Pharmacokinetics of meloxicam in plasma and urine of horses

OBJECTIVE: To determine pharmacokinetic parameters for meloxicam, a nonsteroidal anti-inflammatory drug, in horses. ANIMALS: 8 healthy horses. PROCEDURE: In the first phase of the study, horses were administered meloxicam once in accordance with a 2 x 2 crossover design (IV or PO drug administration; horses fed or not fed). The second phase used a multiple-dose regimen (daily oral administration of meloxicam for 14 days), with meloxicam administered at the recommended dosage (0.6 mg/kg). Plasma and urine concentrations of meloxicam were measured by use of validated methods with a limit of quantification of 10 ng/mL for plasma and 20 ng/mL for urine. RESULTS: Plasma clearance was low (mean +/- SD; 34 +/- 0.5 mL/kg/h), steady-state volume of distribution was limited (0.12 +/- 0.018 L/kg), and terminal half-life was 8.54 +/- 3.02 hours. After oral administration, bioavailability was nearly total regardless of feeding status (98 +/- 12% in fed horses and 85 +/- 19% in nonfed horses). During once-daily administration for 14 days, we did not detect drug accumulation in the plasma. Meloxicam was eliminated via the urine with a urine-to-plasma concentration that ranged from 13 to 18. Concentrations were detected for a relatively short period (3 days) after administration of the final daily dose. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study support once-daily administration of meloxicam regardless of the feeding status of a horse and suggest a period of at least 3 days before urine concentrations of meloxicam reach concentrations that could be used in drug control programs.     

Interindividual variability in plasma concentrations after systemic exposure of swine to dietary doxycycline supplied with and without paracetamol: a population pharmacokinetic approach

Anorexigenic substances released during infection may hinder the therapeutic efficacy of in-feed antibiotics. Paracetamol (acetaminophen; PARA) inhibits the anorexia of infection and seems to improve the clinical efficacy of doxycycline (DOX) against bacterial respiratory disease in swine herds. In order to verify whether PARA selectively stimulates intake of DOX-medicated feed in diseased pigs, we documented the pharmacokinetics (PK) of DOX when coadministered with PARA and examined the effect of in-feed PARA on the interindividual variability in plasma concentrations after systemic exposure to in-feed DOX in swine herds with respiratory disease. Systemic exposure to DOX was measured with the area under the curve (AUC) of its plasma concentrations over time. First, a rich-sampling PK study of in-feed and i.v. DOX (10 mg/kg of BW) and PARA (30 and 10 mg/kg of BW, respectively) was performed on 5 pigs. The PK profiles of in-feed DOX were used in mathematical simulations to determine 5 optimal sampling times for the farm-based population PK study. A randomized, blind, parallel PK study was performed in 2 herds with bacterial respiratory disease, where liquid feed was fortified with DOX alone (5 mg x kg of BW(-1) x meal(-1)) or combined with PARA (15 mg x kg of BW(-1) x meal(-1)). Medicated meals were given twice, 12 h apart, to group-housed growing pigs (n > 50 pigs x treatment(-1) x herd(-1), totaling 215 pigs). Plasma concentrations of DOX and PARA were measured with HPLC. At variance with our expectations, PARA decreased (P = 0.069) mean AUC of in-feed DOX and did not decrease its variability (P > 0.34). Mean AUC of DOX increased with feed intake and with initial exposure to DOX, and was greater in sick animals. Therefore, symptomatic PARA-induced improvement in bacterial respiratory disease control with DOX is more likely caused by its analgesic/antipyretic effects than by its orexigenic effect. Interindividual variation in the AUC of DOX was large in pigs given group medication, even when sufficient feeding space was allowed and the amount of feed offered was greater than their requirements. Therefore, future studies to improve the efficacy of group antibiotic therapy should focus on feeding behavior characteristics as well as biopharmaceutical properties of medicated feeds.     

Disposition of plasma creatinine in non-azotaemic and moderately azotaemic cats

The objectives of this study were to compare assay methods for plasma creatinine (Pl-creat) in cats and to describe the disposition of creatinine and iohexol in 12 healthy and moderately azotaemic cats. Exogenous creatinine and iohexol were injected simultaneously by intravenous bolus, and repeated blood samples were taken to determine the pharmacokinetic parameters of each marker. Pl-creat was assayed by high-performance liquid chromatography (HPLC), Jaffé and enzymatic methods. The enzymatic method was shown to be more reliable than the Jaffé method. Two stereoisomers, exo- and endo-iohexol were identified. The plasma clearance of creatinine (2.3+/-0.66 ml/min/kg) was significantly higher (P<0.001) than that of exo-iohexol (1.7+/-0.40 ml/min/kg). The volume of distribution (447+/-97 ml/kg) and elimination half-life (181+/-77 min) of creatinine were also higher (P<0.001) than those of exo- and endo-iohexol. The estimated daily endogenous production of creatinine was 65+/-23 mg/kg. None of the pharmacokinetic parameters was changed by the azotaemic status of the animals.     

