Pharmacokinetics of single intravenous and single and multiple dose oral administration of rifampin in mares

The disposition of rifampin in six healthy mares after single intravenous (i.v.) and oral (p.o.) doses and after seven oral doses of 10 mg/kg administered twice a day was investigated using a high performance liquid chromatographic (HPLC) method. Pharmacokinetic variables for rifampin determined using the HPLC method were comparable to variables reported from earlier studies utilizing a microbiological assay. Desascetylrifampin, a major metabolite of the parent compound, could not be detected in the serum but was detected at low concentrations in urine. Mean trough concentrations of rifampin increased from the first to the second dose of the multiple dose oral study and then remained unchanged through 72 h. At 84 h after the first dose (i.e. 12 h after the final dose) the rifampin concentration was significantly decreased ( P = 0.001). The harmonic mean of the half-life of rifampin decreased significantly from 13.3 h after a single oral dose of 7.99 h after the seventh oral dose. The mean serum protein binding of rifampin over the concentration range of 2–20 μg/ml was 78%. Mean trough serum concentrations of unbound rifampin after multiple oral doses ranged from 0.67 μg/ml at 24 h to 0.40 μg/ml at 72 h. The mean unbound serum rifampin concentration at 84 h (i.e., 12 h after the final dose) was 0.30 μg/ml. Trough concentrations and the 84-h sample concentration of unbound rifampin exceeded the minimum inhibitory concentration for most gram positive bacterial isolates from horses reported in this study. All organisms with minimum inhibitory concentrations less than 0.125 μg/ml were considered susceptible.
Based on the pharmacokinetics of rifampin after p.o. administration, we concur with the current dosage recommendation of 10 mg/kg twice a day by mouth. At this dose, most streptococci, Rhodococcus equi , and coagulase-positive staphylococci would be considered susceptible to rifampin.     

Pharmacokinetics of ketorolac after intravenous and oral single dose administration in dogs

The pharmacokinetics of ketorolac (Toradol), a human non-narcotic, nonsteroidal anti-inflammatory drug (NSAID) of the pyrrolo-pyrrole group, was studied in six mixed breed dogs of varying ages (1-5 years). The study was performed using a randomized crossover design, with each dog initially assigned to one of two groups (intravenous (i.v.) or oral (p.o.)). Each group of three dogs received either the injectable or oral formulation of ketorolac tromethamine at 0.5 mg/kg. Serial blood samples were collected before and over 96 h following treatment. Samples were analysed by reverse phase HPLC. Individual ketorolac plasma concentration-time curves were initially evaluated by computerized curve stripping techniques followed by nonlinear least squares regression. Following i.v. administration mean (+/- SD) pharmacokinetic parameters were: elimination half-life (t1/2 beta) = 4.55 h, plasma clearance (Clp) = 1.25 (1.13) mL/kg/min, and volume of distribution at steady state (Vss) = 0.33 (0.10) L/kg. Mean (+/- SD) p.o. pharmacokinetic values were: t1/2 beta = 4.07 h, time to reach maximum concentration (tmax) = 51.2 (40.6) min, and p.o. bioavailability (F) = 100.9 (46.7)%. These results suggest that the pharmacodisposition characteristics of a clinically effective 0.5 mg/kg i.v. or p.o. single dose of ketorolac tromethamine administered to dogs is fairly similar to that observed in humans.     

Pharmacokinetics of voriconazole after single dose intravenous and oral administration to alpacas

