Penetration of cefaclor into the interstitial space fluid of skeletal muscle and lung tissue in rats.

PURPOSE: To measure and compare the penetration of cefaclor from the plasma compartment into the interstitial space of lung and skeletal muscle in rats and to integrate the data in a pharmacokinetic model. METHODS: Unbound interstitial concentrations in muscle and lung were measured by in vivo microdialysis following i.v. bolus doses of 50 and 75 mg/kg cefaclor. Unbound muscle concentrations were also measured after a primed, continuous i.v. infusion at an infusion rate of 0.3 mg/kg/min. RESULTS: The cefaclor half-life in plasma, muscle and lung was approximately 1 h. Unbound cefaclor concentrations in muscle and lung were found to be virtually identical. A 2-compartment body model was fitted to the data with a tissue penetration factor (AUC(tissue(unbound)))/AUC(plasma(unbound))) of approximately 0.26 independent of dose, tissue and mode of administration. CONCLUSIONS: Unbound concentrations of cefaclor in the interstitial space fluid of lung and skeletal muscle are of similar magnitude and lower than those in plasma. Using total plasma concentrations would overestimate the antibacterial activity of the drug and therefore its clinical efficacy. Instead, therapeutically active levels of cefaclor at the site of action should be taken into account. Microdialysis allows direct measurement of these unbound concentrations.

Intravenous pharmacokinetics of penicillin G and antipyrine in ostriches (Struthio camelus) and emus (Dromaius novaehollandiae).

Penicillin G and antipyrine, which served as model drugs to assess the relative capacities of renal and hepatic elimination pathways, respectively, were each administered intravenously to six ostriches (Struthio camelus) and to six emus (Dromaius novaehollandiae). Drug concentrations in blood samples collected over a period of 12 hr after administration were assayed, and elimination half-life, mean residence time, clearance, and steady-state volume of distribution were calculated. Mean values for elimination half-life and mean residence time of penicillin G were significantly higher in emus than in ostriches; no significant differences in antipyrine pharmacokinetics between species were demonstrated.

Continuous measurement of caffeine and two metabolites in blood and skeletal muscle of unrestrained adult horses by semi-automated in vivo microdialysis.

Concentrations of caffeine (CA) and two metabolites were measured simultaneously in venous blood and splenius muscle of adult horses using a semi-automated in vivo microdialysis sampling technique. Dialysates from muscle and jugular vein were collected continuously for 48 h and drug levels were determined by high performance liquid chromatography (HPLC). Following i.v. injection, CA (3 mg/kg) attained a peak blood level of nearly 5400 +/- 600 ng/mL and decreased with a half-life of 15.3 +/- 0.7 h. Pharmacokinetic and statistical comparisons between CA concentrations in jugular dialysates and plasma samples revealed no significant differences between these sampling techniques. However, measurements in muscle and blood revealed unexpected pharmacokinetic differences, including significantly elevated concentrations of CA in muscle for 4 h following drug administration. In contrast, the CA metabolites theophylline (TP) and theobromine (TB) exhibited delayed appearances in muscle and blood with peak concentrations of 300 +/- 60 ng/mL (TP) and 150 +/- 50 ng/mL (TB) detected in both tissues 1 day following CA administration. This study demonstrates that our novel semi-automated microdialysis procedure for continuous monitoring of drug and metabolite levels may be useful for related studies in other domesticated large animal species.

Effect of respiratory tract disease on pharmacokinetics of tilmicosin in rats.

BACKGROUND AND PURPOSE: In rats, murine respiratory mycoplasmosis is caused by Mycoplasma pulmonis. Tilmicosin, a macrolide antibiotic, has good tissue penetration and reaches high concentration in the lungs. Therefore, a model for studying the effects of disease on pharmacokinetics of tilmicosin was developed, using LEW rats. METHODS: Seventy-two LEW rats were assigned at random to two groups: one group was inoculated with M. pulmonis, and the other served as an uninoculated control group. On postinoculation day 31, all rats received a single dose of tilmicosin (20 mg/kg of body weight, subcutaneously). RESULTS: Concentration of tilmicosin in the lungs of both groups of rats was significantly higher than serum tilmicosin concentration at all times. Infected rats had significantly higher lung tilmicosin concentration than did noninfected rats. No correlation was found between pH of the lungs and tilmicosin concentration in the lungs in either treatment group, nor did treatment have any effect on pH of the muscle. CONCLUSION: Tilmicosin accumulates in the lungs, and infection/inflammation further improves its tissue penetration.

