Pharmacokinetics Of Chloramphenicol Research Articles

Pharmacokinetics of multiple doses of chloramphenicol in fed adult horses

To the authors’ knowledge, there have been no studies evaluating the pharmacokinetics of chloramphenicol administered orally to horses at the currently recommended dose of 50 mg/kg PO q6 h for multiple days. The published antimicrobial susceptibility breakpoint is 8.0 ug/mL; it is unknown if this concentration is achievable at the recommended dose rate in horses. The aim of this prospective multi-dose pharmacokinetic study was to perform pharmacokinetic analysis of chloramphenicol after multiple doses. The authors hypothesize that the antimicrobial susceptibility breakpoint will not be reached. Seven healthy adult horses were administered 50 mg/kg chloramphenicol base tablets PO q6 h for 4 days. Blood was collected via venipuncture daily at 4 and 6 h after administration for the first 15 doses. After the 16th dose, an IV catheter was aseptically placed in the right jugular vein and blood was collected at regular intervals for pharmacokinetic analysis.Maximum chloramphenicol concentration was variable between horses (2.1–42.7 μg/mL). The highest average chloramphenicol concentration was just below the susceptibility breakpoint at 7.7 ug/mL while the lowest was well below the breakpoint at 1.5 ug/mL. On average, the time above 8.0 μg/mL was 75 min, considerably less than the recommended 50% of the dosing interval. When chloramphenicol is administered at a dose of 50 mg/kg PO q6 h in horses, the highest reliably achievable steady state concentration for at least half of the dosing interval is 2.0 μg/mL. The established susceptibility breakpoint of 8.0 ug/mL is not achievable in adult horses, and should be re-evaluated.

Pharmacokinetics of chloramphenicol (CAP) in gilthead sea bream (Sparus aurata) and its in vitro activities against important bacterial fish pathogens

The pharmacokinetics of chloramphenicol (CAP) in gilthead sea bream (Sparus aurata), a warm water farmed fish species and its in vitro efficacy against important bacterial diseases of Mediterranean mariculture were investigated in this study. After an intravascular injection (10 mg/kg/fish), the distribution half-life (tl/2a) and the elimination half-life (tl/2ß) of CAP were calculated to be 1.6 and 69 h, respectively. Tissue penetration of CAP was found to be moderate since both the apparent volume of distribution of the drug at steady-state (V<i(ss)) and the apparent volume of the central compartment (Vc) were calculated to be 1.13 and 0.90 L/kg. The total clearance (CLp) of the drug was slow (0.022 L/kg/h). The minimum inhibitory concentration (MIC) values of CAP in distilled water supplemented with 2% NaCl against Vibrio anguillarum serotype lb, Photobacterium damsela subsp. piscicida, V alginolyticus and V ßuvialis were determined to be 4.78 pg/mL, while it was 0.60 pg/mL for V. damsela. The addition of 10 mM Ca2+ and 55 mM Mg2+ in the medium revealed MIC values of 19.13 pg/mL for V alginolyticus and V ßuvialis, whereas showed no effect for V anguillarum P. damsela subsp. Piscicida and V damsela. The results indicate that CAP displayed a satisfactory kinetic profile and it is eliminated fast from gilthead sea bream muscle; however, its high MIC values stress show a possible inefficacy against important bacterial pathogens of Mediterranean mariculture.

Pharmacokinetics of chloramphenicol in carp (Cyprinus carpio L.) after drug administration

