Pharmacokinetics of chloramphenicol base after oral administration in adult horses

Eva M. McElligott Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.

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Carla S. Sommardahl Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.

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Sherry K. Cox Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.

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Abstract

OBJECTIVE To determine the pharmacokinetics of chloramphenicol base after PO administration at a dose of SO mg/kg (22.7 mg/lb) in adult horses from which food was not withheld.

DESIGN Prospective crossover study.

ANIMALS 5 adult mares.

PROCEDURES Chloramphenicol base (SO mg/kg) was administered PO to each horse, and blood samples were collected prior to administration (0 minutes) and at 5, 10, 15, and 30 minutes and 1, 2, 4, 8, and 12 hours thereafter. Following a washout period, chloramphenicol sodium succinate (25 mg/kg [11.4 mg/lb]) was administered IV to each horse, and blood samples were collected prior to administration (0 minutes) and at 3, 5, 10, 15, 30, and 45 minutes and 1, 2, 4, and 8 hours thereafter.

RESULTS In horses, plasma half-life, volume of distribution at steady state, clearance, and area under the plasma concentration-time curve for chloramphenicol after IV administration ranged from 0.65 to 1.20 hours, 0.51 to 0.78 L/kg, 0.78 to 1.22 L/h/kg, and 20.5 to 32.1 h·μg/mL, respectively. The elimination half-life, time to maximum plasma concentration, maximum plasma concentration, and area under the plasma concentration-time curve after PO administration ranged from 1.7 to 7.4 hours, 0.25 to 2.00 hours, 1.52 to 5.45 μg/mL, and 10.3 to 21.6 h·μg/mL, respectively. Mean ± SD chloramphenicol bioavailability was 28 ± 10% and terminal half-life was 2.85 ± 1.32 hours following PO administration.

CONCLUSIONS AND CLINICAL RELEVANCE Given that the maximum plasma chloramphenicol concentration in this study was lower than previously reported values, it is recommended to determine the drug's MIC for target bacteria before administration of chloramphenicol in adult horses.

Abstract

OBJECTIVE To determine the pharmacokinetics of chloramphenicol base after PO administration at a dose of SO mg/kg (22.7 mg/lb) in adult horses from which food was not withheld.

DESIGN Prospective crossover study.

ANIMALS 5 adult mares.

PROCEDURES Chloramphenicol base (SO mg/kg) was administered PO to each horse, and blood samples were collected prior to administration (0 minutes) and at 5, 10, 15, and 30 minutes and 1, 2, 4, 8, and 12 hours thereafter. Following a washout period, chloramphenicol sodium succinate (25 mg/kg [11.4 mg/lb]) was administered IV to each horse, and blood samples were collected prior to administration (0 minutes) and at 3, 5, 10, 15, 30, and 45 minutes and 1, 2, 4, and 8 hours thereafter.

RESULTS In horses, plasma half-life, volume of distribution at steady state, clearance, and area under the plasma concentration-time curve for chloramphenicol after IV administration ranged from 0.65 to 1.20 hours, 0.51 to 0.78 L/kg, 0.78 to 1.22 L/h/kg, and 20.5 to 32.1 h·μg/mL, respectively. The elimination half-life, time to maximum plasma concentration, maximum plasma concentration, and area under the plasma concentration-time curve after PO administration ranged from 1.7 to 7.4 hours, 0.25 to 2.00 hours, 1.52 to 5.45 μg/mL, and 10.3 to 21.6 h·μg/mL, respectively. Mean ± SD chloramphenicol bioavailability was 28 ± 10% and terminal half-life was 2.85 ± 1.32 hours following PO administration.

CONCLUSIONS AND CLINICAL RELEVANCE Given that the maximum plasma chloramphenicol concentration in this study was lower than previously reported values, it is recommended to determine the drug's MIC for target bacteria before administration of chloramphenicol in adult horses.