The Food Animal Residue Avoidance Databank (FARAD). Past, present and future.

During the last one-and-one-half decades, FARAD has established an unparalleled compilation of residue and pharmacokinetic information for veterinary species. In order to fulfill its mission, FARAD has become as much a research project as an educational one. Pressing problems, such as disease-altered kinetics, minor-species drug use, and industrial contaminants in livestock, require the new methods of analysis FARAD is developing. The data upon which this work is based can be greatly augmented by participation by other nations. In the United States, it was the cooperation of both academic and regulatory organizations that made the success of FARAD possible. Similar international cooperation can facilitate use of the FARAD model in other countries for the economic benefit of all participants, enhancement of food safety, and promotion of animal welfare.

Development and use of an enzyme-linked immunosorbent assay to monitor serum and urine acepromazine concentrations in thoroghbreds, and possible changes associated with exercise.

OBJECTIVES: To develop an ELISA that is sensitive and suitable for measurement of immunoreactive acepromazine (ACP) in horse serum and urine and to determine the acute effects of exercise on immunoreactive ACP values in Thoroughbreds. ANIMALS: 12 healthy Thoroughbreds (5 mares, 5 geldings, 2 stallions), aged 2 to 8 years. PROCEDURE: A commercially available antibody and a horseradish peroxidase-conjugated oxime derivative of immunoreactive ACP were used to develop a one-step ELISA. Horses were used in a crossover design study to evaluate possible effects of treadmill exercise on serum and urine ACP concentrations after a single (25 mg) IM injection of the drug. RESULTS: Immunoreactive ACP was detectable at concentrations as low as 50 pg/ml in serum and 100 pg/ml in urine, with intra- and interassay variabilities of 1.1 and 5.2%, respectively. The antibody had some cross-reactivity with a limited number of other phenothiazines. After drug administration, serum ACP immunoreactivity achieved a peak concentration (10.5 ng/ml) within 30 minutes and could be measured up to 48 hours in serum and 120 hours in urine. Although exercise had no significant effect on serum drug concentration, immunoreactive ACP disappeared more quickly (by 48 hours) from the urine of horses in the exercised group. CONCLUSIONS: This one-step ELISA provides a simple and sensitive means to measure immunoreactive ACP in equine serum and urine. The ability to detect drug several days after administration of a low dose of ACP should augment efforts to control illicit use of this drug in performance horses. Potential changes in ACP kinetics after exercise warrant further study.

Pharmacokinetics and pharmacodynamics of tilmicosin in sheep and cattle.

Tilmicosin is a long-acting macrolide antibiotic currently approved for treatment of bovine respiratory disease in the USA. Serum pharmacokinetics of tilmicosin were compared between cattle (major species) and sheep (minor species) after subcutaneous injection in order to evaluate a new potential application of the drug in currently nonapproved species. There were no significant differences in the elimination rates, maximum serum concentrations, half-lives (t1/2), areas under the curve (AUC), areas under the first-moment curve (AUMC), and mean residence times. Volume of distribution (Vd(area)) and clearance (Cl), when normalized by body weight, were also similar. The only significantly different parameter was time at which maximum drug concentration was reached (tmax), with sheep having the tmax of 3.9 h, compared to 0.5 h in cattle. Although macrolides are considered to be one of the safest anti-infective drugs, adverse cardiovascular effects of several macrolides have been reported. The cardiopulmonary effects of tilmicosin were monitored in healthy adult sheep after receiving a single subcutaneous (s.c.) injection of tilmicosin at the dose of 10 mg/kg, and no significant changes were found. The study indicates that tilmicosin can be used safely and effectively in sheep at the given dose, with no adverse cardiopulmonary effects.

Intravenous and oral pharmacokinetic evaluation of a 2-hydroxypropyl-beta-cyclodextrin-based formulation of carbamazepine in the dog: comparison with commercially available tablets and suspensions.