Chloramphenicol (CAP) is a banned substance in fish farming; yet, residues are sometimes detected in farmed fish products. Therefore, it is important that tissue distribution and elimination rates of CAP are measured to allow monitoring of fish farms. The tissue distribution and residue of CAP in carp (Cyprinus carpio L.) after muscle injection was investigated. Chloramphenicol concentrations were determined using high-performance liquid chromatography. Pharmacokinetics were used for the studies of CAP residue and the results showed that the CAP was easily assimilated in the liver, serum and gill, with the absorption rates of 6383, 3.02 and 1.39 h−1, respectively, following a single-dose injection of 80 mg kg bw−1. The elimination half-lives (t1/2) were 22.28, 15.47, 14.87, 9.28 and 5.32 h for the liver, serum, gill, muscle and kidney respectively. The t1/2 after 5 days of multi-doses of repeated CAP injection with 40 mg kg bw−1 was 1.09, 0.887, 0.872, 0.476 and 0.617 days for the five tissues respectively. The results validated that CAP in the liver, serum and gill could be markers for CAP residue analysis.

Chloramphenicol Pharmacokinetics in African Children with Severe Malaria

The objective of this study was to determine if the current dosage regimen for chloramphenicol CAP administered to children with severe malaria SM for presumptive treatment of concomitant bacterial meningitis achieves steady state plasma CAP concentrations within the reported therapeutic range of 10-25 mg/l. Fifteen children (11 male, 4 female) with a median age of 45 months (range: 10-108 months) and having SM, were administered multiple intravenous doses (25 mg/kg, 6 hourly for 72 h) of chloramphenicol sodium succinate CAPS for presumptive treatment of concomitant bacterial meningitis. Blood samples were collected over 72 h, and plasma CAPS, CAP and CSF CAP concentrations determined by high performance liquid chromatography. Average steady state CAP concentrations were approximately 17 mg/l, while mean fraction unbound (0.49) and CSF/plasma concentration ratio (0.65) were comparable to previously reported values in Caucasian children. Clearance was variable (mean = 4.3 l/h), and trough plasma concentrations during the first dosing interval were approximately 6 mg/l. Simulations indicated that an initial of loading dose of 40 mg/kg CAPS, followed by a maintenance dose of 25 mg/kg every 6 h would result in trough CAP concentrations of approximately 10 mg/l and peak concentrations <25 mg/l throughout the treatment period. The current dosage regimen for CAP needs to include a loading dose of 40 mg/kg CAPS to rapidly achieve plasma CAP concentrations within the reported therapeutic range.

Pharmacokinetics of Chloramphenicol Following Intravenous and Intramuscular Administration of the Drug to Healthy Sokoto Red Goats

Pharmacokinetics of Chloramphenicol Following Intravenous and Intramuscular Administration of the Drug to Healthy Sokoto Red Goats

Pharmacokinetics of Chloramphenicol in Healthy and Water-deprived Goats

Pharmacokinetics of Chloramphenicol in Healthy and Water-deprived Goats

Enterohepatic circulation of chloramphenicol and its glucuronide in the rat by microdialysis using a hepato-duodenal shunt

A system consisting of a hepato-duodenal shunt in which the bile of a drug-treated donor rat was diverted to the duodenum of an untreated recipient rat via a bile cannula was used to assess the role of hepatic metabolism and enterohepatic circulation in the pharmacokinetics of chloramphenicol. Blood concentrations of unbound chloramphenicol and its glucuronide were measured by on-line microdialysis coupled to a microbore liquid chromatographic system. Results indicated that chloramphenicol and its glucuronide were detected in the blood of both donor and recipient rats following an intravenous 100 mg kg dose of chloramphenicol succinate to the donor rat. Our finding suggests that although enterohepatic circulation contributed only to a minor extent (approximately 1.8%) was involved in the disposition of unbound chloramphenicol in the rat on-line microdialysis techniques were applicable for such studies.

