Effect of sorbitol, single, and multidose activated charcoal administration on carprofen absorption following experimental overdose in dogs
Supported by the Companion Animal Fund, Michigan State University.
The authors declare no conflicts of interest.
Presented in part as a poster at the International Veterinary Emergency and Critical Care Symposium, San Antonio, Texas, September 2010.
Abstract
Objective
To compare the effectiveness of single dose activated charcoal, single dose activated charcoal with sorbitol, and multidose activated charcoal in reducing plasma carprofen concentrations following experimental overdose in dogs.
Design
Randomized, four period cross-over study.
Setting
University research setting.
Animals
Eight healthy Beagles.
Interventions
A 120 mg/kg of carprofen was administered orally to each dog followed by either (i) a single 2 g/kg activated charcoal administration 1 hour following carprofen ingestion (AC); (ii) 2 g/kg activated charcoal with 3.84 g/kg sorbitol 1 hour following carprofen ingestion (ACS); (iii) 2 g/kg activated charcoal 1 hour after carprofen ingestion and repeated every 6 hours for a total of 4 doses (MD); (iv) no treatment (control).
Measurements and Main Results
Plasma carprofen concentrations were obtained over a 36-hour period following carprofen ingestion for each protocol. Pharmacokinetic modeling was performed and time versus concentration, area under the curve, maximum plasma concentration, time to maximum concentration, and elimination half-life were calculated and compared among the groups using ANOVA followed by Tukey's multiple comparisons test. Activated charcoal, activated charcoal with sorbitol (ACS), and multiple-dose activated charcoal (MD) significantly reduced the area under the curve compared to the control group. AC and MD significantly reduced the maximum concentration when compared to the control group. MD significantly reduced elimination half-life when compared to ACS and the control group. There were no other significant differences among the treatment groups.
Conclusions
Activated charcoal and ACS are as effective as MD in reducing serum carprofen concentrations following experimental overdose in dogs. Prospective studies are warranted to evaluate the effectiveness of AC, ACS, and MD in the clinical setting.
Abbreviations
-
- AC
-
- activated charcoal
-
- ACS
-
- activated charcoal with sorbitol
-
- AUC
-
- area under the curve
-
- Cmax
-
- maximum plasma concentration
-
- MD
-
- multiple-dose activated charcoal
-
- Tmax
-
- time to maximum concentration
-
- T ½
-
- elimination half-life
Introduction
Activated charcoal is routinely administered in acutely poisoned people and veterinary patients to reduce the absorption of toxicants. Activated charcoal is composed of small granules of carbon allowing for a large surface area and many binding sites for adsorption of toxicants.1 The most commonly used form of activated charcoal is a suspension that is available with or without the addition of a cathartic such as sorbitol.
Carprofen is one of the most commonly used nonsteroidal anti-inflammatory medications in veterinary medicine.2 It can be administered subcutaneously or orally, and it is readily absorbed when administered orally.3 Carprofen is a racemic mixture of 2 enantiomers (S) and (R), with 34% of the (S) enantiomer undergoing enterohepatic recirculation.4 Carprofen comes as a pill or flavored chewable tablet, which makes accidental ingestion more likely.
Recently, a single dose of activated charcoal was shown to decrease the absorption of orally administered carprofen in dogs.5 Additionally, a separate study showed that activated charcoal is as effective as emesis followed by activated charcoal at reducing carprofen absorption.6 Both of these studies used small overdoses of carprofen (15 and 16 mg/kg), so the effect of charcoal on large overdoses remains unknown.5, 6 Also, these studies did not investigate the efficacy of multiple dose versus single dose activated charcoal at reducing the absorption of carprofen. Because carprofen undergoes enterohepatic circulation, the standard of care for dogs presenting with carprofen toxicosis has been to administer activated charcoal every 6 hours for 24–48 hours. Currently, multiple dose activated charcoal is only recommended in a few specific drug overdoses in people.7 These drugs include carbamazepine, dapsone, phenobarbital, quinine, and theophylline; all of these drugs undergo extensive enterohepatic circulation.7 No specific recommendations are available in veterinary medicine other than to use multiple doses of activated charcoal in animals that have ingested overdoses of drugs that undergo enterohepatic circulation.8 Studies in people have evaluated serum concentrations of toxicant following administration of a single dose of activated charcoal from 1 to 5 hours posttoxicant ingestion.1 These studies suggest that administration of activated charcoal greater than one hour postingestion does not significantly reduce absorption of the toxicant.1
In the clinical setting, multiple-dose activated charcoal administration is associated with significant stress to the patient (if feeding is required), a risk of aspiration, and significant time commitment for the veterinary healthcare team. If multiple-dose charcoal were unnecessary, savings would be noted in cost of delivery of care and client cost (additional time in the hospital, additional cost of activated charcoal). Risk to the patient would also be minimized.
