The pharmacokinetics and metabolism of meloxicam in camels after intravenous administration.

The pharmacokinetics and metabolism of meloxicam was studied in camels (Camelus dromedarus) (n = 6) following intravenous (i.v.) administration of a dose of 0.6 mg·kg/body weight. The results obtained (mean ± SD) were as follows: the terminal elimination half-life (t(1/2ß) ) was 40.2 ± 16.8 h and total body clearance (Cl(T) ) was 1.94 ± 0.66 mL·kg/h. The volume of distribution at steady state (V(SS)) was 92.8 ± 13.7 mL/kg. One metabolite of meloxicam was tentatively identified as methylhydroxy meloxicam. Meloxicam and metabolite were excreted unconjugated in urine. Meloxicam could be detected in plasma 10 days following i.v. administration in camels using a sensitive liquid chromatography tandem mass spectrometry (LC/MS/MS) method.

Pharmacokinetic, metabolism and withdrawal time of orphenadrine in camels (Camelus dromedarius) after intravenous administration.

The pharmacokinetics of orphenadrine (ORPH) following a single intravenous (i.v.) dose was investigated in six camels (Camelus dormedarius). Orphenadrine was extracted from the plasma using a simple sensitive liquid-liquid extraction method and determined by gas chromatography/mass spectrometry (GC/MS). Following i.v. administration plasma concentrations of ORPH decline bi-exponentially with distribution half-life (t(1/2)(alpha)) of 0.50+/-0.07h, elimination half-life (t(1/2)(beta)) of 3.57+/-0.55h, area under the time concentration curve (AUC) of 1.03+/-0.10g/hl(-1). The volume of distribution at steady state (Vd(ss)) 1.92+/-0.22lkg(-1), volume of the central compartment of the two compartment pharmacokinetic model (V(c)) 0.87+/-0.09lkg(-1), and total body clearance (Cl(T)) of 0.60+/-0.09l/hkg(-1). Three orphenadrine metabolites were identified in urine samples of camels. The first metabolite N-desmethyl-orphenadrine resulted from N-dealkylation of ORPH with molecular ion m/z 255. The second N,N-didesmethyl-orphenadrine, resulted from N-didesmethylation with molecular ion m/z 241. The third metabolite, hydroxyl-orphenadrine, resulted from the hydroxylation of ORPH with molecular ion m/z 285. ORPH and its metabolites in camel were extensively eliminated in conjugated form. ORPH remains detectable in camel urine for three days after i.v. administration of a single dose of 350mg orphenadrine aspartate.

The pharmacokinetics, metabolism and urinary detection time of tramadol in camels.

The pharmacokinetics of tramadol in camels (Camelus dromedarius) were studied following a single intravenous (IV) and a single intramuscular (IM) dose of 2.33 mg kg(-1) bodyweight. The drug's metabolism and urinary detection time were also investigated. Following both IV and IM administration, tramadol was extracted from plasma using an automated solid phase extraction method and the concentration measured by gas chromatography-mass spectrometry (GC/MS). The plasma drug concentrations after IV administration were best fitted by an open two-compartment model. However a three-compartment open model best fitted the IM data. The results (means+/-SEM) were as follows: after IV drug administration, the distribution half-life (t(1/2)(alpha)) was 0.22+/-0.05 h, the elimination half-life (t(1/2)(beta)) 1.33+/-0.18 h, the total body clearance (Cl(T)) 1.94+/-0.18 L h kg(-1), the volume of distribution at steady state (Vd(ss)) 2.58+/-0.44 L kg(-1), and the area under the concentration vs. time curve (AUC(0-infinity)) 1.25+/-0.13 mg h L(-1). Following IM administration, the maximal plasma tramadol concentration (C(max)) reached was 0.44+/-0.07 microg mL(-1) at time (T(max)) 0.57+/-0.11h; the absorption half-life (t(1/2 ka)) was 0.17+/-0.03 h, the (t(1/2)(beta)) was 3.24+/-0.55 h, the (AUC(0-infinity)) was 1.27+/-0.12 mg h L(-1), the (Vd(area)) was 8.94+/-1.41 L kg(-1), and the mean systemic bioavailability (F) was 101.62%. Three main tramadol metabolites were detected in urine. These were O-desmethyltramadol, N,O-desmethyltramadol and/or N-bis-desmethyltramadol, and hydroxy-tramadol. O-Desmethyltramadol was found to be the main metabolite. The urinary detection times for tramadol and O-desmethyltramadol were 24 and 48 h, respectively. The pharmacokinetics of tramadol in camels was characterised by a fast clearance, large volume of distribution and brief half-life, which resulted in a short detection time. O-Desmethyltramadol detection in positive cases would increase the reliability of reporting tramadol abuse.

