Pharmacokinetics of cefovecin in cats

The pharmacokinetics of the novel cephalosporin cefovecin were investigated in a series of in vivo, ex vivo and in vitro studies following administration to adult cats at 8 mg/kg bodyweight. Bioavailability and pharmacokinetic parameters were determined in a cross-over study after intravenous (i.v.) and subcutaneous (s.c.) injections. [14C]cefovecin was used to evaluate excretion for 21 days after s.c. administration. Protein binding was determined in vitro in feline plasma and ex vivo in transudate from cats surgically implanted with tissue chambers. After s.c. administration, cefovecin was characterized by rapid absorption with mean peak plasma concentrations of 141+/-12 microg/mL being achieved within 2 h of s.c. injection with full bioavailability (99%). The mean elimination half-life was 166+/-18 h. After i.v. administration, volume of distribution was 0.09+/-0.01 L/kg and mean plasma clearance was 0.35+/-0.04 mL/h/kg. Approximately 50% of the administered radiolabelled dose was eliminated over the 21-day postdose period via urinary excretion and up to approximately 25% in faeces. In vitro and ex vivo plasma protein binding ranged from 99.8% to 99.5% over the plasma concentration range 10-100 microg/mL. Ex vivo protein binding in transudate was as low as 90.7%. From 8 h postdose, concentrations of unbound (free) cefovecin in transudate were consistently higher than in plasma, with mean unbound cefovecin concentrations being maintained above 0.06 microg/mL (MIC90 of Pasteurella multocida) in transudate for at least 14 days postdose. The slow elimination and long-lasting free concentrations in extracellular fluid are desirable pharmacokinetic attributes for an antimicrobial with a 14-day dosing interval.     

Pharmacokinetics of voriconazole following intravenous and oral administration and body fluid concentrations of voriconazole following repeated oral administration in horses

OBJECTIVE: To determine the pharmacokinetics of voriconazole following IV and PO administration and assess the distribution of voriconazole into body fluids following repeated PO administration in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURES: All horses received voriconazole (10 mg/kg) IV and PO (2-week interval between treatments). Plasma voriconazole concentrations were determined prior to and at intervals following administration. Subsequently, voriconazole was administered PO (3 mg/kg) twice daily for 10 days to all horses; plasma, synovial fluid, CSF, urine, and preocular tear film concentrations of voriconazole were then assessed. RESULTS: Mean +/- SD volume of distribution at steady state was 1,604.9 +/- 406.4 mL/kg. Systemic bioavailability of voriconazole following PO administration was 95 +/- 19%; the highest plasma concentration of 6.1 +/- 1.4 microg/mL was attained at 0.6 to 2.3 hours. Mean peak plasma concentration was 2.57 microg/mL, and mean trough plasma concentration was 1.32 microg/mL. Mean plasma, CSF, synovial fluid, urine, and preocular tear film concentrations of voriconazole after long-term PO administration were 5.163 +/- 1.594 microg/mL, 2.508 +/- 1.616 microg/mL, 3.073 +/- 2.093 microg/mL, 4.422 +/- 0.8095 microg/mL, and 3.376 +/- 1.297 microg/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that voriconazole distributed quickly and widely in the body; following a single IV dose, initial plasma concentrations were high with a steady and early decrease in plasma concentration. Absorption of voriconazole after PO administration was excellent, compared with absorption after IV administration. Voriconazole appears to be another option for the treatment of fungal infections in horses.     

Comparison of pharmacodynamic variables following oral versus transdermal administration of atenolol to healthy cats

OBJECTIVE: To describe the disposition of and pharmacodynamic response to atenolol when administered as a novel transdermal gel formulation to healthy cats. ANIMALS: 7 healthy neutered male client-owned cats. PROCEDURES: Atenolol was administered either orally as a quarter of a 25-mg tablet or as an equal dose by transdermal gel. Following 1 week of treatment, an ECG and blood pressure measurements were performed and blood samples were collected for determination of plasma atenolol concentration at 2 and 12 hours after administration. RESULTS: 2 hours after oral administration, 6 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 579 +/- 212 ng/mL. Two hours following transdermal administration, only 2 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 177 +/- 123 ng/mL. The difference in concentration between treatments was significant. Trough plasma atenolol concentrations of 258 +/- 142 ng/mL and 62.4 +/- 17 ng/mL were achieved 12 hours after oral and transdermal administration, respectively. A negative correlation was found between heart rate and plasma atenolol concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of atenolol at a median dose of 1.1 mg/kg every 12 hours (range, 0.8 to 1.5 mg/kg) in cats induced effective plasma concentrations at 2 hours after treatment in most cats. Transdermal administration provided lower and inconsistent plasma atenolol concentrations. Further studies are needed to find an effective formulation and dosing scheme for transdermal administration of atenolol.     