Pharmacokinetic and pharmacodynamic parameters of ramipril and ramiprilat in healthy dogs and dogs with reduced glomerular filtration rate

Ramipril, an angiotensin-converting enzyme (ACE) inhibitor for use in dogs, is converted in vivo to its active form, ramiprilat, which is eliminated in the bile and urine in the dog. The objective of this study was to assess the effect of renal impairment on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ramipril and ramiprilat. Ten adult Beagle dogs were used. PK/PD studies were performed before and after the induction of subclinical renal impairment. Ramiprilat was given at 0.25 mg/kg by a single IV bolus. After a 2-week washout period, ramipril was administered PO at 0.25 mg/kg once daily for 8 days. Ramipril and ramiprilat PKs were studied by using a physiologically based model. The relationship between free plasma ramiprilat concentration and ACE activity was described by using the fractional Hill model. Glomerular filtration rate was decreased by 58%. No biologically relevant changes in usual plasma variables were observed between the 1st and the 8th day of oral treatment with ramipril under either condition. After an IV bolus of ramiprilat, the only changes in renal-impaired dogs were a 14 and 49% decrease in clearance of the free fraction of ramiprilat (P < .01) and free plasma concentration required to produce 50% of the maximal effect (P < .05), respectively. After repeated PO administration of ramipril, there were no alterations in any of the PK and PD parameters in healthy or renal-impaired dogs. No adjustment of the recommended PO dosage of ramipril is needed in dogs with moderate renal impairment.     

Enrofloxacin and marbofloxacin in horses: comparison of pharmacokinetic parameters, use of urinary and metabolite data to estimate first-pass effect and absorbed fraction

Enrofloxacin and marbofloxacin are two veterinary fluoroquinolones used to treat severe bacterial infections in horses. A repeated measures study has been designed to compare their pharmacokinetic parameters, to investigate their bioavailability and to estimate their absorbed fraction and first-pass effect by using plasma, urinary and metabolite data collected from five healthy mares. Clearance and V(d(ss)) were greater for enrofloxacin (mean +/- SD = 6.34 +/- 1.5 mL/min/kg and 2.32 +/- 0.32 L/kg, respectively) than for marbofloxacin (4.62 +/- 0.67 mL/min/kg and 1.6 +/- 0.25 L/kg, respectively). Variance of the AUC(0-inf) of marbofloxacin was lower than that for enrofloxacin, with, respectively, a CV = 15% and 26% intravenously and a CV = 31% and 55% after oral administration. Mean oral bioavailability was not significantly different between marbofloxacin (59%) and enrofloxacin (55%). The mean percentage of the dose eliminated unchanged in urine was significantly higher for marbofloxacin (39.7%) than that for enrofloxacin (3.4%). Absorbed fraction and first-pass effect were only determinable for enrofloxacin, whereas the percentage of the dose absorbed in the portal circulation was estimated to be 78% and the fraction not extracted during the first pass through the liver was 65%. Consequently, the moderate observed bioavailability of enrofloxacin appears to be mainly caused by hepatic first-pass effect.     

Effects of ramipril on renal function during progressive overpacing-induced heart failure in dogs

OBJECTIVE: To investigate the effects of preventive angiotensin converting enzyme inhibitor treatment with ramipril in dogs with progressively severe experimentally induced heart failure. ANIMALS: 20 dogs. PROCEDURES: Dogs were randomly allocated to receive no treatment (control) or ramipril (0.125 mg/kg, PO, daily) for 7 weeks. Physical examination, repetitive catheterization of the right side of the heart, and echocardiography were performed before the study (day 0) and weekly for 7 weeks. Renal plasma flow (RPF) as determined by para-aminohippuric acid clearance and glomerular filtration rate (GFR) as determined by creatinine and iohexol clearances were measured on day 0 and at weeks 4 and 7. RESULTS: Overpacing induced a progressive increase in right atrial pressure (RAP) and pulmonary artery pressure, occluded (PAPO), with a decrease in systemic arterial pressure. There were progressive alterations of echocardiographic indices of diastolic and systolic ventricular function. The RPF and GFR decreased before cardiac output decreased, and filtration fraction increased. The logarithm of the urinary sodium-to-potassium concentration ratio (log(10)[Na(+)/K(+)]) decreased. Significant effects of ramipril included a delay in clinical signs of heart failure, a late decrease in RAP and PAPO, and increases in the sodium excretion fraction and log(10)(Na(+)/K(+)). There was a satisfactory agreement between the creatinine and iohexol clearance measurements. Conclusions AND CLINICAL RELEVANCE: Results suggest that, in this rapid-evolving, dilated cardiomyopathy, activation of the renin-angiotensin system contributes to the pathophysiology of heart failure late in the disease and essentially by an activation of renal salt and water retention.     

New approaches to detect cortisol administration in the horse.

