Because caffeine is metabolized by the hepatic P-450 cytochrome oxidase system, clearance of caffeine is an excellent quantitative test of hepatic function in human beings. It is currently used in much the same way that creatinine clearance is used to assess renal function. Caffeine clearance was measured in lactating dairy cows initially to determine the suitability of caffeine clearance as an indicator of hepatic function in cattle. Pharmacokinetic variables of caffeine were studied in 6 adult lactating dairy cows after IV administration of a single dose of caffeine sodium benzoate (2 mg of caffeine/kg of body weight). Caffeine concentration was analyzed by use of an automated enzyme immunoassay. The lower limit of detection of the assay for caffeine in serum was 0.079 micrograms/ml. Serum caffeine concentration-time curves best fit an open two-compartment pharmacokinetic model. Harmonic mean elimination half-life was 3.8 (range, 2.6 to 6.9) hours, and total clearance was 0.118 (range, 0.090 to 0.197) L/kg/h. Milk caffeine concentration was similar to serum concentration 1.5 to 24 hours after caffeine administration. Adverse effects were not observed in cows given caffeine.

The effects of dexamethasone (0.2 mg/kg of body weight; IV, IM, and PO) and methylprednisolone acetate (120 mg, given intra-articularly) on serum osteocalcin and cortisol concentrations were studied in 6 horses. Serum osteocalcin and cortisol concentrations were serially monitored after each treatment. A significant (P < 0.05) decrease in serum osteocalcin and cortisol concentrations was observed from 12 to 24 and 2 to 48 hours, respectively, after IV and IM administrations of dexamethasone. Serum osteocalcin and cortisol concentrations were significantly decreased from 6 to 48 and 3 to 72 hours, respectively, after oral administration. In contrast, a change in serum osteocalcin concentration was not detected after intra-articular administration of methylprednisolone. Oral, IV, or IM treatment with 0.2 mg of dexamethasone/kg caused a decrease in serum osteocalcin concentration in horses.

Milk antimicrobial residues are a serious concern for the dairy industry. Residues of the tetracycline family of antimicrobials have been reported in market milk by investigators, using radioimmunoassay and microbial receptor technology (hereafter referred to as the Charm II test). In response to these reports, an investigation was conducted to determine the potential of 3 extra-label routes of oxytetracycline (OTC) administration to cause milk residues above the Food and Drug Administration safe value of 30 parts per billion (ppb). Lactating Holstein cows were administered OTC once by use of 1 of 3 routes: IV at 16.5 mg/kg of body weight (n = 6); IM at 11 mg/kg (n = 6); and intrauterine (IU) at 2 g in 500 ml of saline solution/cow (n = 6). Duplicate milk samples were collected at the milking prior to drug administration and for the next 13 milkings at 12-hour intervals. Concentrations of OTC in milk samples were analyzed by use of the Charm II test for tetracyclines (limit of OTC detection, approx 5 ppb) and were compared with concentrations determined by use of a high-performance liquid chromatography (HPLC) method (lower limit of OTC quantitation, approx 2 ppb). The potential for milk OTC residues above the Food and Drug Administration safe value of 30 ppb after treatment was considerably greater for the IV and IM routes, compared with the IU route. Mean peak OTC concentrations in milk at the first milking after treatment for the HPLC and Charm II tests were approximately 3,700 to 4,200 ppb for the IV route, 2,200 to 2,600 ppb for the IM route, and 186 to 192 ppb for the IU route, respectively. Pharmacokinetic analysis, based on milk OTC concentrations, indicated that the area under the curve (AUC) and milk maximal concentration (Cmax) differed significantly (P < 0.001) among routes of administration. The AUC was similar for IV and IM administrations; values for both were greater than the AUC for IU administration. The Cmax was greatest for IV, intermediate for IM, and least for IU administration. There were significant (P less than or equal to 0.01) differences in AUC between assay methods (Charm II vs HPLC) for the IV route. Concentrations of OTC in milk determined by the Charm II test were often greater than those determined by HPLC. Administration of OTC to lactating cows via these routes is extra-label drug use. Failure to withhold the product from early milkings of cows administered OTC by the IV or IM route should be considered a potential cause of OTC residues in market milk. Milk from nearly all cows contained OTC (< 30 ppb), the Food and Drug Administration safe level, by 120 hours after OTC administration. Use of appropriate withholding times and antibiotic residue testing is indicated to avoid OTC residues.

