Aceclofenac as a Potential Threat to Critically Endangered Vultures in India: A Review Author(s): Pradeep Sharma Source: Journal of Raptor Research, 46(3):314-318. 2012. Published By: The Raptor Research Foundation DOI: http://dx.doi.org/10.3356/JRR-11-66.1 URL: http://www.bioone.org/doi/full/10.3356/JRR-11-66.1 BioOne (www.bioone.org) is a nonprofit, online aggregation of core research in the biological, ecological, and environmental sciences. BioOne provides a sustainable online platform for over 170 journals and books published by nonprofit societies, associations, museums, institutions, and presses. Your use of this PDF, the BioOne Web site, and all posted and associated content indicates your acceptance of BioOne’s Terms of Use, available at www.bioone.org/ page/terms_of_use. Usage of BioOne content is strictly limited to personal, educational, and non- commercial use. Commercial inquiries or rights and permissions requests should be directed to the individual publisher as copyright holder. BioOne sees sustainable scholarly publishing as an inherently collaborative enterprise connecting authors, nonprofit publishers, academic institutions, research libraries, and research funders in the common goal of maximizing access to critical research. SHORT COMMUNICATIONS J. Raptor Res. 46(3):314–318 E 2012 The Raptor Research Foundation, Inc. ACECLOFENAC AS A POTENTIAL THREAT TO CRITICALLY ENDANGERED VULTURES IN INDIA:AREVIEW PRADEEP SHARMA1 Department of Veterinary Microbiology and Biotechnology, Rajasthan University of Veterinary and Animal Science, Bikaner 334001, Rajasthan, India KEY WORDS: Vultures; Gyps; aceclofenac; diclofenac; India; cations in humans (Kay and Alldred 2003) and marked South Asia; toxicity. analgesic, antiarthritic and antipyretic properties. In hu- mans, aceclofenac was well-absorbed from the gastrointesti- Understanding the metabolic profile and the environ- nal tract with peak plasma concentrations (Cmax) of 7.6 6 mental effects of veterinary painkillers in India has be- 1.3 micrograms/ml, reached in a period of 2.6 6 1.8 hr come both imperative and critical after the unprecedented (tmax) after an oral dose (Bort et al. 1996), with a plasma decline of critically endangered species of vultures (IUCN elimination half-life of around 4 hr (MHRA 2011). More 2010) endemic to South Asia (White-rumped [Gyps benga- than 99% of the compound is bound to plasma proteins lensis], Long-billed [Gyps indicus] and Slender-billed [Gyps and it has almost 100% bioavailability; the volume of distri- tenuirostris] vultures [henceforth ‘vultures’]), caused by bution (Vd) is approximately 25 liters in humans (see veterinary use of the nonsteroidal anti-inflammatory drug MHRA 2011). The drug is eliminated primarily through (NSAID) diclofenac (Green et al. 2004, Oaks et al. 2004, renal excretion, with 70–80% of the administered dose Schultz et al. 2004). Subsequently, another widely used found in urine as glucoronides and rest excreted in feces veterinary painkiller, ketoprofen, was also found to be toxic in humans (see MHRA 2011). to vultures (Naidoo et al. 2009), whereas the NSAID melox- Aceclofenac produces anti-inflammatory effects in cases icam was found to be safe to vultures and a range of scav- of both acute and chronic inflammation, which is attributed enging birds (Swan et al. 2006, Swarup et al. 2007). Another to its metabolites inhibiting various mediators of pain and entrant to the range of veterinary NSAIDs being manufac- inflammation including Prostaglandin E2 (PGE2; Henro- tured and sold in South Asia is aceclofenac, which bears a tin et al. 2001). In vitro studies indicate inhibition of both close structural and pharmacological resemblance to diclo- Cyclooxygenase-1 (COX-1) and COX-2, with evident selec- fenac (Brogden and Wiseman 1996, Parfitt 1999). Due to tive COX-2 inhibition (Gonzalez et al. 1994). However, this close relationship to diclofenac, I reviewed the available aceclofenac and its major metabolite in human blood literature to assess the potential risk of this drug to South (49-hydroxy-aceclofenac) suppress PGE2 synthesis without Asia’s critically endangered vultures. showing any inhibitory effects on COX activity. This effect is apparently caused by the production of diclofenac and METHODS 49-hydroxy-diclofenac via hydrolysis of aceclofenac and 49- I surveyed the published literature as well as the PubMed hydroxy-aceclofenac, respectively, in human rheumatoid database using the key words ‘‘aceclofenac’’ and ‘‘metab- synovial cells (Yamazaki et al. 1999). The rate of this hy- olites’’ to find information on the comparative pharmaco- drolysis reaction was proportionally correlated to the logical profiles of aceclofenac and diclofenac relative to rate of suppression of PGE2 by aceclofenac, suggesting