Carprofen is an NSAID of the propionic acid class. Oral administration of carprofen can be used for various indications in dogs, such as treatment of chronic orthopedic pain1,2 and perioperative pain.3–5 Carprofen is absorbed rapidly6–8 and effectively6,8 following oral administration. A highly palatable formulation has become available commercially, making administration of the drug to dogs easier for owners. However, owner carelessness has led to cases of accidental overdoses (eg, through negligent storage of the preparation).
Some NSAIDs have been associated with gastrointestinal tract and renal toxicoses because of the inhibition of the enzyme cyclooxygenase, which results in decreased prostaglandin production. Carprofen is generally considered to be well tolerated in dogs,1,2,6,9 but some severe adverse effects, such as hepatocellular toxicosis,10 have been described despite administration of appropriate doses. In 1 safety study,11 carprofen was clinically well tolerated by dogs and no gross or histologic changes were detected after as much as 5.7 times the recommended total daily dose was administered for several weeks. Carprofen has low toxic potential following single-dose administration; the oral LD50 in mice and rats is 282 mg/kg and 149 mg/kg, respectively.12 Even smaller overdoses can be expected to be injurious to dogs. Therefore, more information is needed about practical management of ingested overdoses of carprofen to reduce possible adverse effects.
Carprofen is metabolized in dogs via conjugation and oxidation and is excreted predominantly in feces after biliary secretion.7,12 After IV administration of a dose of the drug, approximately 70% is excreted in feces and 8% to 15% is excreted in urine.7 Carprofen undergoes notable enterohepatic recycling in dogs.13,14 In samples of canine urine, both unchanged carprofen and its metabolites can be detected for as long as 48 hours and the major metabolite can be detected for > 72 hours after administration of the drug.15
Oral administration of AC (dose, 1 to 8 g/kg) is recommended for treatment of drug overdoses in dogs.16,17 It acts by binding the drug (thereby preventing its absorption from the gastrointestinal tract) and by interrupting enterohepatic recycling. However, reports of the efficacy of orally administered AC with regard to the kinetics of carprofen are not yet available, to our knowledge.
Most NSAIDs, including carprofen, act as weak organic acids. Urine alkalization is cited as a method for improving the elimination of weak acids, such as salicylate, although the mechanisms have not yet been clarified.18 Dog owners often have sodium bicarbonate readily available at home. This substance could be administered as a first aid treatment for dogs in an overdose situation, especially as potential adverse effects of sodium bicarbonate administration (such as those that could develop following aspiration of the agent) might be less than the effects of AC administration. The dosage used for urine alkalization in dogs is 10 to 50 mg of sodium bicarbonate/kg administered orally 2 to 3 times daily.19 However, we are not aware of any reports of controlled studies regarding the effects of urine alkalization on the elimination of carprofen in dogs.
Although gastric evacuation via induced emesis could also be considered a first aid measure, emesis is probably most efficient if induced within the first hour after ingestion of carprofen because of the rapid absorption of the drug after oral administration.6–8 However, induction of emesis may still be useful to some extent at a later time after exposure if some quantities of the medication remain in the stomach as a result of delayed gastric emptying (caused by the presence of food or large amounts of tablets20).
The purpose of the study reported here was to investigate the effects of oral administration of AC and urine alkalinization (via oral administration of sodium bicarbonate) on the pharmacokinetics of carprofen after oral administration of a single, high dose in dogs. Our hypothesis was that both treatments would effectively decrease plasma carprofen concentrations.
Materials and Methods
Animals—Six purpose-bred neutered male Beagles were used in the study. The dogs were 9 to 11 years old and weighed 13.2 to 20.7 kg. For all dogs, serum biochemical analyses and urinalyses were performed prior to each experiment and revealed no clinicopathologic findings that were suggestive of renal or hepatic disease. The dogs were routinely housed and maintained in groups; they received commercial food, and water was provided ad libitum. On the day of each experiment, the dogs were not fed until 8 hours after drug administration and were placed in separate cages for the first 24 hours after drug administration. Feces were collected immediately after defecation during the first 8 hours after administration of carprofen to prevent the dogs from ingesting the excreta. The study protocol was approved by the Ethics Committee for Animal Experiments of the University of Helsinki.
Study design and procedures—A controlled crossover study (Latin square design) was applied. Three experiments were performed with each dog. The washout period between experiments was at least 6 weeks. Each dog received a single dose of carprofena orally at the beginning of each experiment; the halved tablets (100 mg/tablet) were ingested willingly and quickly. The accuracy of dosing was 50 mg for each dog, and the mean ± SD actual dose of carprofen administered among the dogs in each experiment was 16.2 ± 0.8 mg/kg.
