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Effects of urine alkalization and activated charcoal on the pharmacokinetics of orally administered carprofen in dogs

DOI:10.2460/ajvr.68.4.423
Authors:
Marja R Raekallio at University of Helsinki
Marja R Raekallio
Juhana M Honkavaara
Juhana M Honkavaara
Juhana M Honkavaara
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Mia S Säkkinen
Mia S Säkkinen
Mia S Säkkinen
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Marikki Peltoniemi at The Pharmaceutical Learning Centre
Marikki Peltoniemi
  • The Pharmaceutical Learning Centre
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Abstract

To investigate the effects of oral administration of activated charcoal (AC) and urine alkalinization via oral administration of sodium bicarbonate on the pharmacokinetics of orally administered carprofen in dogs. 6 neutered male Beagles. Each dog underwent 3 experiments (6-week interval between experiments). The dogs received a single dose of carprofen (16 mg/kg) orally at the beginning of each experiment; after 30 minutes, sodium bicarbonate (40 mg/kg, PO), AC solution (2.5 g/kg, PO), or no other treatments were administered. Plasma concentrations of unchanged carprofen were determined via high-performance liquid chromatography at intervals until 48 hours after carprofen administration. Data were analyzed by use of a Student paired t test or Wilcoxon matched-pairs rank test. Compared with the control treatment, administration of AC decreased plasma carprofen concentrations (mean +/- SD maximum concentration was 85.9 +/- 11.9 mg/L and 58.1 +/- 17.6 mg/L, and area under the time-concentration curve was 960 +/- 233 mg/L x h and 373 +/- 133 mg/L x h after control and AC treatment, respectively). The elimination half-life remained constant. Administration of sodium bicarbonate had no effect on plasma drug concentrations. After oral administration of carprofen in dogs, administration of AC effectively decreased maximum plasma carprofen concentration, compared with the control treatment, probably by decreasing carprofen absorption. Results suggest that AC can be used to reduce systemic carprofen absorption in dogs receiving an overdose of carprofen. Oral administration of 1 dose of sodium bicarbonate had no apparent impact on carprofen kinetics in dogs.
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1
Journal papers
2008 or in print
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2
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4
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5
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6
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Third International Conference on Antimicrobial Agents in Veterinary Medicine
(AAVM), Orlando, Florida, USA 16-20.5.2006.
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Biopsy in Dogs. ScandLas meeting: 36th Symposium on Laboratory Animal
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... 9,10 These decontamination methods have been proven to cause a reduction in plasma carprofen concentration. 10 Intravenous lipid emulsion (ILE) is also used for treating NSAID toxicosis in dogs. A dog with ibuprofen toxicosis 11 and three dogs with naproxen toxicosis 12 were treated successfully with ILE in combination with GID. ...
... 5 It is possible the administration of activated charcoal prior to measuring carprofen levels and beginning ILE contributed to the reduced plasma carprofen concentrations. Several studies in dogs have shown that AC reduces plasma carprofen concentrations 10,30 ; however, the effectiveness of AC in reducing carprofen concentration has not been investigated in cats to the authors' knowledge. ...
Use of intravenous lipid therapy in a cat with carprofen overdose
Article
Full-text available
  • Feb 2020
Intravenous lipid emulsion (ILE) was administered to a cat with no adverse effects. This case report postulates that ILE can be used for the treatment of carprofen toxicity in cats and supports the lipid sink theory as the main mechanism of action. Intravenous lipid emulsion (ILE) was administered to a cat with no adverse effects. This case report postulates that ILE can be used for the treatment of carprofen toxicity in cats and supports the lipid sink theory as the main mechanism of action.