On-line microdialysis coupled with microbore liquid chromatography for the determination of unbound chloramphenicol and its glucuronide in rat blood

On-line microdialysis coupled with microbore liquid chromatography was used to investigate the pharmacokinetics of chloramphenicol and its glucuronide in rat blood. A microdialysis probe was inserted into a jugular vein of male Sprague–Dawley rats. Chloramphenicol succinate (20 mg/kg, intravenously) was then administered via a femoral vein. Dialysates were automatically injected onto a LC system, via an on-line injector. Samples were eluted with a mobile phase containing acetonitrile-10 m M monochloroacetic acid (30:70, v/v, pH 3.0). The UV detector wavelength was set at 278 nm. The limit of quantitation for chloramphenicol was 10 ng/ml. The in vitro recoveries of chloramphenicol and chloramphenicol glucuronide at 500 ng/ml were 32.2±0.3% and 11.4±0.7%, respectively ( n=6). Intra- and inter-assay accuracy and precision of the analyses were ≤10% in the range of 0.01 to 5.0 μg/ml.

Chloramphenicol pharmacokinetics after intravenous and intramuscular administration in sheep.

The pharmacokinetics of chloramphenicol were studied after intravenous and intramuscular administration of 50 mg/kg body weight in Merino sheep. After intravenous administration, the drug was rapidly distributed extravascularly with a half-life of 10.5 +/- 8.83 min. Extensive distribution was confirmed by an apparent volume of distribution at steady state (1.5 +/- 0.43 1/kg). The elimination half-life was 3.24 +/- 0.60 h. After intramuscular injection, the absorption half-life was 44.33 +/- 19.21 min with a bioavailability of 65%. A maximum serum concentration of 15.57 +/- 3.95 micrograms/ml was determined 2 h after administration. Serum concentrations above 5 micrograms/ml were maintained for approximately 12 h with an elimination half-life of 5.75 +/- 1.25 h, longer than the half-life obtained after intravenous administration. In conclusion, the intramuscular administration of chloramphenical at a dose rate of 50 mg/kg permitted the maintenance of inhibitory concentrations of the antibiotic for the majority of Salmonella and Pasteurella isolates for at least 12 h.

Influence of age on the disposition kinetics of chloramphenicol in equine neonates

SUMMARY The effect of age on the pharmacokinetics of chloramphenicol was determined after iv administration of chloramphenicol sodium succinate (25 mg/kg of body weight) to 6 foals at 1 day and 3, 7, 14, and 42 days of age. The disposition of chloramphenicol was best described, using a two-compartment open model in all foals at all ages evaluated. Significant age-related changes were observed in values for the major kinetic terms describing the disposition of chloramphenicol in foals; the greatest changes were observed between 1 day and 3 days of age. The mean ± sd value for elimination rate constant (β) for chloramphenicol in 1-day-old foals (0.131 ± 0.06 h-1) was significantly (P &lt; 0.005) lower than the value in 3-day-old foals (0.514 ± 0.156 h-1), and both values were significantly (P &lt; 0.05) lower than values for β in 7-, 14-, and 42-day-old foals. With increasing age, the increase in the mean value for β resulted in decrease in the harmonic mean elimination half-time (t1/2β) for chloramphenicol, from 5.29 hours in 1-day-old foals to: 1.35 hours in 3-day-old foals; 0.61 hour in 7-day-old foals; 0.51 hour in 14-day-old foals; and 0.34 hour in 42-day-old foals. At 1, 3, and 7 days of age, values for t1/2β of chloramphenicol in a premature foal born after parturition was induced with oxytocin, were considerably longer than comparable t1/2β values for term foals born naturally. The mean body clearance (ClB) of chloramphenicol in 1-day-old foals (2.25 ± 0.67 ml/min·kg of body weight) was significantly lower than values in: 3-day-old (6.23 ± 2.22 ml/min·kg; P &lt; 0.05); 7-day-old (8.86 ± 1.90 ml/min·kg; P &lt; 0.0005); 14-day-old (9.63 · 1.63 ml/min·kg; P &lt; 0.0005); and 42-day-old (9.68 · 2.76 ml/min·kg; P &lt; 0.0001) foals. In foals of all ages, ClB of chloramphenicol in the parturition-induced premature foal was lower than the mean value for term foals born naturally. The volume of distribution (V′d[area]) of chloramphenicol decreased progressively with increasing age between day 1 and day 42, so that the mean value for 42-day-old foals (362 ± 163 ml/kg) was less than a third the mean value for 1-day-old foals (1,101 ± 284 ml/kg). The mean value for V′d(area) in 1-day-old foals was significantly greater than values for: 7-day-old (491 ± 158 ml/kg; P &lt; 0.01); 14-day-old (426 ± 65 ml/kg; P &lt; 0.005); and 42-day-old (362 ± 162; P &lt; 0.0005) foals, and the mean value for V′d(area)on day 3 was significantly (P &lt; 0.05) greater than the mean value for V′d(area) on days 7, 14, and 42. Using dosage calculations based on mean values for the pharmacokinetic terms derived for each age group, it was predicted that to maintain plasma chloramphenicol concentration &gt; 8 μg/ml, chloramphenicol sodium succinate (25 mg/kg) would have to be administered at dose intervals of 10, 3, 1.5, 1.5, and 1 hours in clinically normal foals 1 day and 3, 7, 14, and 42 days, of age, respectively. It was concluded that the marked changes in the disposition of chloramphenicol detectable during the first few days of life, the variation between individuals, the potentially major effect of prematurity, and the potential for compromised liver function in septicemic foals indicate that use of drugs, such as chloramphenicol, which rely heavily on hepatic metabolic processes for elimination, should be avoided whenever possible during the early neonatal period, unless plasma concentration is monitored.