Cathartics such as sorbitol have been used in both human and veterinary medicine to decrease gastrointestinal transit time and therefore reduce toxicant absorption. Studies in animals and people have shown that cathartics alone are not an effective treatment in the acutely poisoned patient.9 Activated charcoal with a cathartic has been associated with a higher complication rate than activated charcoal alone in people.9 These complications include nausea, abdominal cramps, vomiting, and transient hypotension.10-12 Multiple or excessive doses of cathartics have caused dehydration and electrolyte imbalances.13 The effect of sorbitol on the binding of activated charcoal to carprofen has not been investigated. Additionally, the adverse effects of activated charcoal with sorbitol compared to those of activated charcoal alone have not been evaluated in the dog.
We hypothesized that a single dose of activated charcoal alone would be as effective as multiple-dose activated charcoal or activated charcoal with sorbitol at reducing serum carprofen concentration following experimental overdose in healthy dogs. We also hypothesized that activated charcoal would be associated with fewer gastrointestinal adverse effects than multi-dose activated charcoal or activated charcoal with sorbitol.
Materials and Methods
This study protocol was approved by the Institutional Animal Care and Use Committee. Eight healthy, fasted, adult, purpose-bred dogs were used in a randomized, four period cross-over study such that 2 dogs received each treatment during a given treatment period with a 2 week wash-out interval between each of the 4 study periods. For each study period, dogs were administered 120 mg/kg of carprofen1 orally followed by one of the following 4 treatments: (i) a single 2 g/kg dose of activated charcoal2 alone 1 hour following carprofen administration (AC, activated charcoal); (ii) a single 2 g/kg dose of activated charcoal with 3.84 g/kg sorbitol3 1 hour following carprofen administration (ACS, activated charcoal with sorbitol); (iii) 2 g/kg activated charcoal 1 hour after carprofen administration and repeated every 6 hours for a total of 4 treatments (MD, multiple-dose activated charcoal); (iv) no treatment (control). Blood was collected for serum carprofen concentration measurement at time 0; 30 minutes; and 1, 2, 4, 6, 8, 12, 24, and 36 hours postcarprofen administration. At each time point, 3 mL whole blood was collected from each dog into lithium heparin tubes via jugular venipuncture. These samples were centrifuged and the supernatant (plasma) was collected and frozen at –20°C prior to analysis. Serum was also collected 3 days prior to each study period for evaluation of a serum biochemistry profile.
Dogs were observed for gastrointestinal side effects (vomiting, diarrhea, anorexia, abdominal discomfort) and overall activity level at each blood collection time point and then every 12 hours for an additional 72 hours following the last blood collection time.
Sample preparation for plasma carprofen measurement
One gram of plasma was weighed into a glass, screw-cap test tube, and 1 mL of 1% ascorbic acid in 0.1 N hydrochloric acid and 10 mL of ethyl acetate were added. This sample was centrifuged at 830 × g for 5 minutes. An aliquot (8 mL) of the extract was evaporated to dryness using a nitrogen evaporator4 set at 60oC, and redissolved in 0.4 mL of 1 μg/mL d3-carprofen,5 internal standard (IS) solution in 50% methanol in water. The mixture was vortexed for 10 seconds and filtered through a 0.45 μm high performance liquid chromatography (HPLC) filter6 into a glass autosampler vial. All control and fortified samples were prepared in the same manner.