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Systematic review on the use of activated charcoal for gastrointestinal decontamination following acute oral overdose
Article
Full-text available
  • Aug 2021
Introduction The use of activated charcoal in poisoning remains both a pillar of modern toxicology and a source of debate. Following the publication of the joint position statements on the use of single-dose and multiple-dose activated charcoal by the American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists, the routine use of activated charcoal declined. Over subsequent years, many new pharmaceuticals became available in modified or alternative-release formulations and additional data on gastric emptying time in poisoning was published, challenging previous assumptions about absorption kinetics. The American Academy of Clinical Toxicology, the European Association of Poison Centres and Clinical Toxicologists and the Asia Pacific Association of Medical Toxicology founded the Clinical Toxicology Recommendations Collaborative to create a framework for evidence-based recommendations for the management of poisoned patients. The activated charcoal workgroup of the Clinical Toxicology Recommendations Collaborative was tasked with reviewing systematically the evidence pertaining to the use of activated charcoal in poisoning in order to update the previous recommendations. Objectives The main objective was: Does oral activated charcoal given to adults or children prevent toxicity or improve clinical outcome and survival of poisoned patients compared to those who do not receive charcoal? Secondary objectives were to evaluate pharmacokinetic outcomes, the role of cathartics, and adverse events to charcoal administration. This systematic review summarizes the available evidence on the efficacy of activated charcoal. Methods A medical librarian created a systematic search strategy for Medline (Ovid), subsequently translated for Embase (via Ovid), CINAHL (via EBSCO), BIOSIS Previews (via Ovid), Web of Science, Scopus, and the Cochrane Library/DARE. All databases were searched from inception to December 31, 2019. There were no language limitations. One author screened all citations identified in the search based on predefined inclusion/exclusion criteria. Excluded citations were confirmed by an additional author and remaining articles were obtained in full text and evaluated by at least two authors for inclusion. All authors cross-referenced full-text articles to identify articles missed in the searches. Data from included articles were extracted by the authors on a standardized spreadsheet and two authors used the GRADE methodology to independently assess the quality and risk of bias of each included study. Results From 22,950 titles originally identified, the final data set consisted of 296 human studies, 118 animal studies, and 145 in vitro studies. Also included were 71 human and two animal studies that reported adverse events. The quality was judged to have a Low or Very Low GRADE in 469 (83%) of the studies. Ninety studies were judged to be of Moderate or High GRADE. The higher GRADE studies reported on the following drugs: paracetamol (acetaminophen), phenobarbital, carbamazepine, cardiac glycosides (digoxin and oleander), ethanol, iron, salicylates, theophylline, tricyclic antidepressants, and valproate. Data on newer pharmaceuticals not reviewed in the previous American Academy of Clinical Toxicology/European Association of Poison Centres and Clinical Toxicologists statements such as quetiapine, olanzapine, citalopram, and Factor Xa inhibitors were included. No studies on the optimal dosing for either single-dose or multiple-dose activated charcoal were found. In the reviewed clinical data, the time of administration of the first dose of charcoal was beyond one hour in 97% (n = 1006 individuals), beyond two hours in 36% (n = 491 individuals), and beyond 12 h in 4% (n = 43 individuals) whereas the timing of the first dose in controlled studies was within one hour of ingestion in 48% (n = 2359 individuals) and beyond two hours in 36% (n = 484) of individuals. Conclusions This systematic review found heterogenous data. The higher GRADE data was focused on a few select poisonings, while studies that addressed patients with unknown and or mixed ingestions were hampered by low rates of clinically meaningful toxicity or death. Despite these limitations, they reported a benefit of activated charcoal beyond one hour in many clinical scenarios.
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Comparison of the effects on lameness of orally administered acetaminophen-codeine and carprofen in dogs with experimentally induced synovitis
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Objective: To compare the ability of acetaminophen-codeine (AC; 15.5 to 18.5 mg/kg and 1.6 to 2.0 mg/kg, respectively) or carprofen (4.2 to 4.5 mg/kg) administered PO to attenuate experimentally induced lameness in dogs. Animals: 7 purpose-bred dogs. Procedures: A blinded crossover study was performed. Dogs were randomly assigned to receive AC or carprofen treatment first and then the alternate treatment a minimum of 21 days later. Synovitis was induced in 1 stifle joint during each treatment by intra-articular injection of sodium urate (SU). Ground reaction forces were assessed, and clinical lameness was scored at baseline (before lameness induction) and 3, 6, 9, 12, 24, 36, and 48 hours after SU injection. Plasma concentrations of acetaminophen, carprofen, codeine, and morphine were measured at various points. Data were compared between and within treatments by repeated-measures ANOVA. Results: During AC treatment, dogs had significantly higher lameness scores than during carprofen treatment at 3, 6, and 9 hours after SU injection. Peak vertical force and vertical impulse during AC treatment were significantly lower than values during carprofen treatment at 3, 6, and 9 hours. Plasma concentrations of carprofen (R)- and (S)-enantiomers ranged from 2.5 to 19.2 μg/mL and 4.6 to 25.0 μg/mL, respectively, over a 24-hour period. Plasma acetaminophen concentrations ranged from 0.14 to 4.6 μg/mL and codeine concentrations from 7.0 to 26.8 ng/mL, whereas plasma morphine concentrations ranged from 4.0 to 58.6 ng/mL. Conclusions and clinical relevance: Carprofen as administered was more effective than AC at attenuating SU-induced lameness in dogs.