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.

Comparison of the effect of Sporobolus virginicus and Rhodes (Chloris gayana) hay diets on the absorption pattern of phenylbutazone in the camel (Camelus dromedarius).

The effect of feeding Sporobolus and Rhodes hay on phenylbutazone (4 g) relative absorption was examined in six camels using a two-period, two-sequence, two-treatment crossover design. Serum concentration of the drug was measured by high performance liquid chromatography. The measured values (means+/-SD) for Rhodes and Sporobolus hay, respectively, were Cmax 35.59+/-22.36 and 36.55+/-18.99 microg/mL, Tmax 26+/-2.53 and 26.3+/-1.97 h and AUC0-72 h 1552+/-872.6 and 1621+/-903.6 microg h/mL. Broad plateau concentrations of phenylbutazone in serum were observed between 12 and 36 h. There was no significant difference in any parameter between the two feeding regimens. Multiple peaks in serum concentration-time curve were observed, regardless of the type of grass available to and the animals prior to drug administration. It was concluded that the phasic absorption of phenylbutazone was a particular feature of hay feeding in camels, and the Sporobolus hay can be fed to camels without any effect on the rate and extent of phenylbutazone absorption compared to Rhodes grass hay.

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.

Autobrewing revisited: endogenous concentrations of blood ethanol in residents of the United Arab Emirates.

Endogenous ethanol concentrations in blood were determined by sensitive headspace gas chromatography/mass spectrometry in 1557 residents of the United Arab Emirates. The subjects were from 13 nationalities, of both sexes and of different age groups. There was no significant difference in blood ethanol concentration between nationalities or between sexes within and between nationalities. The data was pooled and the overall median, minimum, maximum, 25% percentile and 75% percentile were 0.04, 0.00, 3.52, 0.01 and 0.09 mg/dl respectively. The values of blood ethanol concentration as reported in this study indicate that they are far too low to have any forensic significance.

Lack of gender effect on the pharmacokinetics and pharmacodynamics of dexamethasone in the camel after intravenous administration.

The pharmacokinetics and pharmacodynamics of dexamethasone were studied in six male and six female camels after a single intravenous dose (0.05 mgkg(-1) body weight) of dexamethasone. The pharmacokinetic parameters of the two-compartment pharmacokinetic model for female and male camels, respectively (mean+/-SEM) were as follows: terminal elimination half-lives were 8.02+/-1.15 and 7.33+/-0.80 h, total body clearances were 95.5+/-16.0 and 124.5+/-11.9 ml h(-1) per kg, volumes of distribution at steady state were 0.72+/-0.08 and 0.87+/-0.14 litre kg(-1), and the volumes of the central compartment were 0.12+/-0.02 and 0.17+/-0.02 litre kg(-1). There was no significant difference in any pharmacokinetic parameter between female and male camels. Pharmacodynamic effects were evaluated by measuring endogenous plasma cortisol, circulating lymphocytes and neutrophils numbers and were analysed using indirect pharmacokinetic/pharmacodynamic models. The estimated IC50 of dexamethasone for cortisol and lymphocytes for female and male camels were 3.74+/-0.99 and 2.28+/-1.09 and 2.63+/-0.71 and 2.41+/-0.79 ng ml(-1), respectively. The EC50 for neutrophils for female and male camels were 24.5+/-5.83 and 20.2+/-3.82 ng ml(-1), respectively. There was no significant difference in any pharmacodynamic parameter between female and male camels. Dexamethasone in urine could be detected for 4-5 days by enzyme-linked immunosorbent assay and for 3-4 days by liquid chromatography/mass spectrometry after an intravenous dose of 0.05 mg kg(-1) body weight.

The disposition of diclofenac in camels after intravenous administration.

