Oral pharmacokinetics of acetaminophen to evaluate gastric emptying profiles of Shiba goats

The pharmacokinetics of acetaminophen was investigated following oral dosing to Shiba goats in order to evaluate the properties of gastric emptying. Acetaminophen was intravenously and orally administered at 30 mg/kg body weight to goats using a crossover design with a 3-week washout period. The stability of acetaminophen in rumen juice was also assessed. Acetaminophen concentrations were measured by HPLC. Since acetaminophen was stable in rumen juice for 24 hr, the extremely low bioavailability (16%) was attributed to its hepatic extensive first-pass effect. The mean absorption time and absorption half-life were unexpectedly short (4.93 and 3.35 hr, respectively), indicating its marked absorption from the forestomach, which may have been due to its smaller molecular weight. Therefore, acetaminophen was considered to be unsuitable for evaluating gastric emptying in Shiba goats.     

Pharmacokinetics and dosage of aspirin in cattle.

Sodium salicylate was given intravenously to clinically normal cows, and aspirin (acetylsalicylic acid) was given orally to arthritic and clinically normal cattle. Despite slow absorption (half-time of absorption, 2.91 hours) of orally administered aspirin and rapid elimination (biologic half-life, 32 minutes) of salicylates, oral dosage of 100 mg/kg every 12 hours maintained serum salicylate concentration greater than 30 mug/ml, which was considered to be therapeutically effective.     

Evaluation of the dorsal aorta cannulation technique for pharmacokinetic studies in Atlantic salmon (Salmo salar) in sea water

The antimicrobial drug flumequine was given intravascularly and orally to cannulated and non-cannulated Atlantic salmon (Salmo salar) in sea water at 11°. The cannulated fish were divided into two groups, which were given flumequine (25 mg/kg) intravenously into the caudal vein (n = 8) and orally via a stomach tube down the oesophagus (n= 8). After a washout period of 2 days, the intravenously administered fish were given the drug orally, and the orally administered fish were given the drug intravenously. Blood samples were taken at different time points after drug administration through a cannula inserted into the dorsal aorta. The fish in the non-cannulated group were either given flumequine intravenously or orally, and blood samples were collected by killing five fish at predetermined time points after administration. The haematocrit values were measured in all the fish daily for 4 days after drug administration and thereafter, in all the collected blood samples throughout the whole experiment. The haematocrit values differed significantly between the cannulated and the non-cannulated fish. We found low haematocrit values and slow drug elimination in the cannulated groups, compared with higher haematocrit values and faster drug elimination in the non-cannulated groups, but further investigations are needed to prove any causal relations of this observation. The volume of distribution (V_d(ss)) was twice as large in the cannulated groups compared with the non-cannulated group, in the fish administered the drug intravenously. In the last part of the elimination phase, the half-lives differed considerably between the cannulated and the noncannulated groups both after oral and intravenous administration. The slower depletion of the drug concentration in the plasma of the cannulated fish is due to the large V_d(ss) as there are only small differences in clearance (Cl_T) between the groups. In this study the elimination of flumequine in cannulated Atlantic salmon differed from the elimination of flumequine in non-cannulated Atlantic salmon.     

Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration

Clorsulon was measured in plasma and urine of sheep and goats after administration of a single intravenous (i.v.) and after a single oral dose of 7 mg/kg. A three-compartment model with elimination occurring from the central compartment was determined to best describe the i.v. data, whereas a one-compartment model with a single exponential absorption phase best described the oral plasma data. The bioavailability of orally administered clorsulon was approximately 55% in goats and 60% in sheep. Peak plasma concentrations occurred at 14 h and 15 h after oral administration in goats and sheep, respectively. Absorption from the gastro-intestinal tract effectively prolonged the elimination of clorsulon by increasing the elimination half-life from 17 to 28 h in sheep and from 12 to 23 h in goats for the i.v. and oral routes, respectively. In both goats and sheep, approximately 50% of the i.v. dose was recovered in urine as parent drug at 48 h after administration, whereas 41% and 30% of the dose was recovered after oral administration for goats and sheep, respectively. The elimination rate constant (kel) in goats was nearly twice as large as the value determined in sheep, and the urea under the i.v. plasma curve in goats was only 63% of the value in sheep indicating that goats are more effective in their capacity to eliminate clorsulon than are sheep. These differences in drug disposition between sheep and goats may account for the reduced efficacy of clorsulon reported in goats.     