The cortisol threshold concentration of 1.0 microg/ml in horse urine adopted by the International Federation of the racing Authorities in 1994 is specific. However, an increase in the sensitivity for the detection of cortisol administration would be helpful. Previous studies have shown that 20beta-dihydrocortisol concentration in urine would be a good indicator of cortisol administration. The purpose of the present work was to estimate the population parameters and the critical values of 20beta-dihydrocortisol and 20beta-dihydrocortisone concentration in urine compared with that of cortisol. Using the same probability (1.1 x 10(-4)) which was used for the establishment of the official cortisol threshold, the critical values of 5000 ng/ml for 20beta-dihydrocortisol and 350 ng/ml for 20beta-dihydrocortisone were obtained. Considering these 2 critical values for 20beta-dihydrocortisol and 20beta-dihydrocortisone, the time during which a horse could be declared positive is significantly increased.     

Simultaneous and minimally invasive assessment of muscle tolerance and bioavailability of different volumes of an intramuscular formulation in the same animals

Evaluation of skeletal muscle tolerance during development of new drug formulations for i.m. use is most often based on terminal methods performed in the target species after slaughtering. The objective of this study was to evaluate the effect of muscle damage on the pharmacokinetic parameters of the drug delivered into the muscle using an alternative, noninvasive method. Phenylbutazone (PBZ) was used as the test article. Six ewes received increasing volumes of a 20% PBZ i.m. formulation, according to a cross-over design, and an i.v. bolus of the same formulation. Serial blood samples were taken, and a pharmacokinetic analysis of the plasma activity of creatine kinase and plasma PBZ concentrations was carried out. The amount of muscle damage after i.m. administration of 2, 4, or 8 mL of PBZ, calculated from the area under the curve of plasma creatine kinase across time was 36, 76, and 178 g for a 70-kg ewe. The corresponding absolute bioavailability of PBZ was 100 +/- 32%, 96 +/- 19%, and 100 +/- 17%, and the maximal PBZ concentrations were 42 +/- 3.4, 74 +/- 8.8, and 119 +/- 18.2 microg/mL. The plasma clearance of PBZ (i.v.) was 4.2 +/- 0.94 mL.kg(-1).h(-1). In conclusion, the absolute bioavailability of PBZ after i.m. administration was not altered by the increased volume of formulation administered despite the overall increase in the extent of muscle damage.     

Comparison of ultrasonography and pharmacokinetic analysis of creatine kinase release for quantitative assessment of postinjection muscle damage in sheep.

OBJECTIVES: To investigate and validate noninvasive methods for the quantitative evaluation of postinjection muscle damage. ANIMALS: 5 adult sheep. PROCEDURES: Muscle lesions were induced twice in the lumbar region of the longissimus dorsi muscles (2 sides) by IM administration of a 20% formulation of long-acting oxytetracycline (20 mg/kg of body weight). Clinical signs and local cutaneous temperature above the injection site were recorded. Muscle lesions were quantitatively evaluated by ultrasonography and by use of pharmacokinetic analysis of plasma creatine kinase activity, and both were compared with a comprehensive planimetric computer-assisted analysis of the injection sites after euthanasia. RESULTS: Transient cutaneous hypothermia (temperature change, -3.9+/-0.62 C) and subsequent persistent hyperthermia (3.1+/-1.35 C) were observed after the administrations. Despite coefficient of variation < 10% for precision of ultrasonographic measurement of normal muscle, measurements of the lesions, with coefficient of variation > 60% for precision, were systematically underestimated. Quantitative evaluation of muscle damage by use of pharmacokinetic analysis of creatine kinase (12.1+/-4.96 g) was in agreement with results of macroscopic planimetric evaluation (10.8+/-3.64 g). CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasonography cannot be used for quantitative assessment of postinjection muscle damage. Pharmacokinetic analysis of creatine kinase provides an accurate quantitative evaluation of macroscopic muscle damage after IM administration of drugs.     

Plasma exogenous creatinine clearance test in dogs: comparison with other methods and proposed limited sampling strategy

Plasma clearance of creatinine was evaluated for assessment of glomerular filtration rate (GFR) in dogs. In 6 healthy dogs (Experiment 1), we determined 24-hour urine clearance of endogenous creatinine, plasma, and urine clearances of exogenous creatinine administered at 40, 80, and 160 mg/kg in a crossover design (linearity study), plasma iothalamate clearance, and plasma and urine clearances of 14C-inulin. In Experiment 2, plasma creatinine and iothalamate clearances were compared, and a linearity study was performed as for Experiment 1 in 6 dogs with surgically induced renal impairment. Experiment 3 compared plasma creatinine clearance with plasma iothalamate clearance before and 3 weeks after induction of moderate renal impairment in 6 dogs. Plasma creatinine clearances were calculated by both noncompartmental and compartmental analyses. In Experiment 1, plasma inulin clearance was higher (P < .001) than other clearance values. Plasma creatinine clearances at the 3 dose rates did not differ from urine inulin clearance and each other. In Experiment 2, plasma creatinine clearances were about 14% lower than plasma iothalamate clearance (P < .05). In Experiment 3, decreases in GFR assessed by plasma clearances of iothalamate and creatinine were similar. Renal failure decreased the daily endogenous input rate of creatinine by 25%. Limiting sampling strategies for optimizing GFR calculation were proposed, allowing an error lower than 6.5% with 4 blood samples. These results suggest that determination of plasma creatinine clearance by a noncompartmental approach offers a reliable, inexpensive, rapid, and convenient means of estimating GFR in routine practice.