The pharmacokinetics of diclofenac was studied in camels (Camelus dromedarus) (n=6) following intravenous (i.v.) administration of a dose of 2.5 mg kg(-1) body weight. The metabolism and urinary detection time were also studied. The results obtained (median and range) were as follows: the terminal elimination half-life (t(1/2beta)) was 2.35 (1.90-2.73)h, total body clearance (Cl(T)) was 0.17 (0.16-0.21)lh kg(-1). The volume of distribution at steady state (V(SS)) was 0.31 (0.21-0.39)l(-1)kg(-1), the volume of the central compartment of the two compartment pharmacokinetic model (V(C)) was 0.15 (0.11-0.17)l kg(-1). Five metabolites of diclofenac were tentatively identified in urine and were excreted mainly in conjugate form. The main metabolite was identified as hydroxy diclofenac. Both diclofenac and hydroxy diclofenac, appear to be the main elimination route for diclofenac when administered i.v. in camels. Diclofenac could be identified up to 4 days following i.v. administration in camels using a sensitive gas chromatography/mass spectrometry (GC/MS) method.

Comparative pharmacokinetics of diphenhydramine in camels and horses after intravenous administration.

The pharmacokinetics of diphenhydramine (DPHM) was compared in camels (n = 8) and horses (n = 6) following intravenous (i.v.) administration of a dose of 0.625 mg/kg body weight. In addition, the metabolism and urinary detection time of DPHM was evaluated in camels. The data obtained (median and range in brackets) in camels and horses, respectively, were as follows. The terminal elimination half lives (h) were 1.58 (1.13-2.58) and 6.11 (4.80-14.1), and the total body clearances (L/h per kg) were 1.42 (1.13-1.74) and 0.79 (0.66-0.90). The volumes of distribution at steady state (L/kg) were 2.38 (1.58-4.43) and 5.98 (4.60-8.31) and the volumes of the central compartment of the two compartment pharmacokinetic model were 1.58 (0.80-2.54) and 2.48 (1.79-3.17). All the pharmacokinetic parameters in camels were significantly different from those of horses. Five metabolites of DPHM were tentatively identified in the camel's urine. Two metabolites, diphenylmethoxyacetic acid and 1-(4-hydroxyphenyl)-phenylmethoxyacetic acid, were present in the acid fraction. Two metabolites, desamino-DPHM and diphenylmethanol, were identified in the basic fraction, in addition to DPHM itself, which was present mainly as a conjugate. Even after enzymatic hydrolysis, DPHM could be detected for up to 24 h in camels after an i.v. dose of 0.625 mg/kg body weight.

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.

Comparative disposition of tripelennamine in horses and camels after intravenous administration.

The pharmacokinetics of tripelennamine (T) was compared in horses (n = 6) and camels (n = 5) following intravenous (i.v.) administration of a dose of 0.5 mg/kg body weight. Furthermore, the metabolism and urinary detection time was studied in camels. The data obtained (median and range in brackets) in camels and horses, respectively, were as follows: the terminal elimination half-lives were 2.39 (1.91-6.54) and 2.08 (1.31-5.65) h, total body clearances were 0.97 (0.82-1.42) and 0.84 (0.64-1.17)L/h/kg. The volumes of distribution at steady state were 2.87 (1.59-6.67) and 1.69 (1.18-3.50) L/kg, the volumes of the central compartment of the two compartment pharmacokinetic model were 1.75 (0.68-2.27) and 1.06 (0.91-2.20) L/kg. There was no significant difference (Mann-Whitney) in any parameter between camels and horses. The extent of protein binding (mean +/- SEM) 73.6 + 8.5 and 83.4 +/- 3.6% for horses and camels, respectively, was not significantly statistically different (t-test). Three metabolites of T were identified in urine samples of camels. The first one resulted from N-depyridination of T, with a molecular ion of m/z 178, and was exclusively eliminated in conjugate form. This metabolite was not detected after 6 h of T administration. The second metabolite, resulted from pyridine ring hydroxylation, had a molecular ion of m/z 271, and was also exclusively eliminated in conjugate form. This metabolite could be detected in urine sample for up to 12 h after T administration. The third metabolite has a suspected molecular ion of m/z 285, was eliminated exclusively in conjugate form and could be detected for up to 24 h following T administration. T itself could be detected for up to 27 h after i.v. administration, with about 90% of eliminated T being in the conjugated form.

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.

The pharmacokinetics, metabolism and urinary detection time of caffeine in camels.

