Effect of aspirin, furosemide, and commercial low-salt diet on digoxin pharmacokinetic properties in clinically normal cats

Steady-state serum digoxin concentration ([digoxin]) was measured for 48 hours in 6 healthy cats after they were treated with digoxin tablets (0.01 mg/kg of body weight, q 48 h) for 10 days and again after concurrent treatment of identical duration with orally administered digoxin, aspirin (80 mg, q 48 h), furosemide (2 mg/kg, q 12 h), and a commercial low-salt diet. The concurrent treatment substantially altered digoxin pharmacokinetic properties, with a resultant increase in peak (mean +/- SEM; from 2.1 +/- 0.35 to 3.3 +/- 0.6 ng/ml), 8-hour (from 1.4 +/- 0.35 to 2.5 +/- 0.64 ng/ml), and 48-hour mean (from 1.1 +/- 0.22 to 2.2 +/- 0.57 ng/ml) serum [digoxin]; an increase in the number of hours during which serum [digoxin] was in the toxic range (from 3 +/- 1.7 to 24.7 +/- 9.8 h); and a decrease in oral clearance (from 0.15 +/- 0.04 to 0.08 +/- 0.02 L/h.kg). Of these differences, all but the 8-hour serum [digoxin] were significant at P less than 0.05. Similar sampling procedures were performed in 3 cats after administration of digoxin alone (0.01 mg/kg, q 48 h) until steady-state conditions were reached (10 days) and again after an additional 10 days of treatment. Differences were not noticed in digoxin pharmacokinetic properties. Eight-hour serum [digoxin] was shown to correlate closely with the mean serum [digoxin] at steady-state conditions when digoxin was administered every 48 hours. Variation in digoxin pharmacokinetic properties was noticed between cats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and interactions of digoxin with phenobarbital in dogs

In one experiment, 5 dogs were administered digoxin (0.022 mg/kg of body weight, IV), were rested for 2 weeks, were then given phenobarbital (13.2 mg/kg orally) for 14 days, and then were given digoxin again (0.022 mg/kg, IV). Comparing prephenobarbital (control) digoxin half-lives of 42.4 +/- 8.8 hours and postphenobarbital digoxin half-lives of 18.0 +/- 2.2 hours, the half-life was significantly (P less than 0.05) decreased after phenobarbital administration. Clearance was increased by 84%, and the volume of distribution given was decreased by 34%. In a second experiment, 5 dogs were given digoxin (0.022 mg/kg, orally) daily for 11 days, and the digoxin kinetics were evaluated after the last dosing. The dogs were then rested and given phenobarbital (13.2 mg/kg, orally) once daily for 14 days and digoxin (0.022 mg/kg) once daily for 11 days, and the pharmacokinetics of digoxin was determined on the last day of dosing. Significant differences in steady-state serum concentrations and the pharmacokinetics of digoxin were not found between the control and phenobarbital phases of the experiment. Mean (+/- SD) half-lives of digoxin were 29.0 +/- 7.2 hours before phenobarbital treatment (control) and were 34.8 +/- 7.2 hours after phenobarbital treatment. In comparing results of the single-dose experiment vs the oral multiple-dose experiment, dogs had shorter half-lives for digoxin after multiple dosing. Therefore, if phenobarbital and digoxin are to be chronically coadministered orally, an adjustment in the digoxin dose is not necessary.     

Enrofloxacin-theophylline interaction: influence of enrofloxacin on theophylline steady-state pharmacokinetics in the Beagle dog

Enrofloxacin, a quinolone antibiotic developed exclusively for use in animals, was investigated for its effects on the steady-state pharmacokinetics of theophylline in six healthy Beagle dogs. A sustained-release theophylline formulation was given alone (20 mg/kg per os twice daily at 12 h intervals) for 9 days and then co-administered with enrofloxacin (5 mg/kg i.v. once a day) for 5 days. Mean trough theophylline concentrations progressively and significantly increased during the five days of enrofloxacin co-administration. Theophylline clearance and concentration-time profile were significantly changed by enrofloxacin co-administration. No significant change was observed in enrofloxacin pharmacokinetics. The kinetic interaction between theophylline and enrofloxacin could be of clinical significance and may require plasma drug concentration monitoring and adjustment of theophylline dosage.     