Liquid Chromatography-Mass Spectrometer/Mass Spectrometer Analysis: An Agilent Model 1100 (binary) high performance liquid chromatograph coupled with a hybrid triple quadrupole/linear ion trap mass spectrometer, model 4000 Q TRAP,7 was used for all analyses. The analytical column was a 20 × 2 mm × 3 μ Luna C18(2).8 The injection volume was 20 μL. The mobile phase consisted of: (A) 0.01 M ammonium acetate in 0.1% formic acid in water (v/v); (B) 0.01 M ammonium acetate in 0.1% formic acid in methanol (v/v) at a flow rate of 300 μL/min under a linear gradient of 50% B to 95% B over 7 min. Mass spectral data were acquired in the negative ion electrospray ionization mode, using the enhanced product ion scan function. The precursor ions of carprofen and d3-carprofen were the [M-H]− ions of m/z 272 and m/z 277, respectively. Product ions of m/z 226 for carprofen, and m/z 233 for d3-carprofen were used for quantitation. Each set of samples contained a reagent blank, negative control, duplicate, and fortified samples. Quantification was by comparison with a 7-point calibration curve using external standards in matching matrix and linear regression using the Analyst (version 1.4) software.
Statistical methods
All data analysis was performed using commercial software.9 The data from plasma carprofen concentrations were fitted to a pharmacokinetic model and area under the curve (AUC), maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and elimination half-life (T ½) were calculated. These values were compared among the groups using ANOVA followed by Tukey's multiple comparison test. The frequency of each gastrointestinal complication (vomiting, diarrhea, abdominal discomfort, and anorexia) was compared among the groups using ANOVA followed by Tukey's multiple comparison test. All data were assessed for normality using D'Agostino and Pearson omnibus normality test. Data are presented as mean ± standard deviation. P < 0.05 was considered significant.
Results
The actual dose of carprofen administered ranged from 119 mg/kg to 121.2 mg/kg with a mean dose of 119.9 mg/kg. AC, ACS, and MD significantly reduced AUC compared to the control group. AC and MD, but not ACS, significantly reduced Cmax when compared to the control group. There were no differences in AUC or Cmax among the AC, ACS, and MD groups. MD significantly reduced T ½ when compared to the control group. T ½ did not differ significantly among AC, ACS, and the control group. Tmax was not affected by any treatment (Table 1).
| Single dose activated charcoal (AC) | Activated charcoal and sorbitol (ACS) | Multidose activated charcoal (MD) | Control | |
|---|---|---|---|---|
| AUC (ppm/L × h) | *1,475 ± 707 | *2,554 ± 1159 | *1,256 ± 637 | 4,041 ± 1,179 |
| Cmax (ppm) | *79.5 ± 28.9 | 114 ± 32.8 | *103.4 ± 26.5 | 150 ± 42.9 |
| T ½ (h) | 8.6 ± 3.8 | 13.9 ± 7 | *6 ± 2.9 | 15.8 ± 8.2 |
| Tmax (h) | 3.9 ± 2.5 | 2.8 ± 1.7 | 2.7 ± 1.1 | 4.5 ± 2.5 |
- Data are presented as mean ± standard deviation. *Indicates a significant difference from the control group (AUC, area under the curve; Cmax, maximum plasma concentration; T½, elimination half-life; Tmax, time until maximum concentration).
Gastrointestinal side effects
All dogs had normal appetites during the entire study period. There was no significant abdominal discomfort noted on abdominal palpation at any time point, or were there increased in hepatic enzymes activities at any of the 4 time points (3 days prior to each study period) evaluated during the study.
There were significantly more episodes of diarrhea in the MD compared to both the AC and ACS, but not compared to the control. There was not a significant difference in number of episodes of diarrhea when AC, ACS and the control group were compared. Compared to AC, ACS, and the control group, there were significantly more episodes of vomiting in the MD group. There was no significant difference in frequency of vomiting among the AC, ACS and control groups (Table 2).
| Single dose activated charcoal (AC) | Activated charcoal and sorbitol (ACS) | Multidose activated charcoal (MD) | Control | |
|---|---|---|---|---|
| Change in appetite | 0 | 0 | 0 | 0 |
| Abdominal discomfort | 0 | 0 | 0 | 0 |
| Vomiting | 1.4 ± 1.4 | 1.6 ± 1.3 | §6.1 ±2.3 | 1.8 ± 1.6 |
| Diarrhea | 0 | 0 | *0.9 ± 0.8 | 0.5 ± 0.5 |
- Data are presented as mean ± standard deviation. *Indicates a significant difference from AC and ACS treatment groups. §Indicates a significant difference from AC, ACS, and control groups.