Pharmacokinetics of ceftiofur sodium after intramuscular or subcutaneous administration in green iguanas (Iguana iguana)

OBJECTIVE: To determine the pharmacokinetics of ceftiofur sodium after IM and SC administration in green iguanas. ANIMALS: 6 male and 4 female adult green iguanas. PROCEDURE: In a crossover design, 5 iguanas received a single dose of ceftiofur sodium (5 mg/kg) IM, and 5 iguanas received the same dose SC. Blood samples were taken at 0, 20, and 40 minutes and 1, 2, 4, 8, 24, 48, and 72 hours after administration. After a 10-week washout period, each iguana was given the same dose via the reciprocal administration route, and blood was collected in the same fashion. Ceftiofur free-acid equivalents were measured via high-performance liquid chromatography. RESULTS: The first phase intercepts were significantly different between the 2 administration routes. Mean maximum plasma concentration was significantly higher with the IM (28.6 +/- 8.0 microg/mL) than the SC (18.6 +/- 8.3 microg/mL) administration route. There were no significant differences between terminal half-lives (harmonic mean via IM route, 15.7 +/- 4.7 hours; harmonic mean via SC route, 19.7 +/- 6.7 hours) and mean areas under the curve measured to the last time point (IM route, 11,722 +/- 7,907 microg x h/mL; SC route, 12,143 +/- 9,633 microg x h/mL). Ceftiofur free-acid equivalent concentrations were maintained > or = 2 microg/mL for > 24 hours via both routes. CONCLUSIONS AND CLINICAL RELEVANCE: A suggested dosing schedule for ceftiofur sodium in green iguanas for microbes susceptible at > 2 microg/mL would be 5 mg/kg, IM or SC, every 24 hours.     

Pharmacokinetics of voriconazole after oral and intravenous administration to horses

OBJECTIVE: To characterize pharmacokinetics of voriconazole in horses after oral and IV administration and determine the in vitro physicochemical characteristics of the drug that may affect oral absorption and tissue distribution. ANIMALS: 6 adult horses. PROCEDURES: Horses were administered voriconazole (1 mg/kg, IV, or 4 mg/kg, PO), and plasma concentrations were measured by use of high-performance liquid chromatography. In vitro plasma protein binding and the octanol:water partition coefficient were also assessed. RESULTS: Voriconazole was adequately absorbed after oral administration in horses, with a systemic bioavailability of 135.75 +/- 18.41%. The elimination half-life after a single orally administered dose was 13.11 +/- 2.85 hours, and the maximum plasma concentration was 2.43 +/- 0.4 microg/mL. Plasma protein binding was 31.68%, and the octanol:water partition coefficient was 64.69. No adverse reactions were detected during the study. CONCLUSIONS AND CLINICAL RELEVANCE: Voriconazole has excellent absorption after oral administration and a long half-life in horses. On the basis of the results of this study, it was concluded that administration of voriconazole at a dosage of 4 mg/kg, PO, every 24 hours will attain plasma concentrations adequate for treatment of horses with fungal infections for which the fungi have a minimum inhibitory concentration 相似文献   

Plasma and urine concentrations of marbofloxacin following single subcutaneous administration to cats