Pharmacokinetics of enrofloxacin in fingerling rainbow trout (Oncorhynchus mykiss)

The pharmacokinetics of intravenously and orally administered enrofloxacin was determined in fingerling rainbow trout (Oncorhynchus mykiss). Doses of 5 or 10 mg enrofloxacin/kg body weight were administered intravenously to 26 fish for each dose and blood was sampled over a 60-h period at 15 degrees C. Two groups of fish were treated orally with 5, 10, or 50 mg/kg (80 fish/dose at each temperature) and held at 15 degrees C or 10 degrees C during the 60-h sampling period. Following intravenous administration, the serum concentration-time data of enrofloxacin in rainbow trout were best described by a two-compartment open model for both doses of 5 and 10 mg enrofloxacin/kg. The hybrid rate constants alpha and beta did not differ between doses. The distributional phase was rapid with a half-life of 6-7 min for both doses. Overall half-lives of elimination were 24.4 h (95% CI = 20.2-30.8) and 30.4 h (24.2-41.0), respectively, for the 5- and 10-mg/kg doses. A large Vd(area) was observed following dosing of either 5 or 10 mg enrofloxacin/kg,: 3.22 and 2.56 l/kg, respectively. Whole body clearance for 5 mg/kg was 92 ml/h.kg and 58 ml/h.kg at the 10-mg/kg dose. Following oral administration, the serum concentration-time data for enrofloxacin were best described as a one-compartment open model with first-order absorption and elimination. Apparent Ka over all doses at 10 degrees C averaged 62% less than apparent Ka at 15 degrees C. Estimates of the apparent t(1/2)e over both temperatures ranged from 29.5 h (18.4-73.4) to 56.3 h (38.3-106.6). Bioavailability averaged 42% over all doses at 15 degrees C and was decreased to an average of 25% at 10 degrees C. Peak serum concentrations appeared between 6 and 8 h following dosing. A dose of 5 mg/kg/day was estimated to provide average steady-state serum concentrations at 10 degrees C that are approximately 4.5 times the highest reported MIC values for Streptococcus spp., the fish pathogen least sensitive to enrofloxacin. Owing to the long apparent half-life of elimination of enrofloxacin in fingerling trout, it would take approximately 5 to 9 days to achieve these predicted steady-state serum concentrations; this estimate is important when considering the duration of therapy in clinical trials.     

Serum digoxin concentrations in dogs before and during concomitant administration of furosemide

Healthy dogs were treated once a day for 16 days with a liquid, oral dosage form of digoxin (0.022 mg/kg). From day 9 to 16 they were also injected intramuscularly with furosemide (4.4 mg/kg). Serum digoxin was measured by a radioimmunoassay technique. Eight hours after the eighth dose of digoxin had been administered, serum digoxin concentration was in the accepted therapeutic range. After 8 days of concomitant administration of digoxin and furosemide, serum digoxin concentration was found to be in the accepted moderate-to-severe toxic range. Clinical signs of digitalis toxicosis were consistently observed during the combined digoxin-plus-furosemide treatment period. There was no significant ( P >0.05) change in the serum concentrations of potassium, sodium, or in osmolality during digoxin treatment alone. Serum creatinine concentrations remained within the accepted normal range for dogs. Serum sodium concentration was significantly ( P <0.05) lower during combined digoxin-plus-furosemide treatment when compared to digoxin treatment only.
Results indicate that an interaction between digoxin and furosemide occurred which led to significantly ( P <0.05) higher concentrations of serum digoxin during combined digoxin and furosemide treatment.     