Pharmacokinetic and pharmacodynamic variables of flunixin were studied in calves after IV administration of the drug at a dose rate of 2.2 mg/kg of body weight. The anti-inflammatory properties of flunixin were investigated, using a model of acute inflammation; this involved surgically implanting tissue cages at subcutaneous sites and stimulating the tissue cage granulation tissue by intracavitary injection of carrageenan. The actions of flunixin on exudate concentrations of several substances related to the inflammatory process, including proteases (metalloprotease [active and total] and cysteine and serine proteases), enzymes (lactate dehydrogenase, acid phosphatase, and beta-glucuronidase [beta-glu]), eicosanoid (prostaglandin E2 [PGE2], leukotriene B4, and serum thromboxane B2 [TXB2]) concentrations, and bradykinin (BK)-induced edema, were investigated. Flunixin had a long elimination half-life--6.87 +/- 0.49 hours--and volume of distribution was 2.11 +/- 0.37 L/kg, indicating extensive distribution of the drug in the body. Body clearance was 0.20 +/- 0.03 L/kg/h. Flunixin exerted inhibitory effects on serum TXB2 and exudate PGE2 concentrations, B-glu activity, and BK-induced swelling. Other enzymes and inflammatory mediators were not significantly affected. Pharmacokinetic/pharmacodynamic modeling of the data revealed similar mean concentration producing 50% of the maximal effect values for inhibition of exudate PGE2 and beta-glu and of BK-induced swelling (0.070 +/- 0.006, 0.064 +/- 0.040, and 0.061 +/- 0.030 microgram/ml), respectively). A lower concentration producing 50% of the maximal effect value was obtained for inhibition of serum TXB2 concentration (0.023 +/- 0.004 microgram/ml). Differences also were observed in equilibration half-life for these actions, suggesting the existence of 3 distribution compartments correlating with 3 sites of action--a central compartment and shallow and deep peripheral compartments. Pharmacokinetic/pharmacodynamic modeling proved to be a useful analytical method, providing a quantitative description of in vivo drug pharmacodynamics and indicating possible mechanisms of action.

A high-performance liquid chromatography method was developed for determination of flunixin in bovine plasma. The extraction procedure was easily performed and made it possible to detect low concentrations of flunixin with high accuracy. The limit of quantitation was 7 ng/ml (relative standard deviation = 18%, n = 10). The analytic method permits processing of 60 samples/d. Flunixin, as well as the internal standard (diclofenac sodium), belong to the group of nonsteroidal anti-inflammatory drugs, which are known to have a high degree of binding to plasma proteins. Therefore, an evaluation of several buffer systems was undertaken to optimize analytic conditions. Cattle were given 2.2 mg of flunixin meglumine/kg of body weight. In experiment 1, single injections were administered IV to q cow and IM to 1 heifer (7 days apart), and pharmacokinetic variables were calculated. The IV data were best described by a two-compartment model. The half-life after single IV or IM administration was around 4.0 hours. In experiment 2, the decreasing flunixin concentration was determined after the last of either 4 IM injections daily (n = 3 cows) or 2 IM injections daily (n = 3 cows) administered during a 14-day postpartum period. The half-life, determined between 48 and 96 hours after the last dose, was approximately 26 hours in both groups, and flunixin could be detected in plasma up to 8 days, on average. The protein binding of flunixin was studied, using the method of equilibrium dialysis. Flunixin was found to have a high degree of protein binding (ie, 99.4 +/- 0.2%) at a flunixin concentration in plasma of 3 to micrograms/ml. Differences in protein binding between cattle were not found.