The pharmacokinetic properties of marbofoxacin, a third generation fluoroquinolone, were investigated in 12 healthy adult cats after single subcutaneous (SC) administration of 2 mg/kg BW (Part I, n=8 cats) and 4 mg/kg BW (Part II, n=4 cats). In each part of the study blood and urine samples were collected before treatment and thereafter for 5 days. The plasma and urine concentrations of marbofloxacin were determined by HPLC with UV detection. Pharmacokinetic calculations were performed for each treated animal using an open one-compartment-model with first-order elimination after SC dosing. Marbofloxacin in plasma (means): Maximum concentrations (Cmax) of about 1.2 and 3.0 microg/ml were measured 2.3 and 4 hours (tmax) after dosing of 2 and 4 mg/kg BW, respectively. Elimination from the body was low with a total clearance (Cl/F) of approximately 0.1 l/h/kg for both dosages. The half-life (t 1/2) for this process was calculated with 8-10 hours. AUC increased almost proportional when doubling the dose, i.e., 19.77 +/- 6.25 microg * h/ml (2 mg/kg BW) and 51.26 +/- 11.83 microg * h/ml (4 mg/kg BW). Plasma kinetics measured were in accordance with data from literature. Marbofloxacin in urine (means): Maximum drug concentrations were detected 4 and 8 hours after dosing with 70 microg/ml (2 mg/kg BW) and 160 microg/ml (4 mg/kg BW), respectively. Inhibitory effects of the urinary matrix on the antimicrobial activity of the drug were taken into account when performing PK/PD calculations. However, a concentration-dependent bactericidal activity (Cmax/MIC > 8-10) which is claimed for fluoroquinolones was sufficiently met with focus on Escherichia (E.) coli (MIC90 0.5 microg/ml). In the same matrix a threshold value of 1.0 microg/ml was undercut 82 and 116 hours after SC dosing, respectively. Hence, a time-dependent bacteria killing kinetic (T > MIC) which may be of relevance for some Gram-positive germs like Staphylococcus spp. (MIC90 1.0 microg/ml) should be covered, too.     

Evaluation of bioequivalence after oral, intramuscular, and intravenous administration of racemic ketoprofen in pigs

OBJECTIVE: To assess bioequivalence after oral, IM, and IV administration of racemic ketoprofen in pigs and to investigate the bioavailability after oral and IM administration. ANIMALS: 8 crossbred pigs. PROCEDURES: Each pig received 4 treatments in a randomized crossover design, with a 6-day washout period. Ketoprofen was administered at 3 and 6 mg/kg, PO; 3 mg/kg, IM; and 3 mg/kg, IV. Plasma ketoprofen concentrations were measured by use of high-performance liquid chromatography for up to 48 hours. To assess bioequivalence, a 90% confidence interval was calculated for the area under the time-concentration curve (AUC) and maximum plasma concentration (C(max)). RESULTS: Equivalence was not detected in the AUCs among the various routes of administration nor in C(max) between oral and IM administration of 3 mg/kg. The bioavailability of ketoprofen was almost complete after each oral or IM administration. Mean +/- SD C(max) was 5.09 +/- 1.41 microg/mL and 7.62 +/- 1.22 microg/mL after oral and IM doses of 3 mg/kg, respectively. Mean elimination half-life varied from 3.52 +/- 0.90 hours after oral administration of 3 mg/kg to 2.66 +/- 0.50 hours after IV administration. Time to peak C(max) after administration of all treatments was approximately 1 hour. Increases in AUC and C(max) were proportional when the orally administered dose was increased from 3 to 6 mg/kg. Conclusions and Clinical Relevance: Orally administered ketoprofen was absorbed well in pigs, although bioequivalence with IM administration of ketoprofen was not detected. Orally administered ketoprofen may have potential for use in treating pigs.     

Hydroxyzine and cetirizine pharmacokinetics and pharmacodynamics after oral and intravenous administration of hydroxyzine to healthy dogs

Pharmacokinetic parameters of hydroxyzine and its active metabolite cetirizine were determined after oral and intravenous administration of 2 mg kg(-1) of hydroxyzine to six healthy dogs. Plasma drug levels were determined with high-pressure liquid chromatography. Pharmacodynamic studies evaluated the suppressive effect on histamine and anticanine IgE-mediated cutaneous wheal formation. Pharmacokinetic and pharmacodynamic correlations were determined with computer modelling. The mean systemic availability of oral hydroxyzine was 72%. Hydroxyzine was rapidly converted to cetirizine regardless of the route of administration. The mean area-under-the-curve was eight and ten times higher for cetirizine than hydroxyzine after intravenous and oral dosing, respectively. After oral administration of hydroxyzine, the mean peak concentration of cetirizine was approximately 2.2 microg mL(-1) and that of hydroxyzine 0.16 microg mL(-1). The terminal half-life for cetirizine varied between 10 and 11 h after intravenous and oral administration of hydroxyzine. A sigmoidal relationship was fit to the data comparing cetirizine plasma concentration to wheal suppression. Maximum inhibition (82% and 69% for histamine and anticanine IgE-mediated skin reactions, respectively) was observed during the first 8 h, which correlated with a plasma concentration of cetirizine greater than 1.5 microg mL(-1). Pharmacological modelling suggested that increasing either hydroxyzine dosages or frequencies of administration would not result in histamine inhibition superior to that obtained with twice daily hydroxyzine at 2 mg kg(-1). In conclusion, there was rapid conversion of hydroxyzine to cetirizine. The reduction of wheal formation appeared almost entirely due to cetirizine. Pharmacodynamic modelling predicted that maximal antihistamine effect would occur with twice daily oral administration of hydroxyzine at 2 mg kg(-1).     