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Effect of sorbitol, single, and multidose activated charcoal administration on carprofen absorption following experimental overdose in dogs: Effect of charcoal treatment on carprofen overdose
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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.DesignRandomized, four period cross-over study.SettingUniversity research setting.AnimalsEight healthy Beagles.InterventionsA 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 ResultsPlasma 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.
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Full-text available
  • Dec 2008
Eläinlääketieteellinen farmakologia ja toksikologia Ihmisten käyttämien eläimille potentiaalisesti haitallisten aineiden käyttö lisääntyy jatkuvasti ja hyvänmakuisia eläimille ja ihmisille tarkoitettuja lääkevalmisteita on helposti saatavilla. Eläimen alkaessa oireilla ei usein pystytä varmistumaan mahdollisen myrkytyksen aiheuttajasta. Tällöin on ensisijaisen tärkeää potilaan tilan stabilointi, elintoimintojen tukeminen ja oireenmukainen hoito. Dekontaminaatiolla pyritään samaan myrkyllinen aine pois elimistöstä nopeasti, aiheuttamatta kuitenkaan potilaalle lisäharmia. Sen tehokkuus riippuu suuresti niellystä myrkystä ja kuluvasta ajasta. On siis tärkeää tunnistaa myrkytyksen ensimmäiset oireet ja osata reagoida niihin oikealla tavalla. Gastrointestinaaliseen dekontaminaatioon voidaan käyttää esimerkiksi oksennuttamista, mahahuuhtelua, laksatiiveja ja lääkehiiltä. Tutkielmaan on valittu spesifiset myrkytyksen aiheuttajat mahdollisen vasta-aineen olemassaolon perusteella tai miten yleisiä ne vaikuttavat olevan YES:in potilasaineistossa. Kaakaota sisältävien tuotteiden, esimerkiksi suklaan, toksisia yhdisteitä ovat metyyliksantiinit teobromiini ja kofeiini. Metyyliksantiinit stimuloivat keskushermostoa ja sydänlihasta, relaksoivat sileätä lihasta ja aiheuttavat diureesia. Hoito on indikoitua, kun nielty metyyliksantiiniannos lähenee 20 mg/kg. Spesifistä vasta-ainetta ei ole, joten hoito on tukihoitoa. Antikoagulanttirotanmyrkyt aiheuttavat hyytymishäiriöitä estämällä hyytymistekijöiden tuottoa maksassa. Spesifisenä vasta-aineena käytetään K1-vitamiinia. Antikoagulanttirotanmyrkyt konsentroituvat maksaan ja voivat jäädä enterohepaattiseen kiertoon aiheuttaen täten pitkäaikaisen Kvitamiiniterapian tarpeen. Ksylitoli on tyypillinen makeuttaja purukumissa ja makeisissa. Koirilla ksylitoli aiheuttaa nopean veren insuliinipitoisuuden nousun ja siten veren glukoosin nopean laskun. Ksylitolimyrkytyksen oireita ovat pitkäkestoinen hypoglykemia, maksaentsyymien aktiivisuuden nousu ja mahdollinen maksanekroosi. Hoitona käytetään glukoosi-infuusiota sekä maksaa tukevia aineita. Etyleeniglykolia käytetään esimerkiksi jäänestoaineissa. Se aiheuttaa eläimelle akuutin munuaisvaurion, keskushermosto-oireita ja vakavan metabolisen asidoosin. Etyleeniglykolimyrkytyksen vastaaineena suositaan fomepitsolia. Fomepitsolilla hoidettujen eläinten toipumisesta on saatu hyviä tuloksia. Tulehduskipulääkkeiden myrkyllisyys perustuu useimmissa tapauksissa syklo-oksygenaasin (COX) toiminnan estoon ja siten sen kudoksia suojaavan toiminnan heikentymiseen. Tulehduskipulääkkeet jäävät koirilla helposti enterohepaattiseen kiertoon. Yleisin haittavaikutus on mahasuolikanavan ärsytys. Ibuprofeenilla on koirilla matala terapeuttinen marginaali. Sen ei ole todettu aiheuttavan maksavauriota, mutta sen sijaan niitä on raportoitu karprofeenin käytön yhteydessä. Lääkehoidon pääasiallinen tavoite on pitää yllä mahan suojamekanismeja. Tähän tarkoitukseen voidaan käyttää esimerkiksi H2- reseptorin antagonisteja, protonipumpun salpaajia, sukralfaattia ja misoprostolia. Parasetamolilla niin ikään on matala terapeuttinen marginaali. Se aiheuttaa pääasiassa hepatosellulaarisia vaurioita ja maksanekroosia. Korkeimmilla annoksilla havaitaan methemoglobinemiaa. Parasetamolimyrkytys johtuu maksan glutationivarastojen ehtymisestä. Asetyylikysteiini on glutationin prekursori ja sitä käytetään vasta-aineena parasetamolimyrkytyksessä.