Pharmacokinetic comparison of six anthelmintics in sheep,goats, and cattle

This study was initiated to determine whether a comparative pharmacokinetic (PK) approach could be used to expand the pool of approved anthelmintics for minor ruminant species. Accordingly, the PK profiles of six anthelmintics (levamisole, albendazole, fenbendazole, moxidectin, doramectin, and ivermectin) in sheep, goats, and cattle were determined. The PK values determined for each anthelmintic included T_max, T_last, C_max, AUC, AUC/dose, and C_max/dose. The results of this study demonstrate that a comparative PK approach does not show commonality in the way these six anthelmintics are individually processed by these three ruminants. While some drugs demonstrated identical PK profiles between sheep and goats, none of these drugs demonstrated PK profiles in sheep and goats comparable to the PK profiles found in cattle. The results from this study suggest drug approval across these three ruminants is not a viable concept. However, the resulting PK profiles for each combination of drug and ruminant species represents a new dataset that can be used to support the US FDA Center for Veterinary Medicine's Minor Use/Minor Species indexing process for drug approvals in minor species such as sheep and goats.     

14C]-aflatoxin B1 metabolism in lactating goats and rats

Four dairy goats in the second to third month of lactation were administered [14C]-Aflatoxin B1 ( [14C]-AFB1). Two goats were dosed intravenously (iv) with 130 muCi (182 muCi/mumol) and two were dosed orally with 196 muCi (256 muCi/mumol). Urine, milk and feces were collected for 120 h after [14C]-AFB1 administration. Recoveries (average of two animals) of 14C in urine, milk and feces were, respectively; 22.7, .97 and 65% (iv dose) and 30.9, 1.05 and 52.3% (oral dose). Aflatoxin M1 (AFM1) was found in milk in the highest concentration. Aflatoxin Q1 (AFQ1) and aflatoxicol (AFL) were found in trace quantities in milk of animals administered the oral dose. In general, AFM1 could account for the majority of dicholromethane-soluble 14C. Liver contained 7.3 and 4.9% of the dose after 120 h for the iv and oral doses respectively. Kidney, heart, lung and spleen all contained .1% or less of the dose at 120 h. Muscle contained .48% of the dose at 120 h from the goats administered [14C]-AFB1 orally. There was no detectable radioactivity in the fat of any goat at 120 h. Six lactating Sprague-Dawley rats with 12 nursing pups were used for comparison of ruminants and simple-stomached animals. Rats were administered 2 muCi of [14C]-AFB1 (125 muCi/mumol) iv (three animals) and orally (three animals). Mean recovery of 14C in urine, mammary plus milk and feces were, respectively; 9.5, 2.0 and 60.7% (iv) and 8.8, 2.6 and 65.0% (orally).(ABSTRACT TRUNCATED AT 250 WORDS)     

Some pharmacokinetic parameters of doxycycline in East African goats after intramuscular administration of a long-acting formulation

A compartmental and non-compartmental study was carried out on five adult goats following intramuscular administration of doxycycline at 20 mg/kg bodyweight. The concentration of the drug in serum was determined by a microbiological assay employingBacillus cereus varmycoides (ATCC 11778) as the test organism. The mean serum concentration (C _max) and the time of maximum concentration (T _max) were 1.87 µg/ml and 0.85 h, respectively. Using compartmental analysis, the plasma concentration-time curve of doxycycline best fitted a three-compartment open model with first-order absorption. A three-phase disposition of doxycycline was found, the terminal elimination half-life being approximately 40 h.The statistical moment theory was mainly used for non-compartmental analysis. The value obtained for the mean residence time (MRT) was 16.41 h. The mean values for the volume of distribution at steady state (V _dss), determined by compartmental and non-compartmental analyses, were 8.73 and 13.19 L/kg, respectively. There were no statistically significant differences when the major pharmacokinetic parameters were compared.It was concluded that the pharmacokinetic behaviour of doxycycline in goats after intramuscular administration is characterized by a three-compartment model with a slow terminal elimination phase. Based on current knowledge, this could be due to enterohepatic recycling and/or flip-flop kinetics. The study indicated that a single intramuscular administration of 20 mg/kg of doxycycline may only provide therapeutic concentrations for up to 24 h owing to slow absorption at the injection site.Abbreviations ATCC American Type Culture Collection - AVC total area under the plasma concentration-time curve - AUMC area under the curve of the product from time zero to infinity - C1 total body clearance - i.m. intramuscular - i.v. intravenous - MRT mean residence time - MIC minimum inhibitory concentration - PVP polyvinyl pyrolidone - V_d volume of distribution - V _dss volume of distribution at steady state     

