Pharmacokinetics of chloramphenicol in sheep after intravenous, intramuscular and subcutaneous administration

The pharmacokinetics of chloramphenicol were studied in sheep after 3 single intravenous (IV), intramuscular (IM) and subcutaneous (SC) administrations (30 mg/kg). The two extravascular routes were studied during a crossover trial for a bioequivalence test. After IV and SC administrations, the plasma-concentration time graphs were characteristic of a two-compartment model, and after IM administration it was characteristic of a monocompartment model. The two routes of absorption were not bioequivalent. Using the kinetic values, multidose regimens to maintain the therapeutic chloramphenicol blood level (5 micrograms/ml) were proposed: 60 mg/kg every 12 hours for 72 hours for the IM administration and 45 mg/kg administered subcutaneously according to the same regimen. A study of the chloramphenicol residues in tissues was carried out. Chloramphenicol residues remained at the injection site, and 400 hours would be necessary to obtain the level of 10 micrograms/kg. Determination of the creatinine phosphokinase serum values showed that the subcutaneous route induced less damage to muscle than the intramuscular route.     

Plasma chloramphenicol concentrations in cats after parenteral administration of chloramphenicol sodium succinate

Five cats were dosed on five occasions with 20 mg chloramphenicol/kg body weight. The drug was given three times as chloramphenicol sodium succinate (by intravenous, intramuscular and subcutaneous injections) and twice as crystalline chloramphenicol in capsules. Plasma chloramphenicol concentrations were determined at fixed intervals after administration. Parenteral injection of the ester usually produced highest plasma levels at the initial sampling, 0.5 h after dosing. When capsules were given, there was greater variation between cats: highest plasma levels were recorded usually at 0.5-2 h after dosage but delayed absorption was evident in some cases. There were no statistically significant differences between the different routes with regard to mean plasma antibiotic levels at each sampling or mean area under the curve of plasma level versus time, except that mean plasma levels at 0.5 h were higher with intravenous or intramuscular injection than with oral administration.     

Plasma chloramphenicol concentrations in cats following intramuscular administration of three different chloramphenicol preparations

Five adult cats were given 30 mg chloramphenicol/kg by intramuscular injection on three separate occasions, using a different preparation on each occasion. The preparations were an aqueous suspension of chloramphenicol, a solution of chloramphenicol in methylpyrrolidone, and an aqueous solution of chloramphenicol sodium succinate. Plasma chloramphenicol concentrations were determined chemically at fixed intervals after dosing. Chloramphenicol sodium succinate solution gave higher and more rapidly attained plasma chloramphenicol concentrations than the other two preparations. The extent of chloramphenicol absorption up to 8 h after administration was greater with the succincate ester than with chloramphenicol dissolved in methylpyrrolidone. There was no difference in bioavailability between the aqueous suspension and the solution in methylpyrrolidone.     

Pharmacokinetics of chloramphenicol in normal and Escherichia coli infected chickens

1. Disposition kinetics were compared in healthy chickens and in chickens naturally infected with E. coli following the intravenous, intramuscular and oral administration of chloramphenicol in a single dose of 20 mg/kg body weight. 2. Lower serum chloramphenicol concentration in diseased chickens were reported after intravenous injection, but they were higher than normal 30 min after intramuscular and oral administration. Following intravenous injection the volume of distribution was increased in diseased chickens. 3. The biological half-life in normal chickens was 8.32 +/- 0.5 h and was prolonged in diseased birds (26.21 +/- 0.2 h). The body clearance of chloramphenicol was reduced in diseased chickens. 4. The rate of absorption of chloramphenicol was delayed after administration via the oral route but the extent of absorption was increased. The maximum concentration was higher and it was reached after a longer time in diseased than in normal chickens after administration by both intramuscular and oral routes.     

Pharmacokinetics of chloramphenicol in Chinese spot-billed ducks (Anas poecilorhyncha)*

The pharmacokinetic behavior of chloramphenicol in Chinese spot-billed ducks (Anas poecilorhyncha) was investigated. Single doses of chloramphenicol were given by the intravenous (22 mg/kg), intramuscular (22 mg/kg), and oral route (55 mg/kg) to six, seven and six ducks, respectively. Serum samples were collected at various times and analyzed for chloramphenicol by a radio-enzymatic procedure. The time—concentration curves after intravenous administration were described by one-compartment kinetics. The mean half-lives for the intravenous, intramuscular, and oral route were 102.5, 104.5 and 151.4 min, respectively. There was little individual variation in the time—concentration plots for either the intravenous or intramuscular route. However, following oral administration, there was considerable individual variation indicating erratic absorption. From the intravenously derived, pharmacokinetic parameters, dosage regimens applicable to either the intravenous or intramuscular route, were developed.     