For experiment 1, sodium bicarbonate (40 mg/kg) was administered orally 30 minutes after carprofen administration. Sodium bicarbonate was diluted in 10 mL of water and sprayed gradually into the dog's mouth with a syringe. For experiment 2, standard AC solutionb (approx 2.5 g/kg) mixed with 250 mL of water was administered via bottle feeding 30 minutes after carprofen administration. The AC solution was administered within approximately 5 minutes, and the dogs did not markedly resist swallowing the solution. For experiment 3, no medication other than carprofen was administered (control treatment).
During each experiment, blood samples (4 mL each) were collected into tubes containing heparin at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, and 48 hours after carprofen administration. Plasma was separated via centrifugation and stored at −20°C until analyzed. Plasma concentrations of unchanged carprofen were determined via high-performance liquid chromatography according to a method described for ketoprofen21 with slight modifications. Determinations were carried out on 2 plasma samples in parallel. The high-performance liquid chromatography system was equipped with a piston pump,c an autosampler,d an absorbance detector,e and a workstation.f Sample separation was conducted on a 4.6 X 150-mm column packed with 5 Mm of reversed-phase silica.g The flow rate of the isocratic mobile phase (acetonitrile and 0.03% phosphoric acid [1:1]) was 1.5 mL/min. The analytical wavelength was 254 nm. The method was validated as recommended for bioanalytical assays.22
Samples of urine were collected during episodes of spontaneous voiding 1 to 2 days before each experiment and at 4 to 6 hours, 6 to 8 hours, and 1 and 2 days after administration of carprofen. Urine pH was measuredh in each sample. Some samples were not available because not all dogs urinated at every sampling period.
In addition, glomerular filtration rate was measured by means of plasma iohexol clearance 1 to 2 days before each experiment and during the third day after carprofen administration. After experiments 1 and 3, dogs were anesthetized and a kidney biopsy specimen was collected for other investigations by use of a laparoscopic method; the detailed methods and results are not included in this report.
Pharmacokinetic parameters and statistical analysis—Elimination half-life and AUC0–∞ for carprofen in plasma were determined.i All plasma carprofen concentrations at all time points were used to calculate pharmacokinetic parameters. The AUC0–∞ was calculated by use of the trapezoidal method. Maximum plasma concentration and Tmax for carprofen were determined directly from individual time versus plasma concentration curves. Statistical analyses were carried out by use of a Student paired t test or Wilcoxon matched-pairs rank test. To assess bioequivalence, a 90% confidence interval was calculated for AUC0–∞ (log transformed). The reference confidence interval was 0.8 to 1.25. Significance was set at a value of P < 0.05.
Results
Orally administered AC significantly decreased the Cmax value of carprofen in the group of study dogs, compared with findings after control treatment; however, the elimination half-life and Tmax remained similar in both treatment groups (Table 1). In all groups, plasma concentrations of carprofen at 48 hours were extremely low or below the limit of detection of the assay, as expected. Oral administration of sodium bicarbonate had no effect on plasma concentration or elimination of carprofen (Figure 1). A second peak in plasma carprofen concentration profiles was evident in 3 dogs at 2.2 ± 0.3 hours after administration of carprofen followed by sodium bicarbonate (experiment 1), in 1 dog at 8 hours after administration of carprofen followed by AC solution (experiment 2), and in 4 dogs at 2.7 ± 0.9 hours after administration of carprofen alone (experiment 3; Figure 2). Equivalence of AUC0–∞ was attained between sodium bicarbonate and control treatments (90% confidence interval, 0.84 to 1.16) but not between AC and control treatments (90% confidence interval, 0.29 to 0.48).
Pharmacokinetic parameters (mean ± SD) of carprofen in plasma obtained from 6 dogs after oral administration of a single dose of the drug (approx 16 mg/kg) followed by oral administration of sodium bicarbonate (40 mg/kg) or AC solution (2.5 g/kg) 30 minutes later or no additional treatment (control).
| Parameter | Treatment | ||
|---|---|---|---|
| Sodium bicarbonate | AC solution | ||
| T1/2 (h) | 7.1 ± 2.0 | 6.9 ± 1.4 | 7.2 ± 1.8 |
| Tmax (h) | 1.3 ± 0.4 | 1.0 ± 0 | 1.4 ± 0.5 |
| Cmax (mg/L) | 87.0 ± 14.5 | 58.1 ± 17.6* | 85.9 ± 11.9 |
| AUC0-∞(mg/L·h) | 936 ±171 | 373 ± 133* | 960 ± 233 |
Value significantly (P < 0.05) different from that after control treatment.
T1/2 = Elimination half-life.