Pharmacokinetics of aditoprim in dogs after intravenous and oral administration: a preliminary study

The pharmacokinetics of aditoprim (2,4-diam-ino-5-[4-[dimethylamino]-3,5-dimethoxybenzyl] pyrimidine), a dihydrofolate reductase inhibitor, were studied in three eight to 17-month-old beagle dogs. The drug was alternately injected intravenously and administered orally as a tablet in two separate experiments. The doses ranged from 4–27 to 7–25 mg/kg bodyweight. The mean plasma clearance (CI) was 15-3 ml/min/kg and the mean volume of distribution (V_ss) 13-1 litres/kg. The mean plasma elimination half-life times after intravenous injection and oral administration were 11-6 and 9-6 hours, respectively. Aditoprim was readily (t_max= one to four hours) and completely absorbed from the intestinal tract (f = 89 per cent).     

Pharmacokinetics of sulfaphenazole in sheep

Proprietary formulations of sulfaphenazole were administered intravenously and orally to sheep. After intravenous injection the disposition of sulfaphenazole was described by an open two compartment model, and the elimination half-time was on average 5.58 h. The apparent volume of distribution was 0.273 1/kg and total body clearance 34.1 ml/kg/h. Judged from the area under the curves, the oral dose was completely absorbed, Drug plasma concentrations versus time fitted an open one compartment model, the half-time of absorption and elimination being 2.66 and 7.12 h, respectively. The binding to plasma proteins was high i.e. 93–96 % at therapeutic concentrations, and concentration dependent. The results demonstrate that the doses indicated by the manufacturer appear to be low and more appropriate for drugs with a longer elimination half-time. Consequently, considerable adjustments in the dosage regimen are recommended.     

Pharmacokinetics of florfenicol in veal calves

The pharmacokinetic disposition of florfenicol was described in veal calves after administration of a single 22-mg/kg dose intravenously, orally after a 12-h fast and orally 5 min post feeding. Both serum concentrations and urinary excretion were studied. After intravenous administration the median elimination half-life was 171.9 min while the half-life of the distribution phase was 5.9 min. The median body clearance (Cl) and apparent volume of distribution (Vz) were 2.85 ml/kg/min and 0.78 l/kg, respectively. Following oral administration the median bio-availability (f) was 0.88 for calves dosed after a 12-h fast and 0.65 for calves dosed 5 min post feeding. Calves given the oral doses had a complex absorption pattern with delayed absorption. Slightly more than 50% of the administered dose both orally and intravenously was recovered as unchanged florfenicol in the urine by 30 h.     

Pharmacokinetics, tolerance and serum thromboxane inhibition of carprofen in the dog

The non-steroidal anti-inflammatory drug (NSAID) carprofen was administered to dogs as a mixed-micelle solution at a dose rate of 0–7 mg/kg intravenously, as a palatable paste at a dose rate of 0–7 mg/kg orally, and as an oral tablet formulation at a dose rate of 0–7 mg/kg and 4-0 mg/kg orally for pharmacokinetic studies. It was also administered as an oral tablet formulation at a dose rate of 9-0 mg/kg orally daily for 14 days in a tolerance study. The pharmacokinetics following intravenous administration at a dose rate of 0–7 mg/kg indicate that carprofen has a small volume of distribution (Vd area = 0–09-0-25 litres), a slow systemic clearance (Cls = 1–34-5-57 ml/min) and an elimination half-life of 3–20-11-77 hours. Both oral paste and tablet preparations were highly bioavailable and absorption was proportional to dose rate at 0–7 mg/kg and 4-0 mg/kg bodyweight. Given once daily at dose rates likely to be used clinically it is unlikely to accumulate in the plasma. Carprofen administered as a palatable paste at a dose rate of 0–7 mg/kg did not inhibit serum thromboxane generation and this drug may therefore have a mode of action different from most NSAIDs. Carprofen was well tolerated when administered as an oral tablet formulation at a dose rate of 9.0 mg/kg daily for 14 days in healthy beagle dogs.     