Discussion
In this study, a single dose of activated charcoal was as effective as multiple doses of activated charcoal in reducing both AUC and Cmax in an experimental model of carprofen overdose. When sorbitol was combined with activated charcoal, AUC but not Cmax was reduced when compared to the control. Significantly more gastrointestinal side effects were also seen in the MD group compared to the other treatment groups.
A much larger overdose of carprofen was used in this study than in previously published studies.5, 6 The large overdose was used because in previous studies low concentrations of carprofen were detected in blood for only 6 hours after carprofen ingestion in the dogs that were treated with activated charcoal.5, 6 In order to evaluate the effects of multidose activated charcoal, a larger dose was used to ensure that plasma carprofen concentrations would still be detectable during the entire time the multiple doses of charcoal were to be administered. Additionally, safety studies performed for licensing of carprofen use showed that single overdoses of carprofen up to 160 mg/kg resulted in few side effects, which were limited to vomiting and diarrhea.10 Based on this safety study and previous data regarding carprofen concentrations following single dose activated charcoal administration, we chose a dose of 120 mg/kg for this study to ensure that the dogs would experience minimal side effects while carprofen blood concentrations would be high enough to evaluate the effectiveness of multidose activated charcoal.
Multiple-dose activated charcoal has been evaluated in human and animal studies with conflicting results.5 In a study by Eddleston et al,14 no difference in mortality was found among people presenting for oleander, organophosphate, or carbamate ingestion, or unknown self-poisoning who received single-dose activated charcoal versus multi-dose activated charcoal versus no activated charcoal14 In contrast, a study by de Silva et al15 found that multi-dose activated charcoal significantly reduced mortality when compared to single-dose activated charcoal in patients presenting for yellow oleander poisoning.15 The results of the current study suggest that multi-dose activated charcoal may not be necessary in previously healthy dogs that ingest carprofen when treatment is initiated within one hour. Multi-dose activated charcoal may still be indicated when dogs ingest higher doses than evaluated in this study or in dogs with underlying disease that may predispose them to the adverse effects of carprofen overdose.
While addition of a cathartic can be associated with abdominal discomfort in people, we did not observe any abdominal pain or increase in frequency of vomiting or diarrhea in the current study when the dogs received sorbitol. The lack of abdominal discomfort may be true or may be a reflection of the insensitive measures used to monitor for abdominal discomfort in this study. In addition, the use of sorbitol in combination with activated charcoal was not associated with a higher incidence of adverse gastrointestinal events, as has been previously reported in human studies.9 In our study, significantly more episodes of vomiting were seen in the MD group compared to the 2 other treatment groups that received single doses of activated charcoal. This increase in vomiting is clinically important because it may put the patient at higher risk for aspiration.
Addition of a cathartic to the first dose of activated charcoal has been suggested to reduce gastrointestinal transit time, and therefore reduce toxicant absorption.9 However, routine use of a cathartic is not recommended in people due to a lack of data supporting any benefit of its use in acute intoxications.9 Additionally, cathartics may inhibit the binding of some toxicants to activated charcoal.16-18 Activated charcoal with sorbitol (ACS) reduced the area under the curve when compared to the control, but it did not reduce Cmax when compared to the control. In contrast, activated charcoal alone reduced both AUC and Cmax when compared to the control. While there were no significant differences in either AUC or Cmax when ACS was compared to AC, the lack in reduction of Cmax when ACS was compared to the control group suggests that the use of sorbitol with activated charcoal may inhibit some of the effects of activated charcoal. At a minimum, activated charcoal alone is at least as effective as activated charcoal with sorbitol for moderate carprofen overdose in dogs.
Conclusions
The results of this study suggest that single-dose activated charcoal alone is as effective as either multi-dose activated charcoal or activated charcoal with sorbitol in reducing serum carprofen concentration following moderate experimental overdose in healthy dogs. Further clinical studies are needed to evaluate these different treatment regimens in dogs that receive accidental overdosage in the face of chronic carprofen administration; have concurrent gastrointestinal, hepatic, or renal dysfunction; or in dogs that ingest larger overdoses. In addition, further studies investigating traditional gastrointestinal decontamination strategies such as emesis, the use of sorbitol with activated charcoal, and administration of multiple doses of activated charcoal in other types of toxicant exposure are warranted.
Acknowledgments
The authors would like to thank Elizabeth Tor and John Tahara for their assistance in measuring carprofen concentrations.