Pharmacokinetics and toxicity of bromide following high-dose oral potassium bromide administration in healthy Beagles

The pharmacokinetics of a multidose regimen of potassium bromide (KBr) administration in normal dogs was examined. KBr was administered at 30 mg/kg p.o. q 12 h for a period of 115 days. Serum, urine, and cerebrospinal fluid (CSF) bromide (BR) concentrations were measured at the onset of dosing, during the accumulation phase, at steady-state, and after a subsequent dose adjustment. Median elimination half-life and steady-state serum concentration were 15.2 days and 245 mg/dL, respectively. Apparent total body clearance was 16.4 mL/day/kg and volume of distribution was 0.40 L/kg. The CSF:serum BR ratio at steady-state was 0.77. Dogs showed no neurologic deficits during maintenance dosing but significant latency shifts in waves I and V of the brainstem auditory evoked response were evident. Following a subsequent dose adjustment, serum BR concentrations of approximately 400 mg/dL were associated with caudal paresis in two dogs. Estimated half-life during the accumulation phase was shorter than elimination half-lives reported in other studies and was likely related to dietary chloride content. The range of steady-state concentrations achieved suggests individual differences in clearance and bioavailability between dogs. The described protocol reliably produced serum BR concentrations that are required by many epileptic patients for satisfactory seizure control.     

Tissue distribution and disposition kinetics of enrofloxacin in healthy and E. coli infected broilers

Concentrations of enrofloxacin equivalent activity were determined by microbiological assay in the plasma of healthy and E. coli-infected broilers following single intravenous and oral administrations at 10 mg/kg. Tissue distribution and residue-depletion following multiple oral doses (10 mg/kg for 3 successive days) were investigated. Pharmacokinetic variables were determined using compartmental and non-compartmental analytical methods. Plasma enrofloxacin concentrations after intravenous dosing to healthy and infected birds were best described by a two-compartments model. Enrofloxacin concentrations in plasma of infected birds were lower than those of healthy ones. The disposition kinetics of intravenously administered drug in healthy and infected birds were somewhat different. The elimination half-life (t1/2 beta) was 4.75 vs. 3.63 h; mean residence time (MRT) was 6.72 vs 4.90 h; apparent volume of the central compartment (Vc) was 1.11 vs 1.57 l/kg; rate constant for transfer from peripheral to central compartment (k21) was 1.15 vs 1.41 h-1 and total body clearance (ClB) was 0.35 vs 0.53 l/h/kg in healthy and infected birds, respectively. After oral administration, the absorption half-life (t1/2abs) in the infected birds was significantly longer than in healthy birds, while elimination half-life (t1/2el) and MRT were significantly shorter. Bioavailability was higher in infected birds (72.50%) as compared to healthy ones (69.78%). Enrofloxacin was detected in the tissues of healthy and infected birds after daily oral dosing of 10 mg/kg for 3 days. It was more concentrated in liver, kidney, and breast muscle. The minimal inhibitory concentration (MIC) of enrofloxacin against E. coli was 0.064 microgram/ml. On the basis of maintaining enrofloxacin plasma concentrations over the MIC, a dose of 10 mg/kg given intravenously every 20.14 hrs or orally every 20.86 hrs should provide tissue concentrations effective against E. coli infection in chickens.     

Digoxin-quinidine interaction in the dog

In seven healthy dogs, digoxin was given as an oral loading dose (0.05 mg/kg/day) on the first day, followed by an oral maintenance dose (0.02 mg/kg/day) during the next 14 days. On the sixth day of digoxin treatment, oral quinidine (200 mg b.i.d.) was added until the tenth day. Plasma concentrations of digoxin and quinidine were measured; in three of the seven dogs ECG and physical signs of digitalis toxicity were evaluated. The average steady state plasma concentration of digoxin increased significantly ( P <0.01) during quinidine administration (from 1.4 to 2.3 ng/ml). On the days that digoxin was administered without quinidine, none of the dogs vomited nor was anorectic; the PQ-interval increased significantly ( P <0.01) between 0.01 and 0.03 s. When quinidine was added, vomiting and anorexia occurred but no further increases in die PQ-interval were seen.     

Serum digoxin concentrations in healthy dogs treated without a loading dose

Healthy dogs were treated once-a-day for 20 days, with a liquid oral dosage form of digoxin (0.022 mg/kg). Serum digoxin concentrations, measured by radio immunoassay technique, were in the therapeutic range 8 h after the second daily dose of digoxin had been administered. Of the ten dogs treated, four had digoxin serum concentrations above those accepted to be moderately toxic. Results of a blood urea nitrogen and a phenolsulfonphthalein test, determined at days 0, 5, 8, 12, 15 and 19 after the beginning of the investigation all were within normal limits. Serum osmolality, calcium, potassium, and sodium, determined daily, evidenced no significant difference from control values. Lengthening of the PR interval and a decrease in the heart rate were observed. Digitalization of dogs can be achieved without the use of a loading dose and within a much shorter time than was previously reported.     