Chloramphenicol is a broad-spectrum bacteriostatic antimicrobial that is frequently used in equine patients. Its spectrum of activity is against gram-negative, gram-positive, anaerobic, and intracellular organisms, and the drug is formulated into injectable, oral, ophthalmic, and topical solutions. Oral formulations include chloramphenicol base and chloramphenicol palmitate.1,2 Given the relative lack of microbial resistance against chloramphenicol because of its ban from use in the food animal and human health industries and the availability of oral formulations of the drug, it has become an attractive option in oral antimicrobial treatment regimens for many species. Serious adverse effects associated with chloramphenicol administration in humans include bone marrow suppression, gray baby syndrome, encephalitis, and fatal aplastic anemia.3,4 Bone marrow suppression is usually associated with plasma chloramphenicol concentrations exceeding 25 μg/mL and is typically reversible after drug administration is stopped.3,4 Gray baby syndrome in neonates and encephalitis in adults can develop when plasma chloramphenicol concentrations exceed 40 to 200 μg/mL.3,4 Aplastic anemia is idiosyncratic and fatal; it can develop weeks to months after exposure to chloramphenicol and is estimated to effect 1/25,000 to 1/40,000 humans exposed.3,4 Because of these human health risks, chloramphenicol is banned for use in food animals in the United States. Horses are not generally used as food animals in the United States (although the FDA does recognize that horses can be food-producing animals); however, horse meat is consumed regularly in some cultures and human exposure cannot be completely eliminated.5 There are few studies that have investigated the absorption of chloramphenicol base after PO administration in adult horses from which food has not been withheld. Current dosages of chloramphenicol administered PO in clinical settings range from 44 to 50 mg/kg (20 to 22.7 mg/lb) every 6 to 8 hours; these dosages are based on results of studies done prior to advances in analytical analysis (eg, high-performance liquid chromatography) that are available today6–11 The purpose of the study reported here was to determine the pharmacokinetics of chloramphenicol base after oral administration at a dose of 50 mg/kg in adult horses from which food was not withheld.

Materials and Methods

Animals

Five adult university-owned research mares that were determined to be healthy on the basis of history and results of physical examination were used. The horses' ages ranged from 3 to 20 years and weights ranged from 409 to 523 kg (899.8 to 1,150.6 lb). The Institutional Animal Care and Use Committee of the University of Tennessee approved the study.

Procedures

All 5 horses were used to determine the pharmacokinetics of chloramphenicol following PO administration; subsequently, 3 of the 5 horses were used to determine the pharmacokinetics of chloramphenicol following IV administration. For the PO administration analysis, the horses were housed individually in box stalls for a 24-hour period before and during the experiment. During these experiments, each horse was allowed hay and water ad libitum. For each horse, a 14-gauge, 5.25-inch IV catheter was placed in a jugular vein. Each horse's mouth was flushed with water by use of a dosing syringe before PO administration of a dose of an oral solution that contained chloramphenicol basea given via a 60-mL catheter tip syringe.

The oral solution was compounded in the University of Tennessee College of Veterinary Medicine's pharmacy from bulk chloramphenicol base powder1 and a commercial suspending vehiclec to make a suspension (concentration, 500 mg/mL). The chloramphenicol suspension was prepared fresh within 24 hours of administration. The suspension was shaken prior to administration. The suspensions were not individually tested for quality control.

The dose of chloramphenicol administered PO to each horse was 50 mg/kg. Blood samples were collected prior to administration (0 minutes) and at 5,10,15, and 30 minutes and 1, 2, 4, 8, and 12 hours thereafter. Blood samples were obtained with a standard 3-syringe technique that involved discarding 10 mL of waste blood, collecting 10 mL of blood for analysis, and flushing the catheter with 6 mL of sterile saline (0.9% NaCl) solution containing heparin. The catheters were removed after each experiment. The horses were then returned to the university herd where they were monitored daily by university staff.

After a 2-week washout period, 3 of the 5 adult horses were used for the IV administration analysis. The horses were housed individually in box stalls for a 24-hour period before and during the experiment. During these experiments, each horse was allowed hay and water ad libitum. For each horse, a 14-gauge, 5.25-inch IV catheter was placed in a jugular vein for blood sample collection. In the contralateral jugular vein, an IV catheter was placed for drug administration and removed after drug administration. Chloramphenicol sodium succinateb was administered IV at a dose of 25 mg/kg (11.4 mg/lb). Blood samples were collected with the 3-syringe technique used in the PO administration experiments prior to administration (0 minutes) and at 3, 5,10,15, 30, and 45 minutes and 1, 2, 4, and 8 hours thereafter. The horses were monitored for 24 hours prior to their return to the university herd.

All blood samples were collected into tubes containing EDTA and placed on ice and centrifuged for 20 minutes at 1,700 × g; plasma was removed and stored in polypropylene cryotubes at −80°C until sample analysis.

Analysis of plasma samples

Analysis of chloramphenicol in plasma samples was conducted by means of reversed-phase high-performance liquid chromatography. The system consisted of a separations moduled and a UV detector.e Separation was attained on a C18 (4.6 × 150-mm [5-μm]) column.f The mobile phase was an isocratic mixture of water (liquid A) and acetonitrile (liquid B; ratio of A:B, 66:34). The drug was quantified via UV detection at 280 nm, and the flow rate was 1.0 mL/min.