Effects of furosemide, exercise, and atropine on tracheal mucus transport rate (TMTR) in horses were investigated. Atropine (0.02 mg/kg of body weight) administered IV or by aerosolization significantly (P < 0.05) decreased TMTR at 60, but not at 30 minutes after its administration in standing horses. Furosemide (1.0 mg/kg, IV) did not have any significant effect on TMTR when measured at 2 or 4 hours after its administration in standing horses. Exercise alone or furosemide (1.0 mg/kg, IV) administration followed 4 hours later by exercise did not alter TMTR, compared with values for standing control or exercised horses administered saline solution. Atropine (0.02 mg/kg, IV) administered after exercise significantly (P < 0.05) decreased TMTR, compared with values for no exercise standing controls, for exercise after administration of saline solution, and for furosemide and exercise.

Naproxen (+ 6-methoxy-[alpha - methyl]- 2-naphthalene acetic acid) is a nonsteroidal anti-inflammatory drug that is used for the treatment of inflammatory conditions in horses. We developed a model that describes the drug's disposition and renal excretion, including synovial fluid disposition and elimination after IV administration in horses. The plasma disposition, after IV administration of 5 mg/kg of body weight, was described by a two-compartment model; mean +/- SD distribution and elimination half-lives were 1.42 +/- 0.42 and 8.26 +/- 2.56 hours, respectively. Plasma concentration of naproxen after IV administration of 5 mg/kg was 55.3 +/- 13.5 and 0.61 +/- 0.42 mg/L at 5 minutes and 48 hours after its administration, respectively. Steady-state volume of distribution was 0.163 +/- 0.053 L/kg, and area under the plasma concentration time-curve was 372.1 +/- 128.2 mg/h/L The peak synovial fluid concentration of 12.68 +/- 12.39 mg/L was measured at 6 hours, and decreased to 0.71 +/- 0.38 mg/L at 36 hours after naproxen administration. The decrease of naproxen concentration in synovial fluid paralleled that in plasma. The appearance half-life of naproxen in synovial fluid was 4.64 hours, and the elimination half-life was 6.73 hours. Total body clearance was 0.015 +/- 0.006 L/h/ kg. The percentage of plasma protein binding was 97.0 +/- 2.9% at plasma concentrations between 5 and 100 mg/L. This was significantly (P < 0.05) higher than the percentage of binding at plasma concentrations of 0.5, 1, and 500 mg/L, which was 75.2 +/- 11.8%. Most of the drug was excreted as glucuronidated naproxen and unconjugated desmethylnaproxen. The recovery of naproxen and all metabolites in urine at 36 hours was 64.6 +/- 7.2% of the total dose. Of this total, 39.6 +/- 10.3% and 8.5 +/- 7.9% were glucuronidated naporoxen and desmethylnaproxen, respectively; 0.3 +/- 0.1% and 16.6 +/- 7.9% were free naproxen and desmethylnaproxen, respectively.