Complexation of carbamazepine with 2-hydroxypropyl-beta-cyclodextrin was performed to provide improved formulations of this widely used antiepileptic drug. Based on this approach, liquid dosage forms were configured for both parenteral and oral use. Intravenous administration of an aqueous carbamazepine x 2-hydroxypropyl-beta-cyclodextrin (CBZ x HPbetaCD) complex at a CBZ dose of 20 mg/kg was well tolerated and generated high initial drug levels that fell monoexponentially as a function of time, yielding a plasma elimination half-life of 38 min. Oral studies were completed with three preparations: a commercially available tablet and suspension, as well as a CBZ x HPbetaCD oral solution. Oral administration of tablets gave erratic and slow absorption, leading to maximum CBZ concentrations (C(max)) of <2 microg/mL, which were manifested only at 2.5 h after drug dosing. The absolute bioavailability of CBZ from the tablets was approximately 25%. Both the suspension and CBZ x HPbetaCD solution gave a significantly improved profile. Thus, the liquid oral dosage forms approximately doubled the oral bioavailability of CBZ compared with the tablets.

Evaluation of a brain-targeting zidovudine chemical delivery system in dogs.

AIDS encephalopathy is an insidious complication of human immunodeficiency virus infection which is difficult to treat because of the poor uptake of many potentially useful antiretroviral drugs through the blood-brain barrier. A chemical delivery system (CDS) for zidovudine (AZT) based on redox trapping within the brain has been prepared and tested in several animal models to circumvent this limitation. The behavior of the AZT-CDS in the dog was considered. Parenteral administration of AZT resulted in rapid systemic elimination and poor uptake by the central nervous system. Ratios of the area under the concentration-time curve of AZT for cerebrospinal fluid to that for blood were 0.32, and ratios of the area under the concentration-time curve of AZT for brain to that for blood were approximately 0.25. Administration of an aqueous formulation of the AZT-CDS resulted in rapid tissue uptake and conversion of the CDS to the corresponding quaternary salt with the subsequent production of AZT. Delivered in this way, the levels of AZT in brain were 1.75- to 3.3-fold higher than those associated with conventional AZT administration. In addition, the levels of AZT in blood were 46% lower than those associated with AZT administration. The higher concentrations in brain and lower concentration in blood combined to significantly increase the ratio of the concentration of AZT in the brain to that in blood after AZT-CDS administration compared to that after AZT dosing.

Evidence for a relation between inspired gas mixture and the left ventricular contrast achieved with Albunex in a canine model.

BACKGROUND: In a previous experiment, a marked reduction in the right- and left-sided contrast effect of Albunex was noted in an intubated animal spontaneously breathing isoflurane in 100% oxygen. The theory suggests that the time course of echogenicity of microbubbles in liquid is dependent on the pressure and the gradients of dissolved gases. The present set of experiments tested whether the loss of contrast occurs at commonly used therapeutic concentrations of inspired oxygen. HYPOTHESIS: This research tested the hypothesis that the left ventricular (LV) contrast effect achieved with intravenous injection of the ultrasound contrast agent Albunex is related to the inspired oxygen content. METHODS: Intubated dogs were maintained in a spontaneously respiring anesthetic state on isoflurane and mixtures of oxygen (12-50%) in nitrogen. FIO2 was held steady for 15 min prior to injection of 0.08 ml/kg of Albunex. The contrast effects were recorded from a transthoracic short-axis view. Left and right ventricular brightness curves were generated from digitized sequences of end-diastolic frames. The minimum and maximum brightness and area under the time-brightness curves were determined. RESULTS: The LV maximum brightness and area under the curve showed significant negative correlations (p = < 0.004) with the FIO2, while the minimum brightness showed a significant positive correlation (p = < 0.002). No significant correlations were found for the right ventricular brightness parameters. CONCLUSIONS: These findings show an important relationship between the FIO2 and loss of the contrast effect of Albunex. This loss occurs at oxygen concentrations in the therapeutic range, but could be overcome by increasing the dose of Albunex. The mechanism is likely related to an outward nitrogen gradient causing a loss of echogenicity. The clinical implication is that patients on supplemental oxygen may require higher doses of Albunex to achieve optimal opacification.

The effects of atropine and glycopyrrolate on heart rates in conscious mature goats.