Voriconazole is a new antifungal drug that has shown effectiveness in treating serious fungal infections and has the potential for being used in large animal veterinary medicine. The objective of this study was to determine the plasma concentrations and pharmacokinetic parameters of voriconazole after single-dose intravenous (i.v.) and oral administration to alpacas. Four alpacas were treated with single 4 mg/kg i.v. and oral administrations of voriconazole. Plasma voriconazole concentrations were measured by a high-performance liquid chromatography method. The terminal half-lives following i.v. and oral administration were 8.01 ± 2.88 and 8.75 ± 4.31 h, respectively; observed maximum plasma concentrations were 5.93 ± 1.13 and 1.70 ± 2.71 μg/mL, respectively; and areas under the plasma concentration vs. time curve were 38.5 ± 11.1 and 9.48 ± 6.98 mg·h/L, respectively. The apparent systemic oral availability was low with a value of 22.7 ± 9.5%. The drug plasma concentrations remained above 0.1 μg/mL for at least 24 h after single i.v. dosing. The i.v. administration of 4 mg/kg/day voriconazole may be a safe and appropriate option for antifungal treatment of alpacas. Due to the low extent of absorption in alpacas, oral voriconazole doses of 20.4 to 33.9 mg/kg/day may be needed.     

单次灌胃、静脉注射和肌内注射后多西环素在麻鸭体内的药动学

对麻鸭单次静脉注射、肌内注射和灌胃多西环素后进行药动学研究,给药剂量均为20 mg/kg。麻鸭给药后定点采血,分离血浆,然后以高效液相色谱法测定血浆中的药物浓度,并利用房室分析法计算3种不同给药途径下多西环素的药动学参数。结果显示:静脉注射后,多西环素分布广泛,其表观分布容积(V_d)为(768.50±119.61)m L·kg~(-1),且消除缓慢,消除半衰期(t_(1/2β))为(16.62±0.84)h;而灌胃和肌内注射后,多西环素均迅速吸收,峰浓度(C_(max))分别为(11.32±3.46),(19.70±2.79)mg·L~(-1),达峰时间(t_(max))分别为(2.51±0.23),(1.56±0.09)h,绝对生物利用度则分别为39.44%,77.67%。本研究结果证实多西环素在麻鸭体内具有优异的药动学特征,其吸收迅速、分布广泛、消除缓慢,但同时灌胃后其生物利用度较低。因此推荐多西环素在麻鸭感染性疾病治疗中的给药方案为灌胃或肌内注服给药,剂量均为20 mg·kg~(-1)·d~(-1),连用3 d。     

Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs

Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single‐dose, operator‐blinded, parallel‐dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24‐h period following dosing. Pimobendan and its active metabolite were quantified using an ultra‐high‐performance liquid chromatography–mass spectrometer (UHPLC‐MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (T_max) 1.1 h] and readily converted to the active metabolite (metabolite T_max 1.3 h). The elimination half‐life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2–4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs.     

Pharmacokinetics of rifampin given as a single oral dose in foals

Six foals from 6 to 8 weeks of age were given a single oral dose of rifampin at a dosage of 10 mg/kg of body weight. Serum rifampin concentrations were measured serially during a 24-hour period. The mean peak serum rifampin concentration was 6.7 micrograms/ml at 4 hours after treatment. The concentration decreased slowly, and at 24 hours the mean value was 2.7 micrograms/ml. The elimination half-life was 17.5 hours, and the elimination rate constant was 0.04/hr.     

Pharmacokinetics of amikacin in plasma and selected body fluids of healthy horses after a single intravenous dose

Reasons for performing study: No studies have determined the pharmacokinetics of low‐dose amikacin in the mature horse. Objectives: To determine if a single i.v. dose of amikacin (10 mg/kg bwt) will reach therapeutic concentrations in plasma, synovial, peritoneal and interstitial fluid of mature horses (n = 6). Methods: Drug concentrations of amikacin were measured across time in mature horses (n = 6); plasma, synovial, peritoneal and interstitial fluid were collected after a single i.v. dose of amikacin (10 mg/kg bwt). Results: The mean ± s.d. of selected parameters were: extrapolated plasma concentration of amikacin at time zero 144 ± 21.8 µg/ml; extrapolated plasma concentration for the elimination phase 67.8 ± 7.44 µg/ml, area under the curve 139 ± 34.0 µg*h/ml, elimination half‐life 1.34 ± 0.408 h, total body clearance 1.25 ± 0.281 ml/min/kg bwt; and mean residence time (MRT) 1.81 ± 0.561 h. At 24 h, the plasma concentration of amikacin for all horses was below the minimum detectable concentration for the assay. Selected parameters in synovial and peritoneal fluid were maximum concentration (C_max) 19.7 ± 7.14 µg/ml and 21.4 ± 4.39 µg/ml and time to maximum concentration 65 ± 12.2 min and 115 ± 12.2 min, respectively. Amikacin in the interstitial fluid reached a mean peak concentration of 12.7 ± 5.34 µg/ml and after 24 h the mean concentration was 3.31 ± 1.69 µg/ml. Based on a minimal inhibitory concentration (MIC) of 4 µg/ml, the mean C_max : MIC ratio was 16.9 ± 1.80 in plasma, 4.95 ± 1.78 in synovial fluid, 5.36 ± 1.10 in peritoneal fluid and 3.18 ± 1.33 in interstitial fluid. Conclusions: Amikacin dosed at 10 mg/kg bwt i.v. once a day in mature horses is anticipated to be effective for treatment of infection caused by most Gram‐negative bacteria. Potential relevance: Low dose amikacin (10 mg/kg bwt) administered once a day in mature horses may be efficacious against susceptible microorganisms.     