Pharmacokinetic evaluation of enrofloxacin administered orally to healthy dogs.

Enrofloxacin was administered orally to 6 healthy dogs at dosages of approximately 2.75, 5.5, and 11 mg/kg of body weight, every 12 hours for 4 days, with a 4-week interval between dosage regimens. Serum and tissue cage fluid (TCF) concentrations of enrofloxacin were measured after the first and seventh treatments. The mean peak serum concentration occurred between 1 and 2.5 hours after dosing. Peak serum concentrations increased with increases in dosage. For each dosage regimen, there was an accumulation of enrofloxacin between the first and seventh treatment, as demonstrated by a significant (P = 0.001) increase in peak serum concentrations. The serum elimination half-life increased from 3.39 hours for the 2.75 mg/kg dosage to 4.94 hours for the 11 mg/kg dosage. Enrofloxacin accumulated slowly into TCF, with peak concentrations being approximately 58% of those of serum. The time of peak TCF concentrations occurred between 3.8 hours and 5.9 hours after drug administration, depending on the dosage and whether it was after single or multiple administrations. Compared with serum concentrations (area under the curve TCF/area under the curve serum), the percentage of enrofloxacin penetration into TCF was 85% at a dosage of 2.75 mg/kg, 83% at a dosage of 5.5 mg/kg, and 88% at a dosage of 11 mg/kg. All 3 dosage regimens of enrofloxacin induced continuous serum and TCF concentrations greater than the minimal concentration required to inhibit 90% (MIC90) of the aerobic and facultative anaerobic clinical isolates tested, except Pseudomonas aeruginosa.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of compensated heart failure on digoxin pharmacokinetics in cats

To evaluate the effects of compensated heart failure (HF) on digoxin pharmacokinetic properties in cats, 6 cats with dilated cardiomyopathy were compared with 6 clinically normal (control) cats. Digoxin tablets were administered at a dosage of 0.01 mg/kg of body weight, q 48 h for approximately 10 days, until presumed steady state was reached. Both groups were treated concomitantly with aspirin, furosemide, and a commercial low-salt diet. Retrospectively, control and HF cats were calculated to be at 95% and 97% steady state, respectively. At the time blood samples were collected, HF cats were clinically compensated. Serum digoxin concentration [( DXN]) was determined by radioimmunoassay on samples drawn immediately before and 1, 2, 4, 8, 12, 24, 34, and 48 hours after digoxin administration. Measured and calculated values (peak, 8-hour, and mean [DXN]; elimination half-life [t1/2]; oral clearance; and hours during which [DXN] was in the toxic range) were not significantly different between control and HF cats. To predict individual propensity for digoxin intoxication, serum creatinine and urea concentrations and sulfobromophthalein dye retention were measured in control and HF cats prior to the onset of treatment with digoxin. There was no statistically significant correlation between serum creatinine and urea concentrations when compared with sulfobromophthalein dye retention nor between any of these values and digoxin peak, 8-hour, and mean concentrations or t1/2, oral clearance, or hours during which [DXN] was in the toxic range. Mean serum creatinine and urea nitrogen concentrations were significantly greater (P less than 0.01) and sulfobromophthalein dye retention approached significant prolongation (P less than 0.06) in HF cats, compared with that in control cats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Steady-state pharmacokinetics of oral sustained-release morphine sulphate in dogs