Comparison of pharmacokinetics of fentanyl after intravenous and transdermal administration in cats

OBJECTIVE: To compare pharmacokinetic and pharmacodynamic characteristics of fentanyl citrate after IV or transdermal administration in cats. ANIMALS: 6 healthy adult cats with a mean weight of 3.78 kg. PROCEDURE: Each cat was given fentanyl IV (25 mg/cat; mean +/- SD dosage, 7.19 +/- 1.17 mg/kg of body weight) and via a transdermal patch (25 microg of fentanyl/h). Plasma concentrations of fentanyl were measured by use of radioimmunoassay. Pharmacokinetic analyses of plasma drug concentrations were conducted, using an automated curve-stripping process followed by nonlinear, least-squares regression. Transdermal delivery of drug was calculated by use of IV pharmacokinetic data. RESULTS: Plasma concentrations of fentanyl given IV decreased rapidly (mean elimination half-life, 2.35 +/- 0.57 hours). Mean +/- SEM calculated rate of transdermal delivery of fentanyl was 8.48 +/- 1.7 mg/h (< 36% of the theoretical 25 mg/h). Median steady-state concentration of fentanyl 12 to 100 hours after application of the transdermal patch was 1.58 ng/ml. Plasma concentrations of fentanyl < 1.0 ng/ml were detected in 4 of 6 cats 12 hours after patch application, 5 of 6 cats 18 and 24 hours after application, and 6 of 6 cats 36 hours after application. CONCLUSIONS AND CLINICAL RELEVANCE: In cats, transdermal administration provides sustained plasma concentrations of fentanyl citrate throughout a 5-day period. Variation of plasma drug concentrations with transdermal absorption for each cat was pronounced. Transdermal administration of fentanyl has potential for use in cats for long-term control of pain after surgery or chronic pain associated with cancer.     

Pharmacokinetics of lamivudine in cats

OBJECTIVE: To characterize the pharmacokinetics of lamivudine (3TC) in cats. ANIMALS: 6 sexually intact 9-month-old barrier-reared domestic shorthair cats. PROCEDURE: Cats were randomly alloted into 3 groups, and lamivudine (25 mg/kg) was administered i.v., intragastrically (i.g.), and p.o. in a 3-way crossover study design with 2-week washout periods between experiments. Plasma samples were collected for 12 hours after drug administration, and lamivudine concentrations were determined by high-performance liquid chromatography. Maximum plasma concentrations (Cmax), time to reach Cmax (Tmax), and bioavailability were compared between i.g. and p.o. routes. Area under the curve (AUC) and terminal phase half-life (t(1/2)) among the 3 administration routes were also compared. RESULTS: Plasma concentrations of lamivudine declined rapidly with a t(1/2) of 1.9 +/- 0.21 hours, 2.6 +/- 0.66 hours, and 2.7 +/- 1.50 hours after i.v., i.g., and p.o. administration, respectively. Total body clearance and steady-state volume of distribution were 0.22 +/- 0.09 L/h/kg and 0.60 +/- 0.22 L/kg, respectively. Mean Tmax for i.g. administration (0.5 hours) was significantly shorter than Tmax for p.o. administration (1.1 hours). The AUC after i.v., i.g., and p.o. administration was 130 +/- 55.2 mg x h/L, 115 +/- 97.5 mg x h/L, and 106 +/- 94.9 mg x h/L, respectively. Lamivudine was well absorbed after i.g. and p.o. administration with bioavailability values of 88 +/- 45% and 80 +/- 52%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Cats had a shorter t(1/2) but slower total clearance of lamivudine, compared with humans. Plasma concentrations of lamivudine were maintained above the minimum effective concentration for inhibiting FIV replication by 50% (0.14 microM [0.032 microg/mL] for wild-type FIV clinical isolate) for at least 12 hours after i.v., i.g., or p.o. administration.     