Pharmacokinetics of ponazuril after administration of a single oral dose to green turtles (Chelonia mydas)

The coccidian protozoan, Caryospora cheloniae, has been associated with severe enteritis and encephalitis in immature farm-raised green turtles (Chelonia mydas) in the Cayman Islands, immature green turtles off the coast of Florida, and immature stranded sea turtles in Australia. An effective anti-coccidial drug that is both orally absorbed and well-distributed throughout the body is needed for treatment of turtles diagnosed with coccidiosis in rehabilitation facilities. Ponazuril is a triazine antiprotozoal drug that is approved in the USA for the treatment of another Apicomplexan, Sarcocystis neurona, and has also been successfully used in the therapy of other coccidian parasites. The objective of this study was to perform an oral dose-ranging pilot study (10–100 mg/kg of body weight ponazuril) in green turtles (N = 9), followed by oral administration of ponazuril at 100 mg/kg body weight (N = 8) to assess its disposition. Another goal of this study was to optimize the method of oral drug administration to green turtles. Plasma ponazuril concentrations were quantified using high performance liquid chromatography (HPLC). Standard compartmental models were fit to the data. Ponazuril was absorbed after oral administration at 100 mg/kg BW, with a maximum plasma concentration of 3.3 µg/ml. Dose-dependent pharmacokinetic parameters only weakly correlated with the dose rate, apparently due to considerable pharmacokinetic variability observed between turtles. Administration of ponazuril in gelatin capsules using a balling gun was deemed the least variable and most successful method of drug administration. Further studies are needed to evaluate the safety and efficacy of ponazuril in sea turtles with coccidiosis.     

Pharmacokinetics in plasma and alveolar regions of a healthy calf intramuscularly administered a single dose of orbifloxacin

This study analyzed the pharmacokinetics of orbifloxacin (OBFX) in plasma, and its migration and retention in epithelial lining fluid (ELF) and alveolar cells within the bronchoalveolar lavage fluid (BALF). Four healthy calves received a single dose of OBFX (5.0 mg/kg) intramuscularly. Post-administration OBFX dynamics were in accordance with a non-compartment model, including the absorption phase. The maximum concentration (C_max) of plasma OBFX was 2.2 ± 0.1 μg/ml at 2.3 ± 0.5 hr post administration and gradually decreased to 0.3 ± 0.2 μg/ml at 24 hr following administration. The C_max of ELF OBFX was 9.3 ± 0.4 μg/ml at 3.0 ± 2.0 hr post administration and gradually decreased to 1.2 ± 0.1 μg/ml at 24 hr following administration. The C_max of alveolar cells OBFX was 9.3 ± 2.9 μg/ml at 4.0 hr post administration and gradually decreased to 1.1 ± 0.2 μg/ml at 24 hr following administration. The half-life of OBFX in plasma, ELF, and alveolar cells were 6.9 ± 2.2, 7.0 ± 0.6, and 7.8 ± 1.6 hr, respectively. The C_max and the area under the concentration-time curve for 0–24 hr with OBFX were significantly higher in ELF and alveolar cells than in plasma (P<0.05). These results suggest that OBFX is distributed and retained at high concentrations in ELF and alveolar cells at 24 hr following administration. Hence, a single intramuscular dose of OBFX (5.0 mg/kg) may be an effective therapeutic agent against pneumonia.     

