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Fish Drug Analysis—Phish The AAPS Journal 2005; 7 (2) Article 30 (http://www.aapsj.org). Fish Drug Analysis—Phish-Pharm: A Searchable Database of Pharmacokinetics Data in Fish Submitted: September 23, 2004; Accepted: September 27, 2004; Published: September 22, 2005. Renate Reimschuessel,1 Leslie Stewart,2 Elizabeth Squibb,3 Keiko Hirokawa,4 Tiffany Brady,3 Deborah Brooks,5 Badar Shaikh,1 and Clifford Hodsdon6 1Center for Veterinary Medicine, United States Food and Drug Administration, Laurel, MD 20708 2Northwestern University, Evanston, IL 60201 3University of Maryland, College Park, MD 20770 4St George’s University, PO Box 7, Grenada, West Indies 5Center for Veterinary Medicine, US Food and Drug Administration, Rockville, MD 20855 6Independent Computing, 1520 Slatehill Rd, Drumore, PA 17518 ABSTRACT research needed to generate the data to support a drug approval. Such data include demonstration of drug efficacy Information about drug residues and pharmacokinetic and safety in the target species, human food safety, and envi- parameters in aquatic species is relatively sparse. In addition, ronmental impact assessments.5 The overall cost of obtaining it is difficult to rapidly compare data between studies due to the experimental data required for a New Animal Drug differences in experimental conditions, such as water temper- Application (NADA) can be in excess of $40 million.6-8 atures and salinity. To facilitate the study of aquatic species drug metabolism, we constructed a Fish Drug/Chemical Efforts to increase the availability of therapeutic agents for fish Analysis Phish-Pharm (FDA-PP) database. This database and for other minor species include work being done by the consists of more than 400 articles that include data from 90 National Research Support Project No. 76 and the Proposals species (64 genera) of fish. Data fields include genus, to Increase the Availability of Approved Animal Drugs for species, water temperatures, the average animal weight, sam- Minor Species and Minor Uses.9 One strategy being explored ple types analyzed, drug (or chemical) name, dosage, route of for aquaculture drug products is to group species according to administration, metabolites identified, method of analysis, those species of fish likely to present with similar safety pro- protein binding, clearance, volume of distribution in a central files, effectiveness characteristics, or withdrawal times.10-16 compartment (Vc) or volume of distribution at steady-state Several approaches have been suggested for this “crop group- ing,” and the proposed basis for grouping species has included (Vd), and drug half-lives (t½). Additional fields list the cita- tion, authors, title, and Internet links. The document will be taxonomic class, salinity tolerance, or water temperature. periodically updated, and users are invited to submit addi- The underlying theory for a taxonomic grouping is that organ- tional data. Updates will be announced in future issues of The isms closely related phylogenetically might be expected to AAPS Journal. This database will be a valuable resource to have similar drug metabolism and elimination. This is defi- investigators of drug metabolism in aquatic species as well as nitely the case in fish lacking certain renal elements such as government and private organizations involved in the drug glomeruli and distal tubules.17 Drugs that are normally fil- approval process for aquatic species. tered by the glomerulus are retained much longer in these fish species. Other scientists suggest grouping fish based on their salinity preferences. Marine fish drink large quantities of salt KEYWORDS: aquatic, fish, drug, pharmacokinetics, water and produce little urine, while freshwater fish do not residues, database, Web. drink and produce copious urine. The amount a fish drinks can affect both absorption and excretion of drugs. For exam- 18 INTRODUCTION ple, Sohlberg et al found that flumequine plasma levels were much lower in salmon smolts treated during their transfer to There are currently very few drugs approved by the US Food saltwater as compared with smolts that were returned to fresh- 1-4 and Drug Administration (FDA) for use in fish. Although water. Cations from the water in the gastrointestinal tract were there are several reasons for this shortage, the primary factor thought to bind and facilitate drug elimination. is a lack of pharmaceutical sponsors willing to invest in the The suggestion to group species by temperature is based on Corresponding Author: Renate Reimschuessel, Office of the ability of poikilothermic animals to dramatically change Research, Center for Veterinary Medicine, US Food and their rate of drug metabolism and depuration, depending on Drug Administration, 8401 Muirkirk Road, Laurel, MD holding conditions. In