Experimental chloramphenicol intoxication in neonatal calves: intravenous administration

Chloramphenicol was administered intravenously for eight to 17 days to five newborn calves at a daily dosage of 100 mg kg-1. Haemodynamic, haematological, blood chemistry, serum enzyme, urinalysis and clinical responses were evaluated. High levels of serum chloramphenicol were observed throughout the study although a marked increase in elimination rate was seen with increasing age. The most severe adverse effects were severe hypotension following rapid intravenous administration and severe gastrointestinal dysfunction with diarrhoea accompanying prolonged high dosage. There appeared to have been a haematological effect in one calf, but it was of minor significance compared with the other effects.     

Comparative study of ampicillin and amoxycillin after intravenous, intramuscular and oral administration in homing pigeons (Columba livia)

Pharmacokinetics of ampicillin and amoxycillin after intravenous, intramuscular and oral administration was investigated in homing pigeons. The pharmacokinetic parameters in a cross-over study after intravenous administration of the sodium salts were comparable. The only significant difference was found for the distribution phase. The bioavailability after intramuscular injection of the sodium salts was especially low for ampicillin (26 per cent, as against 57 per cent for amoxycillin). The mean peak blood levels at 0.5 hours were 13.65 and 28.80 mg litre-1 for ampicillin and amoxycillin, respectively. After oral administration of trihydrate solutions (8 mg ml-1) the bioavailability was 20 and 35 per cent, respectively, and the mean peak blood levels were 8.46 and 16.98 mg litre-1, found at 1.04 and 1.26 hours. The recovery from the droppings, which include in birds the urine fraction as well, was unexpectedly low. Based on controls for recovery of added penicillin from the droppings and uric acid suspensions, indications were found that the pigeon enzymically inactivates penicillins. The in vitro activity of ampicillin against 266 strains of bacteria isolated from birds was determined. The minimum inhibitory concentration (MIC) for 65.4 per cent of the Escherichia coli was lower than 4 mg litre-1, for 91.1 per cent of the Salmonella species was lower than 2 mg litre-1 and for 100 per cent of the Yersinia pseudotuberculosis was lower than 0.25 mg litre-1. Based on these data and a literature study dosage regimens were calculated for MIC values of 0.5 and 2.5 mg litre-1.     

Pharmacokinetics and tissue residues of josamycin in fowls.

Josamycin is a macrolide antibiotic which is produced by fermentation of cultures of Streptomyces narbonensis. It was once administrated (18 mg/kg b. wt.) in fowls via intravenous, oral and intramuscular routes for determination of blood concentration, kinetic behaviour and bioavailability. Following a single intravenous injection, the blood concentration-time-curve indicated a two compartments open model with an elimination half life value (t1/2 beta) of 1.83 +/- 0.06 hours. Both oral and intramuscular routes showed higher values, i.e. 2.33 +/- 0.13 and 2.85 +/- 0.17 hours. The lower apparent volume of distribution of Josamycin in fowls than one liter/kg elucidate higher distribution in blood than in tissues. Systemic bioavailability after both oral and intramuscular administration, i.e. 33.88 +/- 2.4 and 27.28 +/- 1.46% respectively, showed lower absorption from site of i.m. application. Josamycin was administered (18 mg/kg b. wt.) intramuscularly and orally once daily for 5 consecutive days. The drug peaked in serum 1 hour (intramuscular) and 2 hours (orally) after each dose. The recorded results revealed that serum level of Josamycin was higher after oral application (29.98 +/- 1.92 micrograms/ml) than after i.m. application. The drug persisted in the lung tissues and fat for 72 hours after administration and disappeared from all body tissues 96 hours after the last dose of repeated administration.     