The pharmacokinetics of steady-state oral sustained-release morphine sulphate (OSRMS) were studied in dogs. Beagles ( n = 6) were randomly assigned to one of two treatment groups. Treatments included 15 mg OSRMS every 8 h for 4 days, or 15 mg OSRMS every 12 h for 4 days. Serum samples, drawn at intervals for the final 24 h of drug administration were analysed for morphine concentration using radioimmunoassay. Pharmacokinetic analysis revealed that there were no significant differences between trough serum concentrations for the concentration–time curves within either treatment group, indicating that steady-state pharmacokinetics had been achieved. There were no significant differences in time to maximum serum concentration among the three sections of the concentration–time curve for the 8-h group or between the two sections of the curve for the 12-h group. Area under the concentration–time curve and maximum serum concentrations were significantly greater for the section of the curve following dosing at 7:30 h than following dosing at 19:30 h in the 12-h treatment group. This chronopharmacokinetic variability was not present in the 8-h treatment group. OSRMS provides sustained periods of elevated serum concentrations following administration every 8 or 12 h at a clinically applicable dosage. The clinical implications of the chronopharmacokinetic variability seen with 12-hourly administration are not known. This formulation has potential for the treatment of chronic pain in dogs, but further studies of efficacy and safety following long-term administration are required.     

Plasma and interstitial fluid pharmacokinetics of enrofloxacin, its metabolite ciprofloxacin, and marbofloxacin after oral administration and a constant rate intravenous infusion in dogs

Enrofloxacin and marbofloxacin were administered to six healthy dogs in separate crossover experiments as a single oral dose (5 mg/kg) and as a constant rate IV infusion (1.24 and 0.12 mg/h.kg, respectively) following a loading dose (4.47 and 2 mg/kg, respectively) to achieve a steady-state concentration of approximately 1 microg/mL for 8 h. Interstitial fluid (ISF) was collected with an in vivo ultrafiltration device at the same time period as plasma to measure protein unbound drug concentrations at the tissue site and assess the dynamics of drug distribution. Plasma and ISF were analyzed for enrofloxacin, its active metabolite ciprofloxacin, and for marbofloxacin by high performance liquid chromatography (HPLC). Lipophilicity and protein binding of enrofloxacin were higher than for marbofloxacin and ciprofloxacin. Compared to enrofloxacin, marbofloxacin had a longer half-life, higher Cmax, and larger AUC(0-infinity) in plasma and ISF after oral administration. Establishing steady state allowed an assessment of the dynamics of drug concentrations between plasma and ISF. The ISF and plasma-unbound concentrations were similar during the steady-state period despite differences in lipophilicity and pharmacokinetic parameters of the drugs.     

Pharmacokinetics of enrofloxacin administered intravenously and orally to foals

OBJECTIVE: To determine the pharmacokinetics of enrofloxacin administered IV and orally to foals. ANIMALS: 5 clinically normal foals. PROCEDURE: A 2-dose cross-over trial with IV and oral administration was performed. Enrofloxacin was administered once IV (5 mg/kg of body weight) to 1-week-old foals, followed by 1 oral administration (10 mg/kg) after a 7-day washout period. Blood samples were collected for 48 hours after the single dose IV and oral administrations and analyzed for plasma enrofloxacin and ciprofloxacin concentrations by use of high-performance liquid chromatography. RESULTS: For IV administration, mean +/- SD total area under the curve (AUC0-infinity) was 48.54 +/- 10.46 microg x h/ml, clearance was 103.72 +/- 0.06 ml/kg/h, half-life (t1/2beta) was 17.10 +/- 0.09 hours, and apparent volume of distribution was 2.49 +/- 0.43 L/kg. For oral administration, AUC0-infinity was 58.47 +/- 16.37 microg x h/ml, t1/2beta was 18.39 +/- 0.06 hours, maximum concentration (Cmax) was 2.12 +/- 00.51 microg/ml, time to Cmax was 2.20 +/- 2.17 hours, mean absorption time was 2.09 +/- 0.51 hours, and bioavailability was 42 +/- 0.42%. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with adult horses given 5 mg of enrofloxacin/kg IV, foals have higher AUC0-infinity, longer t1/2beta, and lower clearance. Concentration of ciprofloxacin was negligible. Using a target Cmax to minimum inhibitory concentration ratio of 1:8 to 1:10, computer modeling suggests that 2.5 to 10 mg of enrofloxacin/kg administered every 24 hours would be effective in foals, depending on minimum inhibitory concentration of the pathogen.     