Plasma pharmacokinetics and tissue fluid concentrations of meropenem after intravenous and subcutaneous administration in dogs

OBJECTIVE: To estimate pharmacokinetic variables and measure tissue fluid concentrations of meropenem after IV and SC administration in dogs. ANIMALS: 6 healthy adult dogs. PROCEDURE: Dogs were administered a single dose of meropenem (20 mg/kg) IV and SC in a crossover design. To characterize the distribution of meropenem in dogs and to evaluate a unique tissue fluid collection method, an in vivo ultrafiltration device was used to collect interstitial fluid. Plasma, tissue fluid, and urine samples were analyzed by use of high-performance liquid chromatography. Protein binding was determined by use of an ultrafiltration device. RESULTS: Plasma data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean +/- SD values for half-life, volume of distribution, and clearance after IV administration for plasma samples were 0.67 +/- 0.07 hours, 0.372 +/- 0.053 L/kg, and 6.53 +/- 1.51 mL/min/kg, respectively, and half-life for tissue fluid samples was 1.15 +/- 0.57 hours. Half-life after SC administration was 0.98 +/- 0.21 and 1.31 +/- 0.54 hours for plasma and tissue fluid, respectively. Protein binding was 11.87%, and bioavailability after SC administration was 84%. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of our data revealed that tissue fluid and plasma (unbound fraction) concentrations were similar. Because of the kinetic similarity of meropenem in the extravascular and vascular spaces, tissue fluid concentrations can be predicted from plasma concentrations. We concluded that a dosage of 8 mg/kg, SC, every 12 hours would achieve adequate tissue fluid and urine concentrations for susceptible bacteria with a minimum inhibitory concentration of 0.12 microg/mL.     

Evaluation of the concentration of marbofloxacin in alveolar macrophages and pulmonary epithelial lining fluid after administration in dogs

OBJECTIVE: To determine concentrations of marbofloxacin in alveolar macrophages (AMs) and epithelial lining fluid (ELF) and compare those concentrations with plasma concentrations in healthy dogs. ANIMALS: 12 adult mixed-breed and purebred hounds. PROCEDURE: 10 dogs received orally administered marbofloxacin at a dosage of 2.75 mg/kg every 24 hours for 5 days. Two dogs served as nontreated controls. Fiberoptic bronchoscopy and bronchoalveolar lavage procedures were performed while dogs were anesthetized with propofol, approximately 6 hours after the fifth dose. The concentrations of marbofloxacin in plasma and bronchoalveolar fluid (cell and supernatant fractions) were determined by use of high-performance liquid chromatography with detection of fluorescence. RESULTS: Mean +/- SD plasma marbofloxacin concentrations 2 and 6 hours after the fifth dose were 2.36 +/- 0.52 microg/mL and 1.81 +/- 0.21 microg/mL, respectively. Mean +/- SD marbofloxacin concentration 6 hours after the fifth dose in AMs (37.43 +/- 24.61 microg/mL) was significantly greater than that in plasma (1.81 +/- 0.21 microg/mL) and ELF (0.82 +/- 0.34 microg/mL), resulting in a mean AM concentration-to-plasma concentration ratio of 20.4, a mean AM:ELF ratio of 60.8, and a mean ELF-to-plasma ratio of 0.46. Marbofloxacin was not detected in any samples from control dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Marbofloxacin concentrations in AMs were greater than the mean inhibitory concentrations of major bacterial pathogens in dogs. Results indicated that marbofloxacin accumulates in AMs at concentrations exceeding those reached in plasma and ELF The accumulation of marbofloxacin in AMs may facilitate treatment for susceptible intracellular pathogens or infections associated with pulmonary macrophage infiltration.     

Pharmacokinetics of ceftriaxone after intravenous, intramuscular and subcutaneous administration to domestic cats

The pharmacokinetic properties of ceftriaxone, a third-generation cephalosporin, were investigated in five cats after single intravenous, intramuscular and subcutaneous administration at a dosage of 25 mg/kg. Ceftriaxone MICs for some gram-negative and positive strains isolated from clinical cases were determined. Efficacy predictor (t > MIC) was calculated. Serum ceftriaxone disposition was best fitted by a bicompartmental and a monocompartmental open models with first-order elimination after intravenous and intramuscular and subcutaneous dosing, respectively. After intravenous administration, distribution was fast (t1/2d 0.14 +/- 0.02 h) and moderate as reflected by the volume of distribution (V(d(ss))) of 0.57 +/- 0.22 L/kg. Furthermore, elimination was rapid with a plasma clearance of 0.37 +/- 0.13 L/h.kg and a t1/2 of 1.73 +/- 0.23 h. Peak serum concentration (Cmax), tmax and bioavailability for the intramuscular administration were 54.40 +/- 12.92 microg/mL, 0.33 +/- 0.07 h and 85.72 +/- 14.74%, respectively; and for the subcutaneous route the same parameters were 42.35 +/- 17.62 microg/mL, 1.27 +/- 0.95 h and 118.28 +/- 39.17%. Ceftriaxone MIC for gram-negative bacteria ranged from 0.0039 to >8 microg/mL and for gram-positive bacteria from 0.5 to 4 microg/mL. t > MIC was in the range 83.31-91.66% (10-12 h) of the recommended dosing interval (12 h) for Escherichia coli (MIC90 = 0.2 microg/mL).     