The effects of intravenously administered atropine (0.2 mg/kg) and glycopyrrolate (0.01 mg/kg) on heart rate were studied in 10 conscious mature goats. In a drug cross-over fashion, either atropine, glycopyrrolate, or 0.9% saline solution was administered using the same volume (0.05 mL/kg). Atropine and glycopyrrolate caused a significant increase in heart rate (P < .05), whereas saline solution (0.09%) did not. The mean percent changes in heart rate from baseline were similar for atropine and glycopyrrolate up to 14 minutes after administration. Thereafter, glycopyrrolate had a significantly greater mean change in heart rate than atropine, ie, up to 29 minutes (P < .05). Within the atropine group, the mean percentage changes in heart rate became significantly lower compared with the initial increase (1 minute) starting at 11 minutes. For the glycopyrrolate group, the mean percent changes became significantly lower starting at 27 minutes. Glycopyrrolate and atropine had a mean percentage change in heart rate of greater than 1.0%, up to 31 and 22 minutes, respectively. At the doses used, glycopyrrolate had longer duration of action than atropine but the magnitude of increase was similar.

Pharmacokinetics and pharmacodynamics of acepromazine in horses.

A specific, sensitive, reverse-phase high-performance liquid chromatographic assay for acepromazine, with analytic sensitivity as low as 5 ng/ml of plasma, and electrochemical detection with an oxidation potential of 0.7 V, was used to study the pharmacokinetics of acepromazine given at a dosage of 0.15 mg/kg of body weight in horses. The relation between effect and pharmacokinetics of the drug was examined. The effects studied included those on blood pressure, pulse, PCV, measures of respiration function, and sedation. Intravenously administered doses led to a biphasic concentration decay pattern with an alpha-phase distribution half-life of < 3 minutes. The beta-phase half-life was in the range of 50 to 150 minutes. The CNS effects peaked at 20 minutes after administration, and the hemodynamic effects peaked at 100 minutes. In all horses, the most sensitive variable was the PCV, which decreased by up to 20% (P < 0.0001). Systolic, diastolic, and mean blood pressures decreased (P < 0.0001); heart rate was unchanged (P > 0.05). Neither blood gas tensions nor blood pH changed noticeably (P > 0.05). In all horses studied, acepromazine had a significant (P < 0.0001) sedative effect, as observed by posture and alertness. None of the observed pharmacodynamic effects correlated well with plasma acepromazine concentration. These effects persisted beyond the time of detectable acepromazine concentration, indicating that they might be caused by active metabolites, or that their timing could result from complex pharmacokinetic compartment influences.

Propofol in rabbits. 1. Determination of an induction dose.

Propofol was evaluated as an intravenous agent for induction of anesthesia in 94 non-premedicated New Zealand White rabbits (mean body weight 3.25 kg). Lack of chewing oral introduction of an endotracheal tube was chosen as the end-point in signaling loss of consciousness. A rapid and excitement-free loss of consciousness was observed. Using probit analysis, a 50% effective dose of 6.44 mg/kg was calculated. No statistically significant difference between genders was shown. Independent of the dose administered, recovery was rapid and smooth.

Propofol in rabbits. 2. Long-term anesthesia.

The cardiopulmonary effects of propofol as the sole anesthetic agent administered as a continuous intravenous infusion over 8 hours were evaluated in ten ventilated New Zealand White rabbits. Heart rate, mean blood pressure, arterial oxygen and carbon dioxide tensions, arterial pH, hemoglobin's saturation with oxygen, packed cell volume, and temperature were continuously monitored and recorded at 0 (baseline), 30, 60, 120, 180, 240, 300, 360, 420, and 480 minutes and then hourly for up to 4 hours during recovery. Only light planes of anesthesia could be achieved with a mean propofol infusion rate of 0.876 mg/kg/min. Hypotension and hypoxemia were common features. Four rabbits did not survive the study period and recovery was slow in the surviving animals. With monitoring being the same, Intralipid 10%, the vehicle of propofol, infused into two rabbits (controls) had no adverse effects. Intravenous administration of propofol alone cannot be recommended for long-term anesthesia in the rabbit. Oxygen supplementation appears to be an important element in improving quality of anesthesia and outcome.