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SELENIUM-DEPENDENT GROWTH INHIBITION OF MASTITIS PATHOGENS IN COW'S MILK
Article
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Adequate selenium (Se) status is needed for maintenance udder health of dairy cows. However, the mechanisms by which Se is supporting health of cows' udder are still unclear. Current work is focused on Se-dependent growth suppression of mastitis pathogens in bovine milk.
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PREVENTION OF WOLF AND OTHER LARGE CARNIVORE DAMAGES IN FINNISH LIVESTOCK HERDS USING LIVESTOCK GUARDING DOGS (LGD)
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Phase 1 of studying a cost-effective method of protecting livestock with LGD for Northern Europe and the Baltic Sea Area included contacting early LGD adopters, semi-structured interviews and in-site-visits to Finnish farms in summer 2006. 4 farms located in traditional large carnivore areas in eastern and 4 in central parts of Finland. Total numbers of dogs were 31 including 19 LGDs (1–4 per farm) of 8 different breeds. The experiences were encouraging: no predation since LGD(s) presence, only minor difficulties. Herding dogs and LGDs got along acceptably. LGDs had also multifunctional influence e.g. increasing the general feeling of security.
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The Therapeutic Efficacy of Carprofen (Rimadyl-V™) in 209 Clinical Cases of Canine Degenerative Joint Disease
Article
  • Jan 1992
Carprofen (D,L-6-chlor-alphamethylcarbazole-2-acetic acid) is a nonsteroidal anti-inflammatory drug with demonstrated therapeutic activity in the relief of clinical signs of degenerative joint disease in laboratory animal models and in human trials. The double-blind clinical study, reported herein, compared the therapeutic efficacy of carprofen with that of a placebo, in the acute relief of clinical canine degenerative joint disease. Twohundred and nine cases were collected from 10 studies in three geographic regions of the USA. The results of logistic analysis showed that dogs treated with carprofen were 24.8 times more likely to receive a positive evaluation by the veterinarian than those treated with a placebo (p <0.01). The odds of showing improvement, when evaluated by the owners, were 13.4 times greater than placebo (p <0.01). The evaluation from the veterinarian and the owner had excellent agreement (Kappa = 0.997) for dogs treated with carprofen and good agreement (Kappa = 0.667) for those treated with the placebo. Regional differences in response rate were not found in these studies. This trial demonstrated that carprofen is efficacious, across geographic regions, in the acute relief of clinical signs associated with canine degenerative joint disease. Carprofen is a new anti-inflammatory drug (NSAID) with analgesic potency. Side effects reported are few. Dogs with degenerative joint disease (DSD) treated with carprofen were 24.8 times more likely to respond favourably than placebo-treated dogs (p <0.01). This study concluded that carprofen is an effective NSAID in relieving the clinical signs of DSD in dogs.
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Pharmacokinetics, tolerance and serum thromboxane inhibition of carprofen in the dog
Article
The non-steroidal anti-inflammatory drug (NSAID) carprofen was administered to dogs as a mixed-micelle solution at a dose rate of 0–7 mg/kg intravenously, as a palatable paste at a dose rate of 0–7 mg/kg orally, and as an oral tablet formulation at a dose rate of 0–7 mg/kg and 4-0 mg/kg orally for pharmacokinetic studies. It was also administered as an oral tablet formulation at a dose rate of 9-0 mg/kg orally daily for 14 days in a tolerance study. The pharmacokinetics following intravenous administration at a dose rate of 0–7 mg/kg indicate that carprofen has a small volume of distribution (Vd area = 0–09-0-25 litres), a slow systemic clearance (Cls = 1–34-5-57 ml/min) and an elimination half-life of 3–20-11-77 hours. Both oral paste and tablet preparations were highly bioavailable and absorption was proportional to dose rate at 0–7 mg/kg and 4-0 mg/kg bodyweight. Given once daily at dose rates likely to be used clinically it is unlikely to accumulate in the plasma. Carprofen administered as a palatable paste at a dose rate of 0–7 mg/kg did not inhibit serum thromboxane generation and this drug may therefore have a mode of action different from most NSAIDs. Carprofen was well tolerated when administered as an oral tablet formulation at a dose rate of 9.0 mg/kg daily for 14 days in healthy beagle dogs.