Effects of intravenous administration of lidocaine on the thermal threshold in cats

OBJECTIVE: To determine the effects of IV administration of lidocaine on thermal antinociception in conscious cats. ANIMALS: 6 cats. PROCEDURE: 2 experiments were performed in each cat (interval of at least 2 months). In experiment 1, lidocaine pharmacokinetics were determined for each conscious cat following IV administration of a bolus of lidocaine (2 mg/kg). In experiment 2, data from experiment 1 were used to calculate appropriate doses of lidocaine that would achieve predetermined plasma lidocaine concentrations in the cats; lidocaine (or an equivalent volume of saline [0.9% NaCl] solution as the control treatment) was administered IV to target pseudo-steady-state plasma concentrations of 0, 0.5, 1, 2, 5, and 8 microg/mL. Skin temperature and thermal threshold were determined at the start of the experiment (baseline) and at each concentration. Samples of venous blood were obtained at each target concentration for plasma lidocaine concentration determination. RESULTS: In experiment 2, actual plasma lidocaine concentrations were 0.00 +/- 0.00 microg/mL, 0.25 +/- 0.18 microg/mL, 0.57 +/- 0.20 microg/mL, 1.39 +/- 0.13 microg/mL, 2.33 +/- 0.45 microg/mL, and 4.32 +/- 0.66 microg/mL for target plasma concentrations of 0, 0.5, 1, 2, 5, and 8 microg/mL, respectively. Compared with baseline values, no significant change in skin temperature or thermal threshold was detected at any lidocaine plasma concentration (or saline solution equivalent). Skin temperature or thermal threshold values did not differ between lidocaine or control treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that these moderate plasma concentrations of lidocaine did not affect thermal antinociception in cats.     

Pharmacokinetics and endometrial tissue concentrations of enrofloxacin and the metabolite ciprofloxacin after i.v. administration of enrofloxacin to mares

Enrofloxacin was administered i.v. to five adult mares at a dose of 5 mg/kg. After administration, blood and endometrial biopsy samples were collected at regular intervals for 24 h. The plasma and tissue samples were analyzed for enrofloxacin and the metabolite ciprofloxacin by high-pressure liquid chromatography. In plasma, enrofloxacin had a terminal half-life (t(1/2)), volume of distribution (area method), and systemic clearance of 6.7 +/- 2.9 h, 1.9 +/- 0.4 L/kg, and 3.7 +/- 1.4 mL/kg/min, respectively. Ciprofloxacin had a maximum plasma concentration (Cmax) of 0.28 +/- 0.09 microg/mL. In endometrial tissue, the enrofloxacin Cmax was 1.7 +/- 0.5 microg/g, and the t(1/2) was 7.8 +/- 3.7 h. Ciprofloxacin Cmax in tissues was 0.15 +/- 0.04 microg/g and the t(1/2) was 5.2 +/- 2.0 h. The tissue:plasma enrofloxacin concentration ratios (w/w:w/v) were 0.175 +/- 0.08 and 0.47 +/- 0.06 for Cmax and AUC, respectively. For ciprofloxacin, these values were 0.55 +/- 0.13 and 0.58 +/- 0.31, respectively. We concluded that plasma concentrations achieved after 5 mg/kg i.v. are high enough to meet surrogate markers for antibacterial activity (Cmax:MIC ratio, and AUC:MIC ratio) considered effective for most susceptible gram-negative bacteria. Endometrial tissue concentrations taken from the mares after dosing showed that enrofloxacin and ciprofloxacin both penetrate this tissue adequately after systemic administration and would attain concentrations high enough in the tissue fluids to treat infections of the endometrium caused by susceptible bacteria.     