Mean ± SEM plasma carprofen concentration in 6 dogs after oral administration of a single dose of the drug (approx 16 mg/kg; time 0 h) followed by oral administration of sodium bicarbonate (40 mg/kg; triangles) or AC solution (2.5 g/kg; squares) 30 minutes later or no additional treatment (control; diamonds). Although all plasma carprofen concentrations at all time points were used to calculate pharmacokinetic parameters, values at 48 hours were extremely low or below the limit of detection of the assay and are not shown in this figure.
Citation: American Journal of Veterinary Research 68, 4; 10.2460/ajvr.68.4.423
Mean ± SEM plasma carprofen concentration in 6 dogs after oral administration of a single dose of the drug (approx 16 mg/kg; time 0 h) followed by oral administration of sodium bicarbonate (40 mg/kg; triangles) or AC solution (2.5 g/kg; squares) 30 minutes later or no additional treatment (control; diamonds). Although all plasma carprofen concentrations at all time points were used to calculate pharmacokinetic parameters, values at 48 hours were extremely low or below the limit of detection of the assay and are not shown in this figure.
Citation: American Journal of Veterinary Research 68, 4; 10.2460/ajvr.68.4.423
Mean ± SEM plasma carprofen concentration in 6 dogs after oral administration of a single dose of the drug (approx 16 mg/kg; time 0 h) followed by oral administration of sodium bicarbonate (40 mg/kg; triangles) or AC solution (2.5 g/kg; squares) 30 minutes later or no additional treatment (control; diamonds). Although all plasma carprofen concentrations at all time points were used to calculate pharmacokinetic parameters, values at 48 hours were extremely low or below the limit of detection of the assay and are not shown in this figure.
Citation: American Journal of Veterinary Research 68, 4; 10.2460/ajvr.68.4.423
Changes in plasma carprofen concentrations in 6 dogs after oral administration of a single dose of the drug (approx 16 mg/kg; time 0 h) followed by no additional treatment (control; A) or oral administration of sodium bicarbonate (40 mg/kg; B) or AC solution (2.5 g/kg; C) 30 minutes later. Although all plasma carprofen concentrations at all time points were used to calculate pharmacokinetic parameters, values at 48 hours were extremely low or below the limit of detection of the assay and are not shown in this figure.
Citation: American Journal of Veterinary Research 68, 4; 10.2460/ajvr.68.4.423
Changes in plasma carprofen concentrations in 6 dogs after oral administration of a single dose of the drug (approx 16 mg/kg; time 0 h) followed by no additional treatment (control; A) or oral administration of sodium bicarbonate (40 mg/kg; B) or AC solution (2.5 g/kg; C) 30 minutes later. Although all plasma carprofen concentrations at all time points were used to calculate pharmacokinetic parameters, values at 48 hours were extremely low or below the limit of detection of the assay and are not shown in this figure.
Citation: American Journal of Veterinary Research 68, 4; 10.2460/ajvr.68.4.423
Changes in plasma carprofen concentrations in 6 dogs after oral administration of a single dose of the drug (approx 16 mg/kg; time 0 h) followed by no additional treatment (control; A) or oral administration of sodium bicarbonate (40 mg/kg; B) or AC solution (2.5 g/kg; C) 30 minutes later. Although all plasma carprofen concentrations at all time points were used to calculate pharmacokinetic parameters, values at 48 hours were extremely low or below the limit of detection of the assay and are not shown in this figure.
Citation: American Journal of Veterinary Research 68, 4; 10.2460/ajvr.68.4.423
Compared with findings after dogs received the control treatment, the pH value in urine samples collected 4 to 6 hours after carprofen administration from dogs that received treatment with sodium bicarbonate was significantly (P = 0.009) higher (7.22 ± 0.61 vs 6.14 ± 0.42). After AC treatment, the pH value in urine was significantly lower than baseline (7.60 ± 0.79) at 4 to 6, 6 to 8, and 24 hours (6.04 ± 0.21, 6.21 ± 0.74, and 5.73 ± 0.33, respectively). Similar changes were detected in dogs receiving the control treatment, but the differences were not significant, possibly because of some missing samples.