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.

The pharmacokinetics of chloramphenicol in plasma and saliva of dairy cows

In the present study the pharmacokinetics of chloramphenicol were investigated in bovine plasma and saliva. The method of detection of chloramphenicol, a radio-immunoassay, requires only small sample volumes, no further clean-up, and a large number of samples can be processed simultaneously. This enabled the collection of a larger number of samples over a longer period of time than in previous studies. The intention was to obtain a complete pharmacokinetic profile of chloramphenicol, to evaluate it according to common open-compartment models, and to compare it with the results of previous studies. The radio-immunoassay results were confirmed by analysing a number of samples distributed over the concentration range of interest by a gas-chromatographic method with electron-capture detection. The suitability of saliva was evaluated as a possible means of monitoring compliance with the ban on chloramphenicol in the Federal Republic of Germany in milk-producing animals.

The effect of exocrine pancreatic function on chloramphenicol pharmacokinetics in patients with cystic fibrosis.

The effect of exocrine pancreatic function on the pharmacokinetics of the choramphenicol oral capsule (CAP-base), chloramphenicol palmitate oral liquid (CAP-P), and chloramphenicol succinate intravenous (CAP-S) formulations was evaluated in 10 patients, aged 16-30 yr, with cystic fibrosis. Pancreatic insufficiency was assessed in each patient by measuring the absorption of p-amino-benzoic acid after oral administration of N-benzoyl-L-tyrosyl-p-aminobenzoic acid which requires chymotrypsin to cleave p-aminobenzoic from the parent molecule. In a controlled cross-over design, the overall biodisposition of each formulation was assessed in each patient with or without concurrent administration of oral pancreatic enzymes. The relative amounts of active chloramphenicol available in systemic circulation was CAP-base greater than CAP-S greater than CAP-P. Pancreatic enzyme replacement had little effect on the biodisposition parameters for the CAP-base and CAP-S formulation, but significantly increased the peak concentration and bioavailability of the CAP-P formulation. Although pancreatic enzyme replacement improved the absorption characteristics of the CAP-P formulation, absorption remained prolonged and unreliable. Serum concentration-time profiles for either CAP-base or CAP-S consistently exceeded the MIC of important nonpseudomonal pathogens. This finding was not observed after CAP-P administration independent of pancreatic enzyme replacement. The results of this study support the continued clinical use of either CAP-base or CAP-S, but the cautious use of CAP-P formulations in CF patients with concurrent pancreatic insufficiency.

Serum concentrations and pharmacokinetics of chloramphenicol in foals after a single oral dose.