Pharmacokinetics of cefotaxime in the dog

Each of five dogs was given cefotaxime at a dose rate of 50 mg/kg by intravenous, intramuscular and subcutaneous routes, in three separate treatments. Plasma concentration time profiles were characterised by a linear two-compartment model after the intravenous administration. After intravenous, intramuscular and subcutaneous injections the mean biological half-lives were 0.74, 0.83 and 1.71 hours, respectively. The apparent steady state volume of distribution was 0.48 litre/kg and body clearance after intravenous injection was approximately 0.63 litre/hour/kg. After intramuscular and subcutaneous injections peak plasma cefotaxime concentrations were 47 +/- 15 and 29.6 +/- 16 micrograms/ml at 0.5 and 0.8 hours, respectively. The average bioavailability of cefotaxime given by intramuscular injection was 86.5 per cent and for cefotaxime given subcutaneously it was approximately 100 per cent. After two hours, the cefotaxime plasma concentration remained higher after subcutaneous than after intramuscular administration.     

A pharmacological study of chloramphenicol in horses.

Pharmacological disposition of chloramphenicol was studied in horses. Minimum levels of the antibiotic (greater than or equal to 5 mu g/ml) in blood or plasma recommended to combat infections could not be achieved by 4.4 and 8.8 mg/kg I.V. or 30 and 50 mg/kg I.M. or 30 mg/kg oral (as palmitate salt) doses of chloramphenicol. Increasing the dose to 19.8 and 26.4 mg/kg I.V. provided such levels for about two and three hours respectively. A combination of 20 mg/kg I.V. and 30 mg/kg I.M. administered simultaneously did not provide more prolonged levels than 26.4 mg/kg I.V. alone. Chloramphenicol succinate produced higher but not more prolonged levels in blood and plasma than those produced by pure chloramphenicol. Succinate salt is very little, if at all, bound to red blood corpuscles. Plasma half life and the apparent volume of distribution of chloramphenicol in horses were determined as 0.98 hours and 0.92 L/kg, respectively. At 5-10 mu g/ml concentrations in equine plasma approximately 30 percent of the chloramphenicol is bound to plasma proteins. From these studies it is concluded that the biological half life of chloramphenicol may be too short for therapeutic application against systemic infections in horses.     

Distribution of chloramphenicol in the genital tract of postpartum cows

Chloramphenicol was administered by constant IV infusion to 7 healthy postpartum cows at rates predicted to approach a steady-state plasma concentration of 5 micrograms/ml. After 8 hours of constant IV infusion, uterine tissues were removed surgically and were assayed for chloramphenicol concentrations. Mean plasma-to-tissue ratios of chloramphenicol concentrations were 3.05, 3.63 (6 cows only), and 3.22 for caruncles, endometrium, and uterine wall, respectively. Plasma-to-tissue ratios of the 3 tissues were not significantly different (P greater than 0.10). Intrauterine (IU) injections of chloramphenicol (20 mg/kg of body weight) were administered to 3 healthy post-partum cows. The mean value of the fraction of the drug absorbed from the uteri of these cows was 0.40. Mean concentrations of chloramphenicol were 43.8 micrograms/g in caruncles, 34.6 micrograms/g in endometrium, 2.8 micrograms/g in uterine wall, and 2.9 micrograms/ml in plasma 8 hours after IU injections. Chloramphenicol has now been banned for use in food-producing animals in the United States because of its potential for causing toxicosis in human beings. It is illegal to use chloramphenicol in food-producing animals in the United States and in some other countries as well. This includes use by the IU route of administration because chloramphenicol and most drugs are absorbed from the uterus into the bloodstream and are distributed to milk and tissues.     

Comparative study of chloramphenicol absorption in calves after oral, intra-ruminal and intra-abomasal administration

The mechanisms responsible for the rapid decline of chloramphenicol plasma levels after oral administration in young calves during their first weeks of life were investigated. Chloramphenicol was administered by stomach tube, to four 2 week old calves on three consecutive days at a dose of 50 mg/kg. The plasma levels increased daily to a peak value on the third day. The minimum therapeutic concentration of 5 μg/ml, however, was barely obtained. Simultaneous estimation of the ruminal contents showed a parallel increase in chloramphenicol concentration. Thus it can be assumed that there is an inefficient absorption of chloramphenicol from the forestomachs of young calves. Chloramphenicol was not metabolized by the ruminal contents until the calves were 9 weeks old. Finally chloramphenicol was administered to 7 week old calves by the intra-abomasal route, intraruminal route and by mouth. Only with the intra-abomasal method could a therapeutically effective level be reached. This indicates that the rapid decline of chloramphenicol plasma levels in calves during their first weeks of life could be attributed to the delayed reticulo-rumen emptying and to inefficient absorption from the forestomachs.     