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Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs
Article
  • Oct 1990
Absorption and disposition characteristics of carprofen were compared in the dog after intravenous, oral, and rectal administrations. Rectal formulations included an aqueous solution and a suppository. Single doses of 100 mg carprofen were given in a cross-over design and plasma concentrations of unchanged drug were determined by HPLC. Plasma concentration-time profiles could be adequately described after intravenous and extravascular administrations by tri-and biexponential functions, respectively. After intravenous applications the basic disposition parameters could be determined: mean (+/- S.D.) elimination half-life was about 11.7 (+/- 3.1) h; volume of distribution ranged from 0.12 to 0.22 l kg-1 and total plasma clearance was about 0.017 +/- 0.003 l h kg-1. After oral dosing, carprofen was rapidly absorbed (time of maximum concentration: 0.83 +/- 0.61 h) and comparison with the intravenous solution indicated complete bioavailability. After rectal administration, the rate of absorption evaluated through tmax and calculation of mean absorption times was always slower than after oral dosing. Relative bioavailabilities of the drug from the suppository were about 20 per cent lower than from rectal solutions. No significant difference in rates of absorption of carprofen from rectal solution and suppository was seen; this allowed the conclusion that drug release from the semi-solid dosage form was not the rate-limiting step in carprofen absorption from the suppository. From the present study, it is concluded that rectal administration of carprofen offers an alternative to the oral route of drug intake.
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Rapid high performance liquid chromatography assay for the simultaneous analysis of non steroidal antiinflammatory drugs in plasma
Article
A high-performance liquid chromatographic assay has been developed for the determination of a number of non-steroidal anti-inflammatory drugs in plasma. The samples were prepared by adding acetonitrile and perchloric acid to 200 microliter of plasma. Diclofenac, fenoprofen, ketoprofen, naproxen, phenylbutazone, piroxicam and sulindac were quantified in the supernatant produced using a mobile phase of phosphoric acid 0.03% (pH 2.5)-acetonitrile and a detecting wavelength of 254 nm. The reproducibility, linearity, precision and specificity of the assay were determined and found to be satisfactory. Alteration of the detection wavelength to 229 nm also permitted accurate determination of ibuprofen concentration in plasma. While reduction of the organic solvent content of the mobile phase and alteration of wavelength to 313 nm produced a system capable of quantifying salicylate and its metabolites in plasma and by further reducing the detecting wavelength to 237 nm, aspirin also was quantifiable. These methods have been applied in a cross-sectional study of medication compliance among rheumatoid arthritis patients treated with non-steroidal anti-inflammatory drugs.
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Metabolism of carprofen, a nonsteroid anti-inflammatory agent, in rats, dogs, and humans
Article
  • Nov 1980
The metabolic disposition of 14C-labeled carprofen [(+/-)-6-chloro-alpha-methylcarbazole-2-acetic acid] was investigated in rats, dogs, and humans. Carprofen is eliminated predominantly by biotransformation in these three species. In dogs and rats, the direct conjugation of carprofen to form an ester glucuronide and oxidation to the C-7 and the C-8 phenols followed by their conjugation represent the major metabolic pathways. Small amounts of the alpha-hydroxy derivative also are formed by these species and are excreted free in the urine. In dogs, biliary secretion predominates, and 70% of an intravenous dose of carprofen is excreted in the feces while 8--15% of the dose is excreted in the urine. In rats, fecal excretion due to biliary secretion varies from 60 to 75%, and urinary excretion accounts for 20--30% of an intravenous dose. In humans direct conjugation of carprofen represents the only significant pathway of metabolism. Between 65 and 70% of the orally administered carprofen was found to be excreted as the ester glucuronide in the urine, and most of the remaining dose was estimated to be secreted as this metabolite in the bile. Due to enterohepatic circulation, only a fraction of the biliary metabolite was recovered in the feces in humans. Less than 5% of the dose was excreted in human urine as free, intact carprofen. In dogs and humans, plasma levels of carprofen and of total radioactivity exhibit a multiphasic decline. In the three human subjects studied, the terminal component declined with a 13--26 hr half-life; the terminal half-life was approximately 40 hr in dogs.
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