Serum concentrations and pharmacokinetics of chloramphenicol in foals after a single oral dose.

Pharmacokinetics and bioavailability of chloramphenicol in normal and febrile goats.

The effect of induced fever on the plasma concentrations and disposition kinetics of chloramphenicol (CHPC) was studied in adult goats. Fever was induced and maintained for 12 h by injecting Escherichia coli endotoxin (0.1 microgram/kg, i.v.) and repeating it at half the dose (0.05 microgram/kg) 8 h later. Pharmacokinetics of CHPC was studied in both normal (n = 6) and febrile (n = 6) animals following intravenous administration of CHPC Na-succinate (25 mg/kg). Intramuscular bioavailability of the drug was also investigated in both normal and febrile animals. Pharmacokinetics of CHPC following intravenous administration could be described by a two-compartment open model in both normal and febrile animals. In normal animals the half-life of CHPC was 73.0 +/- 4.95 min and the volume of distribution was 2.217 +/- 0.24 l/kg. These and other pharmacokinetic parameters did not differ significantly (P less than 0.05) between normal and febrile animals, except for Cop and A. Absorption of CHPC following intramuscular administration was good as indicated by its high bioavailability in both normal (83.34%) and febrile (81.98%) animals. Volume of distribution is usually expected to change when the febrile state is induced. Lack of such an effect in the present study could be due to high individual variation, or to the fact that CHPC already has a relatively large volume of distribution, which is less likely to be altered by a febrile state of short duration.

Chloramphenicol, lincomycin and oxytetracycline disposition in calves with experimental pneumonic pasteurellosis.

The effects of pneumonia on the pharmacokinetics of chloramphenicol, lincomycin, and oxytetracycline were evaluated in two-month-old calves. Pneumonia was induced by injection of Pasteurella haemolytica cultures directly through the thoracic wall into each lung. Six days prior to induction of pneumonia, the antibiotics were administered in a single i.v. dose. The antibiotics were administered again 48 (i.v.), 60 and 72 h (i.m.) following injection of P. haemolytica. The pharmacokinetics of chloramphenicol (25 mg/kg) and lincomycin (10 mg/kg) were not significantly different in calves with pneumonia. The hybrid rate constant beta for oxytetracycline was increased in calves with pneumonia from 0.0034 +/- 0.0003/min to 0.0048 +/- 0.0007/min between 2 h and 8 h. Thus the elimination half-life in serum was shortened from 212.4 +/- 20.3 min to 149.3 +/- 19.5 min. In addition, there was an apparent but not statistically significant decrease in K12 with pneumonia. These findings accentuate the need for observance of 12-h dose intervals with oxytetracycline.

Pharmacokinetics of chloramphenicol in cows after intramuscular application

The concentrations of chloramphenicol and its water-soluble metabolites in the plasma of six clinically healthy heifers were measured at intervals during five days after intramuscular administration of free chloramphenicol (20 mg/kg) in a vehicle containing 40% of an organic solvent. Estimations were carried out by a colorimetric method and by high pressure liquid chromatography (for the very low values beyond the second day). For free chloramphenicol a peak concentration of 1.7 micrograms/ml at 7.3 h after injection was found (MIC: 5 micrograms/ml). Bioavailability was calculated to be 63%. It is shown that absorption was apparently not a uniform process but occurred rather slowly (t 1/2 (ab) = 10.2 h) for the main part of the available dose, whereas one sixth was quickly absorbed (t'1/2 (ab) = 0.7 h). The apparent half-time of elimination was 10.2 h for the unchanged drug. At the fifth day after administration the plasma concentration was below the limit of detectability (10 ng/ml) in all animals.