Pharmacokinetics of norfloxacin in dogs after single intravenous and single and multiple oral administrations of the drug

Norfloxacin was given to 6 healthy dogs at a dosage of 5 mg/kg of body weight IV and orally in a complete crossover study, and orally at dosages of 5, 10, and 20 mg/kg to 6 healthy dogs in a 3-way crossover study. For 24 hours, serum concentration was monitored serially after each administration. Another 6 dogs were given 5 mg of norfloxacin/kg orally every 12 hours for 14 days, and serum concentration was determined serially for 12 hours after the first and last administration of the drug. Complete blood count and serum biochemical analysis were performed before and after 14 days of oral norfloxacin administration, and clinical signs of drug toxicosis were monitored twice daily during norfloxacin administration. Urine concentration of norfloxacin was determined periodically during serum acquisition periods. Norfloxacin concentration was determined, using high-performance liquid chromatography with a limit of detection of 25 ng of norfloxacin/ml of serum or urine. Serum norfloxacin pharmacokinetic values after single IV dosing in dogs were best modeled, using a 2-compartment open model, with distribution and elimination half-lives of 0.467 and 3.56 hours (harmonic means), respectively. Area-derived volume of distribution (Vd area) was 1.77 +/- 0.69 L/kg (arithmetic mean +/- SD), and serum clearance (Cls) was 0.332 +/- 0.115 L/h/kg. Mean residence time was 4.32 +/- 0.98 hour. Comparison of the area under the curve (AUC; derived, using model-independent calculations) after iv administration (5 mg/kg) with AUC after oral administration (5 mg/kg) in the same dogs indicated bioavailability of 35.0 +/- 46.1%, with a mean residence time after oral administration of 5.71 +/-2.24 hours. Urine concentration was 33.8 +/- 15.3 micrograms/ml at 4 hours after a single dose of 5 mg/kg given orally, whereas concentration after 20 mg/kg was given orally was 56.8 +/- 18.0 micrograms/ml at 6 hours after dosing. Twelve hours after drug administration, urine concentration was 47.4 +/- 20.6 micrograms/ml after the 5-mg/kg dose and 80.6 +/- 37.7 micrograms/ml after the 20/mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of morphine and plasma concentrations of morphine-6-glucuronide following morphine administration to dogs

The purpose of this study was to evaluate the pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) following morphine administered intravenously and orally to dogs in a randomized crossover design. Six healthy 3–4-year-old Beagle dogs were administered morphine sulfate (0.5 mg/kg) as an i.v. bolus and extended release tablets were administered orally as whole tablets (1.6 ± 0.1 mg/kg) in a randomized crossover design. Plasma concentrations of morphine and M-6-G were determined using high-pressure liquid chromatography and electrochemical coulometric detection. Following i.v. administration all dogs exhibited dysphoria and sedation, and four or six dogs vomited. Mean ± SE values for half-life, apparent volume of distribution, and clearance after i.v. administration were 1.16 ± 0.15 h, 4.55 ± 0.17 L/kg, and 62.46 ± 10.44 mL/min/kg, respectively. One dog vomited following oral administration and was excluded from the oral analysis. Oral bioavailability was 5% as determined from naïve-averaged analysis. The M-6-G was not detected in any plasma samples following oral or i.v. administration of morphine at a 25 ng/mL the limit of quantification. Computer simulations concluded morphine sulfate administered 0.5 mg/kg intravenously every 2 h would maintain morphine plasma concentrations consistent with analgesic plasma concentrations in humans. Oral morphine is poorly and erratically absorbed in dogs.     

The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs

Methadone is an opioid, which has a high oral bioavailability (>70%) and a long elimination half-life (>20 h) in human beings. The purpose of this study was to evaluate the effects of ketoconazole [a CYP3A and p-glycoprotein (p-gp) inhibitor] and omeprazole (an H+,K(+)-ATPase proton-pump inhibitor) on oral methadone bioavailability in dogs. Six healthy dogs were used in a crossover design. Methadone was administered i.v. (1 mg/kg), orally (2 mg/kg), again orally following oral ketoconazole (10 mg/kg q12 h for two doses), and following omeprazole (1 mg/kg p.o. q12 h for five doses). Plasma concentrations of methadone were analyzed by high-pressure liquid chromatography or fluorescence polarization immunoassay. The mean +/- SD for the elimination half-life, volume of distribution, and clearance were 1.75 +/- 0.25 h, 3.46 +/- 1.09 L/kg, and 25.14 +/- 9.79 mL/min.kg, respectively following i.v. administration. Methadone was not detected in any sample following oral administration alone or following oral administration with omeprazole. Following administration with ketoconazole, detectable concentrations of methadone were present in one dog with a 29% bioavailability. MDR-1 genotyping, encoding p-gp, was normal in all dogs. In contrast to its pharmacokinetics humans, methadone has a short elimination half-life, rapid clearance, and low oral bioavailability in dogs and the extent of absorption is not affected by inhibition of CYP3A, p-gp, and gastric acid secretion.     