general, the colder the environment, 20708. Tel: (301) 827-8025; Fax: (301) 827-8025; Email: the slower most drugs are absorbed and excreted.19-21 This is, [email protected]. however, dependent on the type of drug being examined. E288 The AAPS Journal 2005; 7 (2) Article 30 (http://www.aapsj.org). Compounds such as the anesthetic, benzocaine, have been The data set contains separate sortable fields for the follow- shown to be eliminated just as rapidly in fish held at 7°C ver- ing information: 22 sus those held at 16°C. 1. Articles Once species groups have been developed, a model species a. author(s) could be chosen to represent the entire group in the target animal b. year of publication safety and/or effectiveness studies supporting product approval. c. citation and Web links to the abstracts if available The full human food safety data package could be generated in 2. Experimental animals and the holding conditions the same or different model species. Ultimately, some bridging a. species common name studies would be needed to verify the appropriateness of the pro- b. species scientific name posed grouping for the other species included in that group. c. average water temperature(s) The concept of extrapolating data from one animal species to d. average animal weight another is not unique. Preclinical data may be used to esti- e. type of sample analyzed mate a phase 1 dose to be administered to healthy human vol- 3. Drug/chemical and pharmacokinetic parameters unteers.23 It is also used to generate allometric equations for a. drug name predicting pharmacokinetic parameters in man,24-25 or to determine action levels for environmental contaminants, tox- b. drug class icants, and carcinogens.26-27 This approach has, however, c. dosage only been incorporated into the drug-approval process for d. route of administration animal drugs in selected cases. During the past decade, the e. metabolites identified farming of minor species has become more popular and such f. method of analysis nontraditional farm animals require veterinary care and ther- g. protein binding apeutic drugs. It is for these minor species, especially the h. clearance aquatic species, that a reliable and predictable method of i. volume of distribution in a central compartment species grouping would be extremely advantageous. (Vc) or volume of distribution at steady-state (Vd) A large amount of supportive data, however, must be com- j. drug half-lives (t ) piled in order to demonstrate that information from a model ½ species will accurately predict the responses of all the mem- Values for t½ were either entered as reported or extrapolated bers of a group. Since these pharmacokinetic data are often from data or graphs provided in the articles. If the t½ was used to make decisions about the conduct of human food extrapolated, a notation was made in another column to iden- safety studies, it is essential that conclusions are drawn from tify such entries as estimates. The t½, average temperature, an adequately sized data set. There are several online data- and average weight fields are defined as numerical entries to bases available for human pharmacokinetic data.28-33 One facilitate plotting the data. Additional detailed fields were online resource, the Food Animal Residue Avoidance incorporated at the end of the master spreadsheet to expand Databank,30 provides residue information for food animals, the information from numerical columns. For example, the primarily terrestrial species.34-35 actual range of water temperatures is entered in the “detailed water temperature” field, while numerical averages are Compared with what is available for mammals, there is a gen- entered into “average water temperature” field. So too, the eral lack of the literature describing drug depletion or pharma- detailed weight and detailed dosage fields allow additional, cokinetic studies in fish. There are also a few fish species, such nonnumerical information to be included. as channel catfish and salmonids, which dominate the litera- ture. The information that does exist needs to be organized in The database is provided in 2 formats. In its simplest “raw” a way that will allow the reviewer to evaluate the many differ- form of a Microsoft Excel spreadsheet, the data should be ent study variables inherent in the aquatic animal literature. As readily accessible to most scientists. A searchable Microsoft part of the Center for Veterinary Medicine (CVM)/Office of Access Database is also available. Research’s work on crop grouping, we have begun to develop such a literature database to detail information on drug metab- Contents and Structure of the Spreadsheet olism, depuration, and pharmacokinetics in fish. The field names and a description of their contents are listed below.
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