Effect of trikatu pretreatment on the pharmacokinetics of pefloxacin administered orally in mountain Gaddi goats

The pharmacokinetics of orally administered pefloxacin were studied to evaluate the bio-enhancing effect of the herbal bio-enhancer, trikatu, in mountain Gaddi goats (n = 6). The findings of the study revealed a decreased plasma concentration (p > 0.05) of pefloxacin following trikatu administration during the absorption phase (10, 15, 20 min post pefloxacin administration). In contrast, the plasma concentrations of pefloxacin were significantly higher at 4, 6, 8 and 12 h (during the elimination phase) of the pefloxacin administration. The findings of the investigation revealed higher values for the area under the curve, the area under the first moment of the plasma drug concentration time curve, the mean residential time, the total duration of pharmacological action and bioavailability. Trikatu treatment, however, significantly reduced the elimination half life (t_1/2β) and zero time intercept of the elimination phase. The apparent volume of distribution based on the total area under the plasma drug concentration curve [(Vd_(area)] and the apparent volume of distribution based on the zero time plasma concentration intercept of the elimination phase [Vd_(B)] were significantly higher in trikatu treated animals indicating a better penetration of the drug. Based on the MIC of 0.8 µg/ml of pefloxacin, a priming dose of 6.0 mg/kg and a maintenance dose of 2.21 mg/kg is required to be administered at 8 h intervals. For practical purposes in goats this would mean a priming dose of 6 mg/kg and a maintenance dose of 2 mg/kg given by the oral route, to be repeated at 8 h intervals.     

Disposition of flunixin meglumine injectable preparation administered orally to healthy horses

An injectable preparation of flunixin meglumine was administered orally and intravenously at a dose of 1.1 mg/kg to six healthy adult horses in a cross-over design. Flunixin meglumine was detected in plasma within 15 min of administration and peak plasma concentrations were observed 45-60 min after oral administration. Mean bioavailability of the oral drug was 71.9 +/- 26.0%, with an absorption half-life of 0.76 h. The apparent elimination half-life after oral administration was 2.4 h. The injectable preparation of flunixin meglumine is suitable for oral administration to horses.     

Effect of organic vehicles on the pharmacokinetics of aminophylline administered intravenously to goats

Aminophylline dissolved in water, propylene glycol, or dimethyl sulfoxide was administered intravenously to goats in a randomized cross-over experiment. Model-dependent and model-independent pharmacokinetic parameters for theophylline were compared on the basis of the solvent used in the dosage form administered. No difference was found in any pharmacokinetic parameter. Thus, we found no evidence for the possibility that the organic solvents studied would confound pharmacokinetic investigations of theophylline and similar lipophilic drugs.     

Pharmacokinetics and elimination of salicylic acid in rabbits

Sodium salicylate was administered to rabbits in order to compare its disposition with that in other major and minor agricultural species. A dose of 44 mg/kg was given orally (p.o.) or intravenously (i.v.), and plasma and urine samples were collected for 36 h and 96 h, respectively. The majority of the drug was excreted as salicylic acid (SA) within 12 h. The major metabolites following an oral dose were salicyluric acid (SUA) and the glucuronide conjugates of SA and SUA. Following i.v. dosing, sulfate conjugates of both SA and SUA were also evident. Both SA and SUA were detected in plasma. Following i.v. administration, SA was distributed with a Vss of 0.249 +/- 0.082 l/kg and cleared at a rate of 0.0432 +/- 0.006 l/h/kg. The biological half-life, calculated from the terminal disposition-rate constant, was 4.3 h (i.v.) or 9.7 h (p.o.). The urinary elimination pattern of SA and metabolites in the rabbit was similar to that previously reported by our laboratories for cattle and goats, although total recovery of the administered dose was not as high as for the latter two species. However, the volume of distribution was larger than for cattle and goats, and rabbits cleared the drug more slowly than those species. As a consequence, the biological half-life was eight to ten times longer than in the ruminants studied previously.     