A radioimmunoassay test for tetracyclines (Charm II) was compared with high-pressure liquid chromatography (HPLC) for detection of oxytetracycline (OTC) residues in milk samples from individual lactating cows. Oxytetracycline was administered by 1 of 3 routes (IV, IM, or intrauterine) to 21 lactating dairy cows. A total of 292 duplicate milk samples were collected from milkings before and through 156 hours after OTC administration. Concentration of OTC in these samples was determined by use of the Charm II test and an HPLC method with a lower limit of quantitation, approximately 2 ng of OTC/ml. Samples were also classified with respect to presence of OTC residues relative to the FDA safe concentration (less than or equal to 30 ng/ml), using the Charm II (by control point determination) and HPLC methods. There was a significant (P less than or equal to 0.05) difference between test methods in classification of milk samples with respect to presence or absence of OTC at the FDA safe concentration. A total of 48 of the 292 test results (16.4%) did not agree. Using the HPLC test results as the standard with which Charm II test results were compared, 47 false presumptive-violative test results and 1 false presumptive-nonviolative Charm II test result (a sample containing 31 ng of OTC/ml, as evaluated by HPLC) were obtained. The samples with false presumptive-violative Charm II results contained (less than or equal to 30 ng of OTC/ml, as evaluated by HPLC. In some respects, the Charm II test performed appropriately as a screening test to detect OTC residues in milk samples from individual cows. However, the tendency for the test to yield presumptive-violative test results at OTC concentrations lower than the FDA safe concentration (as evaluated by HPLC), suggests that caution should be exercised in using the test as the sole basis on which a decision is made to reject milk. As indicated by the manufacturer, presumptive-violative Charm II test results should be confirmed by additional testing Although not specifically evaluated, the tendency for misclassification of milk samples as presumptive-violative by the Charm II test may or may not occur in commingled milk, compared with milk samples from individual cows.

The pharmacokinetic properties of enrofloxacin were determined in broiler chickens after single IV and orally administered doses of 10 mg/kg of body weight. After IV and oral administrations, the plasma concentration-time graph was characteristic of a two-compartment open model. The elimination half-life and the mean +/- SEM residence time of enrofloxacin for plasma were 10.29 +/- 0.45 and 9.65 +/- 0.48 hours, respectively, after IV administration and 14.23 +/- 0.46 and 15.30 +/- 0.53 hours, respectively, after oral administration. After single oral administration, enrofloxacin was absorbed slowly, with time to reach maximal plasma concentration of 1.64 +/- 0.04 hours. Maximal plasma concentration was 2.44 +/- 0.06 micrograms/ml. Oral bioavailability was found to be 64.0 +/- 0.9%. Statistically significant differences between the routes of administration were found for the pharmacokinetic variables-half-lives of the distribution and elimination phase and apparent volume of distribution and volume of distribution at steady state. In chickens, enrofloxacin was extensively metabolized into ciprofloxacin. Residues of enrofloxacin and the major metabolite ciprofloxacin in fat, kidney, liver, lungs, muscles, and skin were measured in chickens that received an orally administered dose of 10 mg/kg once daily for 4 days. The results indicate that enrofloxacin and ciprofloxacin residues were cleared slowly. Mean muscle, liver, and kidney concentrations of the metabolite ciprofloxacin ranging between 0.020 and 0.075 micrograms/g persisted on day 12 in chickens after dosing. However, at the time of slaughter (12 days), enrofloxacin residues were only detected in liver and mean +/- SEM concentration was 0.025 +/- 0.003 micrograms/g.

Pharmacokinetic variables of bupivacaine (BPV) were determined after IV and epidural administrations in the same 6 dogs. Plasma BPV concentration curves after IV administration were adjusted to biexponential kinetics: a rapid distribution phase was followed by a slower elimination phase, with half-life of 34.5 +/- 7.8 minutes. Mean plasma clearance was 20.2 +/- 7.4 ml/min/kg of body weight, and mean volume of distribution at steady state was 0.7 +/- 0.2 L/kg. After epidural administration, absorption was rapid. Peak plasma concentration, 1.4 +/- 0.4 microgram/ml, was detected approximately 5 minutes after BPV administration. The half-life corresponding to epidural administration (179 +/- 33.6 minutes) was 5 to 6 times longer than that observed after IV administration, possibly because of the slow release of BPV from the epidural space. Induction times were short (2.3 +/- 2.2 minutes); anesthesia quickly began and lasted for more than 2 hours (158 +/- 48.8 minutes). During that period, BPV plasma concentration ranged between 1.4 and 0.2 microgram/ml. Changes in systolic blood pressure and heart rate were correlated to high plasma concentration of BPV. These modifications were observed for the first 30 minutes, reaching baseline values after 60 minutes.