Absence of a pharmacokinetic interaction between chloramphenicol and acetaminophen in children

The pharmacokinetics of chloramphenicol (CAP; administered intravenously as chloramphenicol succinate, CAPS) was studied in 26 acutely ill febrile children 3 to 58 months of age who either did (n = 18) or did not (n = 8) receive acetaminophen (APAP) for antipyresis. CAP pharmacokinetics were evaluated after the first dose and at steady state. CAP serum levels were quantitated by high-performance liquid chromatography. There were no significant differences between groups (APAP vs non-APAP) or between first dose and steady-state evaluations for the elimination rate constant, serum half-life, apparent volume of distribution, and serum clearance of CAP. Likewise, there were no statistically significant differences when the APAP group was evaluated according to the presence or absence of APAP in serum before the first dose of CAP. Elimination of CAP in subjects with serum CAPS level less than 1 microgram/ml was similar in the first dose and steady-state evaluations and in the APAP and non-APAP groups. The presence or absence of CAPS or APAP did not affect the estimation of CAP elimination. Thus a pharmacokinetic interaction between CAP and APAP was not demonstrated in acutely ill febrile children during concomitant therapy.

The pharmacokinetic behaviour of chloramphenicol in liver-damaged mini-pigs.

Using mini-pigs with an indwelling vascular catheter, the pharmacokinetics of chloramphenicol were investigated in healthy and liver-damaged animals. The liver damage was induced by thioacetamide and its degree was estimated by measuring the level of bile acids in serum. Employing a two-compartment open model for analysing the time-dependent course of the chloramphenicol concentration in serum, it was shown that in liver-damaged animals the elimination half-time was almost doubled as a result of reduced total body clearance. The consequences of liver damage for withdrawal times and dosage schedules are discussed.

Clinical pharmacokinetics of chloramphenicol and chloramphenicol succinate.

In recent years there has been a renewal of interest in chloramphenicol, predominantly because of the emergence of ampicillin-resistant Haemophilus influenzae, the leading cause of bacterial meningitis in infants and children. Three preparations of chloramphenicol are most commonly used in clinical practice: a crystalline powder for oral administration, a palmitate ester for oral administration as a suspension, and a succinate ester for parenteral administration. Both esters are inactive, requiring hydrolysis to chloramphenicol for anti-bacterial activity. The palmitate ester is hydrolysed in the small intestine to active chloramphenicol prior to absorption. Chloramphenicol succinate acts as a prodrug, being converted to active chloramphenicol while it is circulating in the body. Various assays have been developed to determine the concentration of chloramphenicol in biological fluids. Of these, high-performance liquid chromatographic and radioenzymatic assays are accurate, precise, specific, and have excellent sensitivities for chloramphenicol. They are rapid and have made therapeutic drug monitoring practical for chloramphenicol. The bioavailability of oral crystalline chloramphenicol and chloramphenicol palmitate is approximately 80%. The time for peak plasma concentrations is dependent on particle size and correlates with in vitro dissolution and deaggregation rates. The bioavailability of chloramphenicol after intravenous administration of the succinate ester averages approximately 70%, but the range is quite variable. Incomplete bioavailability is the result of renal excretion of unchanged chloramphenicol succinate prior to it being hydrolysed to active chloramphenicol. Plasma protein binding of chloramphenicol is approximately 60% in healthy adults. The drug is extensively distributed to many tissues and body fluids, including cerebrospinal fluid and breast milk, and it crosses the placenta. Reported mean values for the apparent volume of distribution range from 0.6 to 1.0 L/kg. Most of a chloramphenicol dose is metabolised by the liver to inactive products, the chief metabolite being a glucuronide conjugate; only 5 to 15% of chloramphenicol is excreted unchanged in the urine. The elimination half-life is approximately 4 hours. Inaccurate determinations of the pharmacokinetic parameters may result by incorrectly assuming rapid and complete hydrolysis of chloramphenicol succinate. The pharmacokinetics of chloramphenicol succinate have been described by a 2-compartment model. The reported values for the apparent volume of distribution range from 0.2 to 3.1 L/kg.(ABSTRACT TRUNCATED AT 400 WORDS)