Chloramphenicol was extracted from plasma samples by liquid-liquid extraction. Briefly, previously frozen plasma samples were thawed and vortexed; 500 μL of each sample was transferred to a clean screw-top test tube, and then 25 μL of internal standard (100 μg of thiamphenicol/mL) was added. Three milliliters of acetonitrile was added to the tube, which was capped and rocked for 20 minutes followed by centrifugation at 1,000 × g for 20 minutes. The supernatant was removed to a clean tube and evaporated to dryness under a steady stream of nitrogen gas. Samples were reconstituted in 250 μL of mobile phase, and a volume of 100 μL was injected into the high-performance liquid chromatography system.

Standard curves for plasma analysis were prepared by spiking untreated plasma samples with chloramphenicol to obtain a linear drug concentration range of 0.1 to 100 μg/mL. Spiked standards were processed as were the experimental plasma samples. Mean recovery for chloramphenicol was 97%. For quality control standards of 0.75, 7.5, 20, and 75 μg/mL, the intraassay coefficient of variation ranged from 1.5% to 4.6%, whereas the interassay coefficient of variation ranged from 2.9% to 6.5%. The lower limit of quantification was 0.1 μg/mL.

Plasma chloramphenicol concentrations in samples obtained from each horse were analyzed by compartmental and noncompartmental approaches with nonlinear modeling software.8 To fit the observed data, a biexponential equation for a 2-compartment model was used as follows:

article image

where Cp is the observed concentration, A and B are y-intercept constants, a is the rate constant of the distribution phase, t is time, and P is the rate constant of the elimination phase. Weighting of the data by calculation of 1/observed concentration (ie, 1/Y) was used to improve the line fit and residual plots. The goodness of fit of the data with the model was determined by visual examination of the line fits, residual plots, and Akaike information criteria.12 Values of the elimination rate constant, plasma half-life, Cmax, Tmax, Vdarea, Vdss, total body clearance, and AUC0-∞ were calculated via noncompartmental analysis. The AUC and AUMC were calculated with the log-linear trapezoidal rule. Mean residence time was calculated as AUMC from time 0 to infinity/AUC0-∞. Absolute systemic bioavailability of chloramphenicol was calculated from noncompartmental parameters with the following equation:

article image

Pharmacokinetic values are reported as the arithmetic mean of individually estimated parameters. Variability in pharmacokinetic parameters is expressed as the SD. For plasma half-life of chloramphenicol, the harmonic mean and pseudoSD are reported. The systemic bioavailability was calculated as the mean of the individual values from the 3 horses that received the IV formulation of chloramphenicol.

Results

No adverse effects were detected in any horse after PO or IV administration of chloramphenicol. The plasma concentration–time profiles of chloramphenicol after IV administration (Figure 1) and PO administration (Figure 2) were plotted. The plasma pharmacokinetic parameters for chloramphenicol after IV administration at a dose of 25 mg/kg and PO administration at a dose of 50 mg/kg were summarized (Table 1).

Figure 1—
Figure 1—

Mean ± SD plasma concentrations of chloramphenicol following IV administration of chloramphenicol sodium succinate (25 mg/kg [11.4 mg/lb]) to 3 healthy adult horses. Blood samples were collected prior to administration (0 minutes) and at 3, 5, 10, 15, 30, and 45 minutes and 1, 2, 4, and 8 hours after dose administration. The 8 points on the curve represent the points when chloramphenicol was detected (ie, at 0 minutes and 8 hours, no drug was detected).

Citation: Journal of the American Veterinary Medical Association 251, 1; 10.2460/javma.251.1.90

Figure 2—
Figure 2—

Mean ± SD plasma concentrations of chloramphenicol following PO administration of chloramphenicol base (mixed in a commercial suspending vehicle to make a solution; dose administered, 50 mg/kg [22.7 mg/lb]) to 5 healthy adult horses. Blood samples were collected prior to administration (0 minutes) and at 5, 10, 15, and 30 minutes and 1, 2, 4, 8, and 12 hours after dose administration. There was no drug detected at 0 minutes.

Citation: Journal of the American Veterinary Medical Association 251, 1; 10.2460/javma.251.1.90

Table 1—

Mean ± SD plasma pharmacokinetic parameters determined after PO administration of chloramphenicol base (50 mg/kg [22.7 mg/lb]) to 5 healthy adult horses or IV administration of chloramphenicol sodium succinate (25 mg/kg [11.4 mg/lb]) to 3 of those 5 horses.