their toxicity to vultures. In addition to the peer-reviewed that diclofenac and 49-hydroxy-diclofenac were directly literature, I also included information accompanying com- responsible for suppression of PGE2 synthesis, and not mercially available aceclofenac preparations manufactured aceclofenac and 49-hydroxy-aceclofenac as such. both for human and veterinary practices. Neither aceclofenac nor 49-hydroxy-aceclofenac affected COX-1 or COX-2 activity in short-term in vitro assays, and RESULTS suppression of both COX isoforms in long-term assays The compound aceclofenac (2-[2-[2-(2,6- dichloropheny- was mediated by conversion to diclofenac and 49-hydroxy- l)aminophenyl]acetyl]oxyacetic acid; Fig. 1; Grau et al. diclofenac, respectively, in humans (Hinz et al. 2003a). 1991a, Alvarez-Larena et al. 1992) was reported as a new Moreover, 49-hydroxy-diclofenac is a metabolite of both derivative of diclofenac, with fewer gastrointestinal compli- diclofenac and aceclofenac in several mammalian test sub- jects including rats, monkeys, and humans (see Bort et al. 1 Present address: 30-B, New Civil Lines, Bharatpur District 1996, Tang et al. 1999, 2007). The COX-inhibitory action 321001, Rajasthan, India; email address: [email protected]. of aceclofenac, due to limited but sustained biotransformation 314 SEPTEMBER 2012 SHORT COMMUNICATIONS 315 Figure 1. Chemical structure of (a) Aceclofenac, (b) Diclofenac, (c) Ketoprofen, and (d) Meloxicam. in to diclofenac, has been substantiated convincingly for Whether the toxicity of diclofenac to vultures is caused human subjects (Hinz et al. 2003b). by diclofenac itself or by its metabolites or a combination Structurally aceclofenac, diclofenac, and ketoprofen are of both, is as yet unknown. all related (Fig. 1) as arylalkanoic acid derivatives (Aronson While maintaining its potency, aceclofenac has better 2009). The relatively safer NSAID meloxicam (see Swarup gastric tolerance and consequently offers greater potential et al. 2007) is an enolic acid (oxicam) derivative (Montoya security from adverse gastrointestinal events than does et al. 2004). diclofenac both in humans and rodents (Grau et al. 1991b, Ward et al. 1995, Schattenkirchner and Milachowski DISCUSSION 2003). Based on wide clinical experience in human sub- The paucity of data on NSAID toxicity in general, species- jects, aceclofenac has a better safety profile compared to dependent variation in both NSAID’s pharmacological diclofenac, at least in rheumatic disorders (see Brogden and associated physiological responses in avian species and Wiseman 1996), and thus may have acceptance among (Baert and De Backer 2003, Meteyer et al. 2005), and veterinary practitioners in South Asia. Interactions with the almost complete lack of information on the metabolic practicing veterinarians, veterinary sales representatives, profile of diclofenac in vultures have limited a conclusive and dealers in the state of Rajasthan, India, revealed that understanding of the observed toxicity of diclofenac. Sev- practitioners considered aceclofenac a cost-effective and eral hypotheses have been proposed to explain the toxic- clinically effective substitute for diclofenac. Accordingly, ity of diclofenac to vultures, including impairment of re- its market share has grown considerably over the last two nal physiology by diclofenac (see Meteyer et al. 2005), years (P. Sharma unpubl. data). Generic injectable aceclo- differential toxicity of diclofenac to both proximal and fenac for veterinary use in cheap and relatively concentrat- distal kidney tubules via a mitochondrial cell death path- ed (150 mg/ml) forms compared to diclofenac (25 mg/ml) way (Ng et al. 2006), and a combination of cell death are now available and require fewer needlesticks than diclo- from increased reactive oxygen species (ROS) interfer- fenac (P. Sharma unpubl. data). Aceclofenac, being both ence with uric acid transport and the duration of expo- cost effective and less uncomfortable for animals, may merit sure (Naidoo and Swan 2009). Relatively few studies have preferential veterinary use over other painkillers, including elaborated diclofenac-metabolite-mediated cytotoxicity in diclofenac, which may lead to both increased volume and other species (Miyamoto et al. 1997, Bort et al. 1998). extent of use. Further, patented injectable aceclofenac for 316 SHORT COMMUNICATIONS VOL. 46, NO.3 Table 1. Metabolites of aceclofenac (Bort et al. 1996) and diclofenac (Bort et al. 1999). SERIAL NUMBER METABOLITES OF ACECLOFENAC METABOLITES OF DICLOFENAC 149- hydroxy-aceclofenac 39–hydroxy-diclofenac 2 5- hydroxy-aceclofenac N,5-dihydroxy-diclofenac 349-hydroxy-diclofenac 49- hydroxy-diclofenac 4 diclofenac 49- 5- dihydroxy-diclofenac 5 5- hydroxy-diclofenac 5 -hydroxy-diclofenac