Pharmacokinetics of pioglitazone after multiple oral dose administration in horses

Pioglitazone is a thiazolidinedione class of antidiabetic agent with proven efficacy in increasing insulin sensitivity in humans with noninsulin-dependent diabetes mellitus, a syndrome of insulin resistance sharing similarities with equine metabolic syndrome. The purpose of this study was to determine the pharmacokinetics of pioglitazone in adult horses following multiple oral dose administration. Pioglitazone hydrochloride (1 mg/kg) was administered orally for 11 doses at 24-h intervals, and plasma samples were collected. Initially, a pilot study was performed using one horse; and thereafter the drug was administered to six horses. Samples were analyzed by liquid chromatography with tandem mass spectrometry, and pharmacokinetic parameters were calculated using noncompartmental modeling. The maximum plasma concentration was 509.1 ± 413.5 ng/mL achieved at 1.88 ± 1.39 h following oral administration of the first dose, and 448.1 ± 303.5 ng/mL achieved at 2.83 ± 1.81 h (mean ± SD) following the eleventh dose. Apparent elimination half-life was 9.94 ± 4.57 and 9.63 ± 5.33 h after the first and eleventh dose, respectively. This study showed that in healthy horses, pioglitazone administered at a daily oral dose of 1 mg/kg results in plasma concentrations and total drug exposure approximating, but slightly below, those considered therapeutic in humans.     

Pharmacokinetics of isavuconazole in healthy cats after oral and intravenous administration

BackgroundIsavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.ObjectivesTo determine the pharmacokinetics of isavuconazole in cats given a single IV or PO dose.AnimalsEight healthy, adult research cats.MethodsFour cats received 100 mg capsules of isavuconazole PO. Four cats received 5 mg/kg isavuconazole solution IV. Serum was collected at predetermined intervals for analysis using ultra‐high performance liquid chromatography‐tandem mass spectrometry. Data were analyzed using a 2‐compartment uniform weighting pharmacokinetic analysis with lag time for PO administration and a 2 compartment, 1/y² weighting for IV administration. Predicted 24 and 48‐hour dosing intervals of 100 mg isavuconazole administered PO were modeled and in vitro plasma protein binding was assessed.ResultsBoth PO and IV drug administration resulted in high serum concentrations. Intravenous and PO formulations of isavuconazole appear to be able to be used interchangeably. Peak serum isavuconazole concentrations occurred 5 ± 3.8 hours after PO administration with an elimination rate half‐life of 66.2 ± 55.3 hours. Intersubject variability was apparent in both the PO and IV groups. Two cats vomited 6 to 8 hours after PO administration. No adverse effects were observed in the IV group. Oral bioavailability was estimated to be approximately 88%. Serum protein binding was calculated to be approximately 99.0% ± 0.03%.Conclusions and Clinical ImportanceIsavuconazole might prove to be useful in cats with fungal disease given its favorable pharmacokinetics. Additional studies on safety, efficacy, and tolerability of long‐term isavuconazole use are needed.     

Pharmacokinetics of doxycycline after a single intravenous,oral or intramuscular dose in Muscovy ducks (Cairina moschata)

1. The pharmacokinetics of doxycycline in ducks were investigated after a single intravenous (IV), intramuscular (IM) or oral (PO) dose at 20 mg/kg body weight.

2. The concentrations of doxycycline in plasma samples were assayed using a high performance liquid chromatography method, and pharmacokinetic parameters were calculated using a non-compartmental model.