Serum chloramphenicol concentrations in preruminant calves: a comparison of two formulations dosed orally

Serum concentrations of chloramphenicol were determined after oral doses (55 mg/kg body weight) were administered to 7–9 day old Holstein-Friesian calves. Chloramphenicol in an oral solution produced greater serum concentrations than did an equivalent dose of chloramphenicol in capsules ( P <0.005). A second dose of each formulation administered 12 h after the first dose elevated serum chloramphenicol concentrations significantly ( P <0.001). The average serum chloramphenicol concentration exceeded 5 μg/ml of serum 1 h after administration of the solution compared with 4 h for the capsules. Average serum chloramphenicol concentration was greater than 5 μg/ml for at least 12 h after the dose was administered for both formulations. Of the eight calves receiving repeat doses of chloramphenicol, seven (87.5%) developed diarrhea in 76 ± 8.6 h. Six of the eight calves (75%) died during or shortly after the period of chloramphenicol administration.     

Concentrations sériques et biodisponibilité sanguine du chloramphénicol chez les bovins

Serum concentrations and factors affecting the blood bioavailability of chloramphenicol in bovine

The authors have compared the serum concentrations and the factors affecting blood bioavailability of chloramphenicol after intramuscular administration of canadian commercial preparations containing 500 mg/mL of antibiotic.

The animals (dairy cows and heifers) received each drug (20 mg/kg) in one or two injection sites. The serum samples, analysed by colorimetric or microbiological methods, showed that considerable differences in concentration exist between the two methods.

The evolution of biodisponibility factors proved identical in both cases. It appears that therapeutic levels of chloramphenicol are reached only by drug A for four to five hours.

The usual dosage (2-10 mg/kg), by intramuscular route, is not sufficient to attain these active concentrations using the other drugs. However, the important variability obtained during the experiment and reflected in the standard deviation values, has not proved that drug A has a better bioavailability based on the criteria of the only microbiological analysis.

     

Pharmacokinetic profile of cefotaxime in goats

Cefotaxime was once administered in goats via intravenous, intramuscular and subcutaneous routes for determination of blood and urine concentration, kinetic behaviour and bioavailability. Following a single intravenous injection, the blood concentration-time curve indicated two compartments open model, with an elimination half-life value (t1/2 beta) of 22.38 +/- 0.41 minutes. Both intramuscular and subcutaneous routes showed lower values i.e. 38.64 and 69.58 minutes. The lower apparent volume of distribution of cefotaxime in goats than one liter/kg elucidated lower distribution in tissues than in blood. After intramuscular and subcutaneous injections peak plasma cefotaxime concentrations were 77.8 +/- 1.7 and 44.0 +/- 0.8 micrograms/ml at 29.6 and 40.4 minutes, respectively. The average bioavailability of cefotaxime given by intramuscular and subcutaneous injection was 1.08 and 1.25, respectively. The cefotaxime concentration remained in urine 24 hours longer after subcutaneous injection than after intramuscular administration.     

Pharmacokinetic profile of cefotaxime in goats

Cefotaxime was administered to goats intravenously, intramuscularly and subcutaneously to determine blood and urine concentration, kinetic behaviour and bioavailability. Following a single intravenous injection, the blood concentration-time curve indicated a two compartment open model, with an elimination half-life value (t1/2 beta) of 22.38 +/- 0.41 minutes. Both intramuscular and subcutaneous routes showed slower values, that is, 38.64 and 69.58 minutes. The apparent volume of distribution of cefotaxime in goats was less than 1 litre kg-1 and suggested a lower distribution in tissues than in blood. After intramuscular and subcutaneous injections peak plasma cefotaxime concentrations were 77.8 +/- 1.7 and 44.0 +/- 0.8 micrograms ml-1 at 29.6 and 40.4 minutes, respectively. The average bioavailability of cefotaxime given by intramuscular and subcutaneous injection was 1.08 and 1.25 times the intravenous availability, respectively. The cefotaxime concentration remained in urine 24 hours longer after subcutaneous injection than after intramuscular administration.     