Effects of dopamine receptor agonists on food intake and rumen motility in dwarf goats

Kaya, F., Van Duin, C.T.M. & Van Miert, A.S.J.P.A.M. Food intake and rumen motility in dwarf goats. Effects of some dopamine receptor agonists. J. vet. PharmacolTherap, 17 , 120–126. In ruminants, the dopaminergic regulation of feeding behaviour has not been investigated. Therefore, the effects of dopamine receptor agonists and antagonists on food intake and forestomach motility were studied in dwarf goats Goats treated i.v. with bromocriptine (1 μg or 2.5 μg/kg body wt/min during 10 min) ate less food than when treated with saline. This inhibitory effect on food intake could not be prevented by the peripheral dopamine receptor antagonist domperidone (0.5 mg/kg body wt i.v.). In contrast, dopamine (i.v. 20 μg/kg body wt/min during 15 min), levodopa (i.v. 40 μg/kg body weight during 10 min), apomorphine (i.v. 2 μg/kg body wt/min during 10 min) and lisuride (i.v. 0.2 μg/kg body wt/min during 15 min and 0.5 μg/kg body wt during 10 min) failed to modify food intake. Given in association with benserazide, a decarboxylase inhibitor (i.v. 20 μg/kg body wt/min during 10 min), levodopa was still inactive as an anorectie agent. Levopoda, bromocriptine and lisuride administered at similar dose rates to those which were used in the food intake experiments, induced some clinical signs including inhibition of forestomach contractions. The inhibition of rumen contractions induced by these drugs was completely antagonized by domperidone pretreatment. These results, together with earlier in vivo and in vitro observations, suggest that the inhibitory effects of dopamine receptor agonists on forestomach contractions are due to interactions with peripheral dopaminergic receptors. The change in smooth muscle tension, which leads to a change in the signals transmitted via vagal afferents to the central nervous system, probably does not modify feeding behaviour in dwarf goats. Furthermore, i.v. infusion of lisuride induced rumination when the inhibition of the forestomach contractions was prevented by domperidone; this effect may involve α₂-adrenoceptor activation.     

Clinical pharmacokinetics of a dexmedetomidine–methadone combination in dogs undergoing routine anaesthesia after buccal or intramuscular administration

This study aimed to define the pharmacokinetic profiles of dexmedetomidine and methadone administered simultaneously in dogs by either an oral transmucosal route or intramuscular route and to determine the bioavailability of the oral transmucosal administration relative to the intramuscular one of both drugs, so as the applicability of this administration route in dogs. Twelve client‐owned dogs, scheduled for diagnostic procedures, were treated with a combination of dexmedetomidine hydrochloride (10 μg/kg) and methadone hydrochloride (0.4 mg/kg) through an oral transmucosal route or intramuscularly. Oral transmucosal administration caused ptyalism in most subjects, and intramuscular administration caused transient peripheral vasoconstriction. The results showed reduced and delayed absorption of both dexmedetomidine and methadone when administered through an oral transmucosal route, with median (range) C_max values of 0.82 (0.42–1.49) ng/ml and 13.22 (2.80–52.30) ng/ml, respectively. The relative bioavailability was low: 16.34% (dexmedetomidine) and 15.5% (methadone). Intramuscular administration resulted in a more efficient absorption profile, with AUC and C_max values for both drugs approximately 10 times higher. Dexmedetomidine and methadone administered simultaneously by an oral transmucosal route using injectable formulations were not well absorbed through the oral mucosa. Nevertheless, additional studies on these drugs combination using alternative administration routes are recommended.     