The pharmacokinetics of caffeine were determined in 10 camels after an intravenous dose of 2.35 mg kg(-1). The data obtained (median and range) were as follows. The elimination half-life (t(1/2)) was 31.4 (21.2 to 58.9) hours, the steady state volume of distribution (V(SS)) was 0.62 (0.51 to 0.74) litre kg(-1)and the total body clearance (Cl(T)) was 14.7 (8.70 to 19.7) ml kg(-1)per hour. Renal clearance estimated in two camels was 0.62 and 0.34 ml kg(-1)per hour. In vitro plasma protein binding (mean +/-SEM, n = 10) to a concentration of 2 and 8 microg ml(-1)was 36.0 +/- 0.24 and 39.2 +/- 0.36 per cent respectively. Theophylline and theobromine were identified as caffeine metabolites in serum and urine. The terminal elimination half-life of the former, estimated in two camels, was 70. 4 and 124.4 hours. Caffeine could be detected in the urine for 14 days.

Identification and confirmation of 3-hydroxy metabolite of ketoprofen in camels by gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy.

The metabolites of ketoprofen were investigated in five camels following intravenous administration of a dose of 2.0 mg/kg body weight. Two metabolites were identified. The first one was purified with thin-layer chromatography. It was identified by gas chromatography-mass spectrometry (GC-MS) in comparison with authenticated reference standard and was found to be hydroxyketoprofen due to reduction of the ketone group of ketoprofen. The second metabolite was purified by high-performance liquid chromatography. It was identified with GC-MS and nuclear magnetic resonance spectroscopy as 3-hydroxybenzolketoprofen resulting from oxidation of the aromatic ring.

The disposition of theophylline in camels after intravenous administration.

The pharmacokinetics of theophylline were determined after an intravenous (i.v.) dose of 2.36 mg/kg in six camels and 4.72 mg/kg body weight in three camels. The data obtained (median and range) for the low and high dose, respectively, were as follows: the distribution half-lives (t1/2 alpha) were 1.37 (0.64-3.25) and 2.66 (0.83-3.5) h, the elimination half-lives (t1/2 beta) were 11.8 (8.25-14.9) and 10.4 (10.0-13.5) h, the steady state volumes of distribution (Vss) were 0.88 (0.62-1.54) and 0.76 (0.63-0.76) L/kg, volumes of the central compartment (Vc) were 0.41 (0.35-0.63) and 0.51 (0.36-0.52) L/kg, total body clearances (Clt) were 62.3 (39.4-97.0) and 50.2 (47.7-67.4) mL/h.kg body weight and renal clearance (Vr) for the low dose was 0.6 (0.42-0.96) mL/h.kg body weight. There was no significant difference in the pharmacokinetic parameters between the two doses. Theophylline protein binding at a concentration of 5 micrograms/mL was 32.2 +/- 3.3%. Caffeine was identified as a theophylline metabolite but its concentration in serum and urine was small. Based on the pharmacokinetic values obtained in this study, a dosage of 7.5 mg/kg body weight administered by i.v. injection at 12 h intervals can be recommended. This dosing regimen should achieve an average steady state serum concentration of 10 micrograms/mL with peak serum concentration not exceeding 15 micrograms/mL.

Pharmacokinetics and metabolism of ketoprofen after intravenous and intramuscular administration in camels.

The pharmacokinetics of ketoprofen were determined after an intravenous (i.v.) and intramuscular (i.m.) dose of 2.0 mg/kg body weight in five camels (Camelus dromedarius) using gas chromatography/mass spectrometry (GC/MS). The data obtained (median and range) following i.v. administration was as follows: the elimination half-life (t(1/2beta)) was 4.16 (2.65-4.29) h, the steady state volume of distribution (Vss) was 130.2 (103.4-165.3) mL/kg, volume of distribution (area method) (Vd(area)) was 321.5 (211.4-371.0) mL/kg, total body clearance (Cl) was 1.00 (0.88-1.08) mL/min x kg and renal clearance was 0.01 (0.003-0.033) mL/min x kg. Following i.m. administration, the drug was rapidly absorbed with peak serum concentration of 12.2 (4.80-14.4) microg/mL at 1.50 (1.00-2.00) h. The systemic availability of ketoprofen was complete. The apparent half-life was 3.28 (2.56-4.14) h. A hydroxylated metabolite of ketoprofen was identified by (GC/MS) under electron impact (EI) and chemical ionization (CI) scan modes. The detection times for ketoprofen and hydroxy ketoprofen in urine after an intravenous (i.v.) dose of 3.0 mg/kg body weight was 24.00 and 70.00 h, respectively. Serum protein binding of ketoprofen at 20 microg/mL was extensive; (99.1+/-0.15%).