Physicochemical methods for pharmacokinetic and residue analysis of chloramphenicol and degradation products in dairy cows

The disposition of chloramphenicol after intramammary and intravenous administration was followed through determinations of chloramphenicol in blood and milk by means of high-performance differential pulse polarography. The concentration-time curves obtained reflected the different modes of administration, and allowed calculation of some pharmacokinetic parameters. The results of the polarographic determination in blood agreed fairly well with those of the microbiological assay in serum. Several body fluids and tissues of the cows were examined for residues of chloramphenicol and degradation products, both by the microbiological method and by high-performance liquid chromatography with ultraviolet detection. In urine, chloramphenicol and chloramphenicol glucuronide were found; in the other fluids and tissues only now and then a trace of chloramphenicol or a degradation product was detected. From these results it appears that chloramphenicol and degradation products are eliminated rapidly and completely after intravenous or intrammary application. No accumulation of degradation products occurred.     

Chloramphenicol sodium succinate in the horse: serum, synovial, peritoneal, and urine concentrations after single-dose intravenous administration

Six healthy adult mares were given a single IV dose (25 mg/kg of body weight) of chloramphenicol sodium succinate. Chloramphenicol concentrations in serum, synovial fluid, peritoneal fluid, and urine were measured serially over a 48-hour period. The highest measured serum chloramphenicol concentration was 6.21 micrograms/ml at 0.5 hour. Chloramphenicol was detected in synovial and peritoneal fluids, with mean peak concentrations of 3.89 micrograms/ml and 3.50 micrograms/ml, respectively, at 0.5 hour. Serum and synovial concentrations declined rapidly and were not measurable at 3 hours. Chloramphenicol could not be detected in peritoneal fluid at 6 hours. The serum half-life was 0.43 hour and the apparent volume of distribution was 2.83 L/kg. Urine concentrations of chloramphenicol peaked at 0.5 hour at 106.72 micrograms/ml and also declined rapidly. The drug could not be detected in the urine at 36 hours.     

Plasma levels of chloramphenicol after oral administration in calves during the first weeks of life

Three experiments were carried out to investigate the mechanisms whereby adequate plasma levels of chloramphenicol may be obtained following oral administration in young calves but not in older animals. In the first experiment, plasma levels of chloramphenicol following an oral dose of 50 mg/kg were followed in six calves, given weekly doses for the first 11 weeks of life. A plasma chloramphenicol level of 5 μg/ml, taken as the minimum therapeutic level, was attained only for a few hours in the 1 week old calves. Thereafter plasma levels decreased very rapidly until the fourth week, and rather more slowly between the fourth and eleventh weeks. At 11 weeks the plasma chloramphenicol level fell to around 0.3 μg/ml, which was the lower limit of sensitivity for the assay technique used. In the second experiment, the same single dose was administered to calves in the twelfth or eighteenth weeks of life which had not previously been exposed to the antibiotic. Plasma levels of 1 μg/ml were barely reached. This suggests that the non-absorbtion of chloramphenicol is unlikely to be related to repeated administration of the antibiotic. In the third experiment, the same single dose was administered orally to two cows. Chloramphenicol could not be detected in the plasma following such administration, and some side-effects were observed in the 48 h following dosing. It is suggested that rumen function may interfere with the absorbtion of chloramphenicol following oral administration to ruminants, even in relatively young animals.     

Vitamin E levels in the ovine serum after administration of vitamin E and selenium]

The effects of drugs containing vitamin E for peroral administration (Combinal E), intramuscular injection (Erevit) and parenteral administration of a combined drug containing vitamin E and selenium (Selevit) on vitamin E levels in the ovine blood serum were studied. A uniform dose of 15 mg tocopherol acetate per 1 kg live weight was administered to the experimental animals. The level of vitamin E after the peroral administration of Combinal E was affected to a lesser extent than in swine and calves. The serum was examined before and after saponification to determine the effect of the intramuscular injection of Erevit; it was found out that tocopherol acetate prevailed in the blood serum in the first hours after such a route of administration. The best results were obtained after both subcutaneous and intramuscular administration of Selevit, the levels of free tocopherol showing high values even at the end of the experiments. These results may be made use of in determining effective preventive and therapeutic measures to do away with the white muscle disease in practice.