ParameterChloramphenicol administered IVChloramphenicol administered PO
Terminal half-life* (h)0.88 ± 0.232.85 ± 1.32
Elimination rate constant (l/h)0.80 ± 0.200.24 ± 0.12
C0 (μg/mL)65.16 ± 15.50NA
Tmax (h)NA0.79 ± 0.64
Cmax (μg/mL)NA3.46 ± 1.43
CL (L/h/kg)1.03 ± 0.20NA
Vdss (L/kg)0.66 ± 0.11NA
Vdarea (L/kg)1.31 ± 0.17NA
AUC0-∞ (h·μg/mL)25.00 ± 5.2013.44 ± 5.27
%AUC extrapolated1.73 ± 2.0217.12 ± 1.32
MRT0-∞ (h)0.66 ± 0.0.165.82 ± 4.23
A (μg/mL)75.39 ± 17.22NA
B (μg/mL)4.54 ± 3.93NA
α (l/h)4.51 ± 1.79NA
β (l/h)0.63 ± 0.31NA
t1/2 α (h)0.17 ± 0.07NA
t1/2 β (h)1.35 ± 0.71NA
F (%)NA28 ± 10

For PO administration, blood samples were collected prior to administration (0 minutes) and at 5, 10, 15, and 30 minutes and 1, 2, 4, 8, and 12 hours. For IV administration, blood samples were collected prior to administration (0 minutes) and at 3, 5, 10, 15, 30, and 45 minutes and 1, 2, 4, and 8 hours.

Values are reported as harmonic mean ± pseudoSD.

%AUC extrapolated = Percentage of AUC extrapolated. A = Distribution intercept α = Distribution constant B = Elimination intercept β = Elimination constant. CL = Total body clearance. F = Systemic bioavailability. MRT0-∞ = Mean resident time from time 0 to infinity. NA = Not applicable. t1/2 = Plasma half-life, t1/2 α = Distribution half-life. t1/2 β = Elimination half-life.

Compartmental and noncompartmental models were used to evaluate plasma chloramphenicol concentrations after IV or PO administration. After IV administration, the harmonic mean ± pseudoSD plasma chloramphenicol half-life was 0.88 ± 0.23 hours. Mean ± SD Vdss and total body clearance for chloramphenicol after IV administration were 0.66 ± 0.11 L/kg and 1.03 ± 0.20 L/h/kg, respectively. Following PO administration, the mean systemic bioavailability was 28 ± 10% and the elimination half-life was 2.85 ± 1.32 hours.

Discussion

Chloramphenicol is a bacteriostatic drug that inhibits bacterial protein synthesis by binding the bacterial 50S ribosomal subunit.1,2 There is little antimicrobial resistance to chloramphenicol, and the drug is routinely administered PO in horses. The present study was performed to determine the pharmacokinetics of chloramphenicol when administered PO at a dose that is routinely given in clinical settings. Although chloramphenicol is relatively easy to administer because it can be given PO, precautions should be taken when handling chloramphenicol given that it has serious human health risks.3,4 Chloramphenicol should also be used with caution because it can affect the metabolism of other drugs. It is metabolized via the cytochrome P-450 enzyme pathway in the liver; administration of chloramphenicol concomitantly with other drugs that are metabolized by this pathway may result in higher concentrations of those drugs over a prolonged period and increased likelihood of toxicosis, especially in patients with liver injury13–15

As results of the present study indicated, chloramphenicol is rapidly cleared from plasma in horses and frequent administration would therefore be needed to maintain therapeutic plasma concentrations. Plasma half-life is a hybrid pharmacokinetic parameter determined by clearance and apparent volume of distribution. In turn, plasma clearance is the sum of different organ clearances (eg, hepatic and renal clearances), which are dependent on many factors including (for hepatic clearance) hepatic blood flow, intrinsic hepatic clearance, and free drug fraction in plasma. Intrinsic hepatic clearance reflects maximum metabolism capacity and the Michaelis-Menten metabolism constant, which is linked to drug affinity of the metabolic enzymatic system. Many factors also influence renal clearance. In addition, plasma half-life is also influenced by the extent of drug distribution, which in turn depends on the drug's affinity for circulating proteins. It is certainly possible that some of these processes could have been saturated, thereby creating a difference in half-lives of the chloramphenicol doses administered IV or PO in the present study.