Pharmacokinetics of a high dose of amikacin administered at extended intervals to neonatal foals

OBJECTIVE: To determine disposition kinetics of amikacin in neonatal foals administered high doses at extended intervals. ANIMALS: 7 neonatal foals. PROCEDURE: Amikacin was administered (21 mg/kg, i.v., q 24 h) for 10 days. On days 1, 5, and 10, serial plasma samples were obtained for measurement of amikacin concentrations and determination of pharmacokinetics. RESULTS: Mean +/- SD peak plasma concentrations of amikacin extrapolated to time 0 were 103.1 +/- 23.4, 102.9 +/- 9.8, and 120.7 +/- 17.9 microg/mL on days 1, 5, and 10, respectively. Plasma concentrations at 1 hour were 37.5 +/- 6.7, 32.9 +/- 2.6, and 30.6 +/- 3.5 microg/mL; area under the curve (AUC) was 293.0 +/- 61.0, 202.3 +/- 40.4, and 180.9 +/- 31.2 (microg x h)/mL; elimination half-life (t(1/2)beta) was 5.33, 4.08, and 3.85 hours; and clearance was 1.3 +/- 0.3, 1.8 +/- 0.4, and 2.0 +/- 0.3 mL/(min x kg), respectively. There were significant increases in clearance and decreases in t(1/2)beta, AUC, mean residence time, and plasma concentrations of amikacin at 1, 4, 8, 12, and 24 hours as foals matured. CONCLUSIONS AND CLINICAL RELEVANCE: Once-daily administration of high doses of amikacin to foals resulted in high peak plasma amikacin concentrations, high 1-hour peak concentrations, and large values for AUC, consistent with potentially enhanced bactericidal activity. Age-related findings suggested maturation of renal function during the first 10 days after birth, reflected in enhanced clearance of amikacin. High-dose, extended-interval dosing regimens of amikacin in neonatal foals appear rational, although clinical use remains to be confirmed.     

Pharmacokinetics, bioavailability, and in vitro antibacterial activity of rifampin in the horse

The pharmacokinetics and bioavailability of rifampin were determined after IV (10 mg/kg of body weight) and intragastric (20 mg/kg of body weight) administration to 6 healthy, adult horses. After IV administration, the disposition kinetics of rifampin were best described by a 2-compartment open model. A rapid distribution phase was followed by a slower elimination phase, with a half-life (t1/2[beta]) of 7.27 +/- 1.11 hours. The mean body clearance was 1.49 +/- 0.41 ml/min.kg, and the mean volume of distribution was 932 +/- 292 ml/kg, indicating that rifampin was widely distributed in the body. After intragastric administration of rifampin in aqueous suspension, a brief lag period (0.31 +/- 0.09 hour) was followed by rapid, but incomplete, absorption (t1/2[a] = 0.51 +/- 0.32 hour) and slow elimination (t1/2[d] = 11.50 +/- 1.55 hours). The mean bioavailability (fractional absorption) of the administered dose during the first 24 hours was 53.94 +/- 18.90%, and we estimated that 70.0 +/- 23.6% of the drug would eventually be absorbed. The mean peak plasma rifampin concentration was 13.25 +/- 2.70 micrograms/ml at 2.5 +/- 1.6 hours after dosing. All 6 horses had plasma rifampin concentrations greater than 2 micrograms/ml by 45 minutes after dosing; concentrations greater than 3 micrograms/ml persisted for at least 24 hours. Mean plasma rifampin concentrations at 12 and 24 hours after dosing were 6.86 +/- 1.69 micrograms/ml and 3.83 +/- 0.87 micrograms/ml, respectively. We tested 162 isolates of 16 bacterial species cultured from clinically ill horses for susceptibility to rifampin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of zidovudine in cats

