinetics of ketoprofen (KP) enantiomers were studied in ten female and eight male camels after a single intravenous dose (2.0 mg/kg) of racemic KP. A high performance liquid chromatographic (HPLC) method was developed for the quantitation of the R- and S-enantiomers without derivatization of the samples using a S,S-Whelk-01 chiral stationary phase column. The data collected (median and range) were as follows: the areas under the curve to infinity (AUC) (microg/mL per h) were 22.4 (13.5-29.7) and 19.8 (13.8-22.1) for R- and S-KP, respectively, in female camels while the corresponding values in male camels were 16.0 (12.9-22.4) and 14.4 (11.0-19.3). In both sexes, the AUC for the R-enantiomer was significantly larger than that of the S-enantiomer. Total body clearances (Cl(t)) were 44.6 (33.7-74.1) and 50.6 (45.2-72.4) mL/kg per h for R- and S-KP, respectively, in female camels and were 62.8 (44.6-77.8) and 69.6 (51.8-91.1) mL/kg per h for R- and S-KP, respectively, in male camels. In both sexes of camels, the Cl(t) values for R-KP were significantly lower than its corresponding antipode. The steady-state volumes of distribution (Vss) were 97.9 (82.8-147.2) and 102.0 (90.1-169.0) mL/kg for R- and S-KP, respectively, in female camels and were significantly different from each other, while the respective values in male camels were 151.5 (105.3-222.3) and 154.0 (114.7-229.0) mL/kg but were not significantly different from each other. The volumes of distribution (area) followed a similar pattern, where the values for R- and S-KP in female camels were 118.5 (95.6-195.2) and 137.6 (115.8-236.2) mL/kg, respectively, and the respective values in male camels were 215.6 (119.1-270.1) and 229.1 (143.3-277.4) mL/kg. The elimination half-lives (t1/2beta) were 1.88 (1.42-2.34) h and 1.83 (1.67-2.26) h for R- and S-KP, respectively, in female camels and were significantly different from each other, while the corresponding values in male camels were 2.11 (1.50-4.20) and 2.33 (1.52-3.83) h for R and S-KP, respectively, but were not significantly different from each other. The mean residence time followed a similar pattern. All pharmacokinetic parameters for R- and S-KP in female camels were significantly different from their corresponding values in male camels. The extent of protein binding for R- and S-KP was evaluated in vitro by ultrafiltration. The extents of protein binding for R- and S-KP were not significantly different from each other when each enantiomer was supplemented separately. However, when the enantiomers were supplemented together, protein binding of R-KP was significantly higher than that of S-KP in female but not in male camels.