Intramuscular and oral disposition of enrofloxacin in African grey parrots following single and multiple doses

The intramuscular (IM) and oral (PO) disposition of enrofloxacin, a new fluoroquinolone antimicrobial drug, were evaluated in African grey parrots. Peak enrofloxacin concentration, mean (+/- SEM), at 1 h following a 15-mg/kg IM dose was 3.87 (+/- 0.27) micrograms/ml and declined with a mean residence time of 3.05 h. Peak enrofloxacin plasma concentrations at 2 to 4 h following oral doses of 3, 15, and 30 mg/kg were 0.31 (+/- 0.11), 1.12 (+/- 0.11), and 1.69 (+/- 0.23) micrograms/ml, respectively, and declined with a mean residence time of 3.44-5.28 h. The relative bioavailability of the 15-mg/kg oral dose was 48%. An equipotent metabolite, ciprofloxacin, was detected in plasma at concentrations ranging from 3 to 78% of those of enrofloxacin. Enrofloxacin concentrations and area under the curve were significantly lower, the mean residence time significantly shorter and the ciprofloxacin/enrofloxacin ratios higher, following 10 days of oral treatment at 30 mg/kg every 12 h. Following 10 days of treatment, no significant biochemical changes were noted; however, polydipsia and polyuria occurred in treated birds, but resolved quickly upon discontinuation of enrofloxacin administration. These studies indicate that a rational starting dose for enrofloxacin in psittacines (7.5-30 mg/kg BID) should be higher than those in other domestic animals.     

Digoxin in dogs: once a day or twice a day?

Healthy mature dogs were given digoxin orally at the same dose once a day (SID) or divided (BID) at 12-hour intervals. Blood concentrations of digoxin were determined by radioimmunoassay. When the drug was given SID, peak blood concentrations were higher than, but lowest blood concentrations were not different than, those obtained when the drug was given BID. Thus, average blood concentration throughout 24 hours was significantly (P less than 0.05) greater when digoxin was given SID than when given BID. This suggested a reduced rate of clearance and an increased risk for toxicosis for digoxin when given SID versus BID. Peaks of digoxin blood concentrations were lower when the drug was given BID rather than SID; however, we do not know whether the smaller fluctuations can be translated into greater efficacy and/or less toxicity. Unless those questions are answered, we recommend that digoxin be administered BID to mature dogs.     

Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intravenous and oral administration of enrofloxacin in dogs

Rung, K., Riond, J.-L. & Wanner, M. Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intravenous and oral administration of enrofloxacin in dogs. J. vet
Four dogs were given 5 mg/kg body weight enrofloxacin intravenously (i.v.) and orally (p.o.) in a cross-over study. Plasma concentrations of the active ingredient enrofloxacin and its main metabolite ciprofloxacin were determined by a reversed phase liquid chromatographic method. Pharmacokinetic parameters of both substances were calculated by use of statistical moments and were compared to those of enrofloxacin described in the veterinary literature. Mean enrofloxacin t _½λZ was 2.4 h, mean Cl_s was 27.1 ml/min-kg, and mean V_ss was 7.0 1/kg. After i.v. and p.o. administration, concentrations of ciprofloxacin exceeding minimal inhibitory concentrations of several microorganisms were reached (C_max= 0.2 ng/ml, max = 2.2 h after intravenous administration; C_max= 0.2 (ig/ml, t _max= 3.6 h after oral administration). A considerable part of the antimicrobial activity is due to ciprofloxacin, the main metabolite of enrofloxacin.