3. After IV administration, doxycycline had a mean (±SD) distribution volume (V_z) of 1761.9 ± 328.5 ml/kg and was slowly eliminated with a terminal half-life (t_1/2λz) of 21.21±1.47 h and a total body clearance (Cl) of 57.51 ± 9.50 ml/h/kg. Following PO and IM administration, doxycycline was relatively slowly absorbed – the peak concentrations (C_max) were 17.57 ± 4.66 μg/ml at 2 h and 25.01 ± 4.18 μg/ml at 1.5 h, respectively. The absolute bioavailabilities (F) of doxycycline after PO and IM administration were 39.13% and 70.71%, respectively.

4. The plasma profile of doxycycline exhibited favourable pharmacokinetics characteristics in Muscovy ducks, such as wide distribution, relatively slow absorption and slow elimination, though oral bioavailability was low.

     

Pharmacokinetics of marbofloxacin after a single oral dose to loggerhead sea turtles (Caretta caretta)

The single-dose disposition kinetics of marbofloxacin (MBX) were determined in clinically healthy loggerhead sea turtles (n = 5) after oral (PO) administration of 2 mg kg⁻¹ bodyweight. Marbofloxacin plasma concentrations were determined by DAD–HPLC (LOD/LOQ 0.015/0.05 μg ml⁻¹). Data were subjected to non-compartmental analysis. Following PO administration, marbofloxacin achieved maximum plasma concentrations of 11.66 ± 2.53 mg L⁻¹ at 15.00 ± 3.00 h. The absence of general adverse reactions in the turtles of the study, and the favourable pharmacokinetic properties (long half-life and high maximum plasma concentration) of MBX administered PO at the single-dose of 2 mg kg⁻¹ suggest the possibility of its safe and effective clinical use in loggerhead sea turtles.     

Pharmacokinetics of enrofloxacin after single dose oral and intravenous administration in the African penguin (Spheniscus demersus)

The pharmacokinetics of a single dose of enrofloxacin administered orally, both pilled and in fish, and i.v. to African penguins (Spheniscus demersus) at 15 mg/kg were determined. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were measured via high-pressure liquid chromatography with mass spectrometry. An i.v. administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 7.86 microg/ml at time zero. Plasma volume of distribution for i.v. administration was 3.00 L/kg, with a mean elimination half-life of 13.67 hr and a mean total body clearance rate of 3.03 ml/min/kg. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of4.38 microg/ml at 4.8 hr after administration when pilled, whereas mean maximum plasma concentration was 4.77 microg/ml at 1.59 hr after administration when given in fish. Mean terminal elimination half-life was 13.79 hr pilled and 11.93 hr when given in fish. Low concentrations of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration. Enrofloxacin administered to African penguins at 15 mg/kg p.o.q. 24 hr, whether in fish or pilled, is expected to achieve the surrogate markers of efficacy for bacteria with a minimum inhibitory concentration of 0.5 microg/ml or less; however, clinical studies are needed to determine efficacy.     

Pharmacokinetics of the calcium-channel blocker diltiazem after a single intravenous dose in horses

The pharmacokinetics of diltiazem were determined in eight healthy horses. Diltiazem HCl, 1 mg/kg i.v., was administered over 5 min. Venous blood samples were collected at regular intervals after administration. Plasma concentrations of diltiazem and desacetyldiltiazem were determined by high-performance liquid chromatography. A second, putative metabolite was detected, but could not be identified due to the lack of an authentic standard. Data were analyzed by nonlinear least-squares regression analysis. The median (minimum-maximum) peak plasma concentration of diltiazem was 727 (539-976) ng/mL. Plasma diltiazem concentration vs. time data were best described by a two-compartment model with first-order drug elimination. The distribution half-life was 12 (6-23) min, the terminal half-life was 93 (73-161) min, the mean residence time was 125 (99-206) min, total plasma clearance was 14.4 (10.4-18.6) mL/kg/min, and the volume of distribution at steady-state was 1.84 (1.46-2.51) L/kg. The normalized ratio of the area under the curve (AUC) of desacetyldiltiazem to the AUC of diltiazem was 0.088 (0.062-0.179). The disposition of diltiazem in horses was characterized by rapid distribution and elimination and a terminal half-life shorter than reported in humans and dogs. Because of the reported low pharmacologic activity, plasma diltiazem metabolite concentrations were not considered clinically important.