Discussion
In the present study, orally administered AC solution proved to be effective in decreasing plasma carprofen concentration after oral administration of that drug in dogs, probably by preventing primary drug absorption. The AUC0–∞ of carprofen was more than halved by administration of the AC solution, which is a clinically important response. The Cmax of carprofen was not much greater than the plasma carprofen concentration detected at the time of AC administration (30 minutes after administration of carprofen), indicating that oral administration of AC prevented further absorption of carprofen quickly and effectively. It can be expected that gastric emptying of carprofen tablets took longer than an hour.20 Thus, AC could have bound a considerable amount of carprofen in the stomach, when it was administered after a 30-minute period, and prevented intestinal absorption of the drug. The second peak in plasma carprofen concentration profiles detected after control and sodium bicarbonate treatments may have been caused by enterohepatic recirculation. Interestingly, that double peak was not detected after oral administration of AC solution. However, enterohepatic recirculation should be confirmed after IV administration of carprofen. Administration of AC did not influence the elimination half-life of carprofen, and the shapes of the elimination phases in time versus plasma concentration curves were similar after each treatment, suggesting that clearance of carprofen remained unchanged. Activated charcoal has not been reported to affect clearance of other NSAIDs.23
Oral administration of sodium bicarbonate had no effect on the Cmax value and AUC0–∞ of carprofen, compared with findings following control treatment. On the basis of the pH partition theory, carprofen could have been excreted via the kidneys more effectively into alkaline urine. Theoretically, when urine pH increases from 6.1 to 7.2 (as were the mean urine pH values among the study dogs after control and bicarbonate treatments, respectively), the excretion of a weak acid, such as carprofen (pKa, 4.39), into urine could increase by a factor of approximately 10. In another study15 in dogs, urine carprofen concentration peaked at 4 hours after oral administration; this corresponds to the time at which the sodium bicarbonate–induced change in urine pH was detected in the dogs of the present study. It has also been suggested, however, that urine alkalization could not significantly increase the extent of ionization of salicylic acid further, as it is almost completely ionized within physiologic pH limits.18 As an acid, the same apparently applies to carprofen. Thus, the conventional view of the mechanism by which urine alkalinization is effective is apparently impossible, and the mechanisms by which urine alkalinization enhances salicylate elimination are still unknown.18 When sodium bicarbonate is administered orally soon after carprofen ingestion, it could also enhance dissolution of the poorly soluble carprofen in the gastrointestinal tract, thereby affecting bioavailability of the acidic drug. However, no significant effects in the extent of drug absorption (AUC0–d) or in the absorption rate (Tmax) were detected in the present study.
In the study of this report, the elimination half-life of carprofen did not differ between treatments and was similar to findings of other studies6,8,24 after oral administration of the drug in dogs. With the dose of carprofen used in our study (approx 16 mg/kg), the increase in AUC0–∞ was linear, compared with the time versus plasma concentration curves reported previously for doses of 0.7 and 4.0 mg of carprofen/kg in dogs.6 When our results are combined with earlier findings,6,7 it seems that in dogs, at least for a dose range of 0.7 to 16 mg/kg, plasma carprofen concentrations are proportional to dose, whereas elimination half-life is independent of dose.
We chose aged dogs for our study because carprofen is widely used to treat chronic orthopedic pain in elderly dogs and owners of those dogs are more likely to have large amounts of this drug available at home. The dose of carprofen used was 4 times as great as that usually recommended for oral administration in dogs and was selected to ensure that the plasma concentrations would be sufficiently high to be accurately detected and reflect marked changes in plasma concentration of carprofen that could potentially occur after administration of AC solution or sodium bicarbonate. However, it was also important to avoid development of toxicoses or tissue damage in the study dogs. In an earlier report,6 carprofen was tolerated well when administered orally at a daily dose of 9.0 mg/kg for 14 days in healthy Beagles, and in a safety study,11 doses as great as 25.3 mg of carprofen/kg/d for several weeks were tolerated well clinically in dogs. For the dogs used in the present study, routine serum biochemical analyses and urinalyses before any of the experiments revealed no exceptional findings; this suggested that they had fully recovered from each treatment during the 6-week washout periods.
Our data have indicated that oral administration of AC solution can be valuable clinically in reducing systemic carprofen absorption following acute overdose in dogs if the solution is administered soon after carprofen ingestion. By contrast, oral administration of sodium bicarbonate had no effect on plasma carprofen concentration, at least when administered as a single dose.
ABBREVIATIONS
| NSAID | Nonsteroidal anti-inflammatory drug |
| AC | Activated charcoal |
| AUC0–∞ | Area under the time-concentration curve |
| Tmax | Time to peak plasma concentration |
| Cmax | Maximum plasma concentration |
Rimadyl vet chewables, 100 mg, Pfizer, Espoo, Finland.
Carbo-mix, Leiras Finland, Turku, Finland.
Waters 501 piston pump, Waters Corp, Milford, Mass.
Waters 717 autosampler, Waters Corp, Milford, Mass.
Waters 486 tunable absorbance detector, Waters Corp, Milford, Mass.
Millennium 32 Chromatography Manager workstation, Waters Corp, Milford, Mass.
SunFire C18, Waters Corp, Milford, Mass.
pH-Meter CG843, Schott, Meinz, Germany.
KineticaTM program, Thermo Electron Corp, Waltham, Mass.
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