Pharmacokinetics of pethidine administered intramuscularly and intravenously to dogs over 10 years old

The pharmacokinetics of pethidine administered postoperatively both intravenously and intramuscularly was investigated in dogs aged over 10 years. When the drug was given intravenously (2 mg kg-1), plasma levels declined in a biexponential manner, with an elimination half-life of 62.7 minutes. Following its intramuscular administration at the same dose rate, absorption was very slow and two distinct rates of absorption were observed. Maximum plasma concentrations were not achieved until 33 minutes after drug administration. The elimination of the intramuscularly administered drug was also slow with a t 1/2 beta' of 145.9 minutes. Thus, it seems that in elderly animals pethidine has a long elimination half-life and a slowed rate of absorption. However, the total body clearance of the drug does not seem to be affected by age.     

Pharmacokinetics of allopurinol in Dalmatian dogs

The pharmacokinetics of allopurinol were studied in Dalmatian dogs. Eight dogs were given allopurinol orally at a dose of 10 mg/kg for seven doses prior to sample collection. After a period of at least two weeks, four of these dogs and four additional Dalmatians were later given a single intravenous (i.v.) dose of allopurinol (6 mg/kg) prior to sample collection.Allopurinol was found to follow first-order absorption and elimination kinetics. In the i.v. kinetic study, the elimination constant (K_el) = 0.31±0.03 per h, the half-life (t_½) = 2.22±0.20 h, the initial concentration (C₀) = 5.26±0.34 μg/mL and the specific volume (V_d) = 1.14±0.07 L/kg. Clearance of allopurinol was estimated to be 0.36±0.03 L/kg·h. In the oral kinetic study, the absorption rate constant (K_ab) = 1.06±0.13 per h, the elimination rate constant (K_el) = 0.26±0.01 per h, the absorption half-life (t_½ab) = 0.66±0.06 h, and the elimination half-life (t_½el) = 2.69±0.14 h. Peak plasma concentrations (C_max) = 6.43±0.18 μg/mL were obtained within 1 to 3 h (mean time of maximum concentration (T_max) = 1.9±0.1 h). The volume of distribution corrected by the fraction of dose absorbed (V_d/F) was estimated to be 1.17±0.07 L/kg.Good agreement was obtained between mean kinetic parameters in the oral and i.v. studies. There was little variation between individual dogs in the i.v. study, whereas the rate of absorption and elimination of orally administered allopurinol was more varied among individual dogs. Because of this, and the fact that the magnitude of hyperuricosuria varies among Dalmatians, it is not possible to specify an exact dose of allopurinol that will effectively lower the urinary uric acid concentration to acceptable values in all Dalmatians with hyperuricosuria; rather, the dose must be titrated to the needs of each dog.     

Bioequivalence in dogs of a meloxicam formulation administered as a transmucosal oral mist with an orally administered pioneer suspension product

Lees, P., Cheng, Z., Keefe, T. J., Weich, E., Bryd, J., Cedergren, R., Cozzi, E. Bioequivalence in dogs of a meloxicam formulation administered as a transmucosal oral mist with an orally administered pioneer suspension product. J. vet. Pharmacol. Therap.  36 , 78–84. A mucosal mist formulation of meloxicam, administered as a spray into the mouth (test article), was compared for bioequivalence to a pioneer meloxicam suspension for oral administration (reference article). Pharmacokinetic profiles and average bioequivalence were investigated in 20 dogs. The study design comprised a two‐period, two‐sequence, two‐treatment cross‐over design, with maximum concentration (C_max) and area under plasma concentration–time curve to last sampling time (AUC_last) used as pivotal bioequivalence variables. Bioequivalence of the products was confirmed, based on relative ratios of geometric mean concentrations (and 90% confidence intervals within the range 0.80–1.25) for C_max of 101.9 (97.99–106.0) and for AUC_last of 97.24 (94.44–100.1). The initial absorption of meloxicam was more rapid for the test article, despite virtually identical C_max values for the two products. Mean elimination half‐lives were 29.6 h (test article) and 30.0 h (reference article). The meloxicam plasma concentration–time profiles were considered in relation to published data on the inhibition of the cyclooxygenase‐1 (COX‐1) and COX‐2 isoenzymes by meloxicam.