The percentage of AUC extrapolated is a useful measure of precision estimates. If the percentage extrapolated is > 20%, then the total AUC may be unreliable because more samples would need to be collected during the elimination phase of the pharmacokinetic curve for an accurate estimate of the elimination rate constant and the observed AUC. In the present study, the percentage AUC extrapolated for either dose of chloramphenicol was < 20%, which is considered acceptable for studies conducted in veterinary medicine.

The systemic bioavailability of chloramphenicol following PO administration in horses in the present study was similar to previously reported values (21% to 40%).16 In the present study, the apparent volume of distribution was lower than previously reported (0.92 to 3.9 L/kg), suggesting possible lower tissue concentrations than previously thought.7,16–18 In the horses used in the present study, the chloramphenicol Cmax was much lower than that reported as the target therapeutic plasma concentration in humans (10 to 25 μg/mL).3,4 The chloramphenicol Cmax determined for the study horses was also lower than that determined in a previous study6 in which intragastric administration of a 50-mg/kg dose of chloramphenicol base or chloramphenicol palmitate maintained plasma concentrations > 5 μg/mL (when measured by colorimetry) for 8 hours in horses. In the present study, high-performance liquid chromatography was used in place of colorimetry, which achieved a lower limit of detection and allowed more precise and accurate measurement of chloramphenicol concentrations in plasma. Also, in the present study, only chloramphenicol base was used, but chloramphenicol palmitate, which is an ester of chloramphenicol base, should have values of Cmax similar to or less than those of chloramphenicol base. The chloramphenicol base suspension used in the present study was a compounded product that was not tested for potency or stability, which could have affected the results. The chloramphenicol suspension consisted of powdered chloramphenicola combined with a suspending vehicle.c Use of commercial powder versus commercial tablets allows for a more exact measurement and more uniform distribution of chloramphenicol in the suspension, compared with use of crushed tablets. The commercial suspending vehiclec was a water-based colloidal solution designed to minimize particle settling. Because chloramphenicol was a compounded product, it was given a 30-day expiration date from the day it was made, but both constituents (the chloramphenicol powder and suspending vehicle) had expiration dates that extended beyond that time frame. The University of Tennessee Veterinary Medical Center Pharmacy is a licensed pharmacy that meets all the Tennessee state requirements for compounding, and chloramphenicol suspension is compounded from bulk powder because a 500 mg/mL suspension cannot be obtained by use of commercially available tablets. It should be noted that this suspension is compounded for hospital patients only (when a prescription is presented) or for research purposes and is administered only to horses that are not intended for use as food animals.

Another factor was that food was not withheld from the horses to simulate how chloramphenicol is given in a clinical setting. This lack of food withholding could explain why the results of the present study were different from those of previous studies.

In the present study we evaluated a single dose of chloramphenicol, but the authors do not believe that multiple doses would have achieved higher plasma concentrations because previous studies15,16 with repeated intragastric administration of chloramphenicol in horses did not result in comparatively greater plasma concentrations; moreover, those studies15,16 revealed that absorption decreased with repeated intragastric dosing. Future research is needed to determine whether a higher dose of chloramphenicol, food withholding prior to drug administration, or administration of a different concentration or formulation of compounded chloramphenicol base would affect plasma concentration. Tissue sample analysis could also be performed to determine whether tissue concentrations of chloramphenicol differ from plasma concentrations.

There is a wide range of MICs for chloramphenicol among target bacteria, but a plasma concentration of 5 to 8 μg/mL is likely required for effective treatment. This does not mean Cmax would be theoretically ineffective for all organisms, as there have been lower MICs determined in vitro.6,7,16,19–23 It is the authors' recommendation to determine the drug's MIC for the target bacteria before initiating treatment with PO administration of chloramphenicol in adult horses.

Acknowledgments

The authors thank Celia Hurley and Lea Valentine for technical assistance.

ABBREVIATIONS

AUC

Area under the plasma concentration–time curve

AUC0-∞

Area under the plasma concentration–time curve from time 0 to infinity

AUMC

Area under the first moment curve

Cmax

Maximum plasma concentration

MIC

Minimum inhibitory concentration

Tmax

Time to maximum plasma concentration

Vdarea

Apparent volume of distribution

Vdss

Apparent volume of distribution at steady state

Footnotes

a.

MEDISCA Inc, Plattsburg, NY.

b.

APP Pharmaceuticals LLC, Lake Zurich, Ill.

c.

Ora-blend, Perigo Company PLC, Dublin, Ireland.

d.

2695 separations module, Waters, Milford, Mass.

e.

2487 UV detector, Waters, Milford, Mass.

f.

WinNonlin 5.2, Pharsight Corp, Mountain View, Calif.

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