OBJECTIVE: To characterize the pharmacokinetics of zidovudine (AZT) in cats. ANIMALS: 6 sexually intact 9-month-old barrier-reared domestic shorthair cats. PROCEDURE: Cats were randomly alloted into 3 groups, and zidovudine (25 mg/kg) was administered i.v., intragastrically (i.g.), and p.o. in a 3-way crossover study design with 2-week washout periods between experiments. Plasma samples were collected for 12 hours after drug administration, and zidovudine concentrations were determined by high-performance liquid chromatography. Maximum plasma concentrations (Cmax), time to reach Cmax (Tmax), and bioavailability were compared between i.g. and p.o. routes. Area under the curve (AUC) and terminal phase half-life (t(1/2)) among the 3 administration routes were also compared. RESULTS: Plasma concentrations of zidovudine declined rapidly with t(1/2) of 1.4 +/- 0.19 hours, 1.4 +/- 0.16 hours, and 1.5 +/- 0.28 hours after i.v., i.g., and p.o. administration, respectively. Total body clearance and steady-state volume of distribution were 0.41 +/- 0.10 L/h/kg and 0.82 +/- 0.15 L/kg, respectively. Mean Tmax for i.g. administration (0.22 hours) was significantly shorter than Tmax for p.o. administration (0.67 hours). The AUC after i.v. and p.o. administration was 64.7 +/- 16.6 mg x h/L and 60.5 +/- 17.0 mg x h/L, respectively, whereas AUC for the i.g. route was significantly less at 42.5 +/- 9.41 mg x h/L. Zidovudine was well absorbed after i.g. and p.o. administration with bioavailability values of 70 +/- 24% and 95 +/- 23%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Cats had slower clearance of zidovudine, compared with other species. Plasma concentrations of zidovudine were maintained above the minimum effective concentration for inhibiting FIV replication by 50% (0.07 microM [0.019 microg/mL] for wild-type FIV clinical isolate) for at least 12 hours after i.v., i.g., or p.o. administration.     

Pharmacokinetics of marbofloxacin after single intravenous and repeat oral administration to cats

The pharmacokinetic properties of marbofloxacin, a third generation fluoroquinolone, were investigated in six cats after single intravenous (IV) and repeat oral (PO) administration at a daily dose of 2 mg/kg. Marbofloxacin serum concentration was analysed by microbiological assay using Klebsiella pneumoniae ATCC 10031 as micro-organism test. Serum marbofloxacin disposition was best described by bicompartmental and mono-compartmental open models with first-order elimination after IV and oral dosing respectively. After IV administration, distribution was rapid (T(1/2(d)) 0.23+/-0.24 h) and wide, as reflected by the steady-state volume of distribution of 1.01+/-0.15 L/kg. Elimination from the body was slow with a body clearance of 0.09+/-0.02 L/h kg and a T(1/2) of 7.98+/-0.57 h. After repeat oral administration, absorption half-life was 0.86+/-1.59 h and T(max) of 1.94+/-2.11 h. Bioavailability was almost complete (99+/-29%) with a peak plasma concentration at the steady-state of 1.97+/-0.61 mug/mL. Drug accumulation was not significant after six oral administrations. Calculation of efficacy predictors showed that marbofloxacin has good therapeutic profile against Gram-negative and Gram-positive bacteria with a MIC(50) value <0.25 microg/mL.     

Pharmacokinetics of ceftazidime after intravenous and intramuscular administration to domestic cats

The pharmacokinetic properties of ceftazidime, a third generation cephalosporin, were investigated in five cats after single intravenous (IV) and intramuscular (IM) administration at a dose rate of 30 mg/kg. Minimum inhibitory concentrations (MICs) of ceftazidime for some Gram-negative (Escherichia coli, n=11) and Gram-positive (Staphylococcus spp., n=10) strains isolated from clinical cases were determined. An efficacy predictor, measured as the time over which the active drug exceeds the bacteria minimum inhibitory concentration (T>MIC), was calculated. Serum ceftazidime disposition was best fitted by a bi-compartmental and a mono-compartmental open model with first-order elimination after IV and IM dosing, respectively. After IV administration, distribution was rapid (t(1/2(d)) 0.04+/-0.03 h), with an area under the ceftazidime serum concentration:time curve (AUC((0-infinity))) of 173.14+/-48.69 microg h/mL and a volume of distribution (V((d(ss)))) of 0.18+/-0.04 L/kg. Furthermore, elimination was rapid with a plasma clearance of 0.19+/-0.08 L/hkg and a t(1/2) of 0.77+/-0.06 h. Peak serum concentration (C(max)), T(max), AUC((0-infinity)) and bioavailability for the IM administration were 89.42+/-12.15 microg/mL, 0.48+/-0.49 h, 192.68+/-65.28 microg h/mL and 82.47+/-14.37%, respectively. Ceftazidime MIC for E. coli ranged from 0.0625 to 32 microg/mL and for Staphylococcus spp. from 1 to 64 microg/mL. T>MIC was in the range 35-52% (IV) and 48-72% (IM) of the recommended dosing interval (8-12h) for bacteria with a MIC(90)4 microg/mL.