J. vet. Pharmacol. Therap. Pharmacokinetics of …

1 Pharmacokinetics of veterinary drugs in laying hens and residues in eggs:a review of the literatureV. GOETTINGK. A. LEE &L. A. TELLD epartment of Medicine and Epidemiology,School of veterinary Medicine, Universityof California, Davis, CA, USAG oetting, V., Lee, K. A., Tell, L. A. Pharmacokinetics of veterinary drugs inlaying hens and residues in eggs: a review of the vet. : treated with pharmaceutical products can produce eggs contaminatedwith drug residues. Such residues could pose a risk to consumer health. Thefollowing is a review of the information available in the literature regardingdrug Pharmacokinetics in laying hens, and the deposition of drugs into eggs ofpoultry species, primarily chickens.

2 The available data suggest that, whenadministered to laying hens, a wide variety of drugs leave detectable residues ineggs laid days to weeks after the cessation of treatment.(Paper received 10 September 2010; accepted for publication 12 February2011)Lisa A. Tell, Department of Medicine and Epidemiology, University of California atDavis, One Shields Avenue, Davis, CA 95616, USA. E-mail: latell@ucdavisINTRODUCTIONIn poultry, antibiotics and antiparasitics are used extensively fordisease prevention and treatment. In the United States, antibioticsare also used for growth promotion, although this type of use hasbeen prohibited in the European Union since 2006 (Donoghue,2003; Castanon, 2007; Companyoet al.)

3 , 2009). Edible tissuescontaining veterinary drug residues can pose risks to humanhealth, including direct toxic effects, allergic reactions andincreased bacterial resistance to common antibiotics (Botsoglou& Fletouris, 2001; Donoghue, 2003; Companyoet al., 2009). drug residues in chicken eggs are of concern becauserelatively few drugs are labelled for laying hens, althoughseveral medications are approved for other production classes ofpoultry (Hofacre, 2006; Castanon, 2007). drug residues in eggsmay arise when laying hens are mistakenly given medicatedfeed, when feed is contaminated at the mill during mixing, orwhen drugs are given off-label (Kennedyet al.

4 , 2000; Donoghue,2003). While a chicken lays an egg roughly every 24 h, eachegg takes several days to developin vivo, and some eggcomponents are in existence months before the fully developedand shelled egg containing them is laid (Etches, 1996; Whittow,2000). Because of the protracted nature of egg development,many weeks may be required following treatment or exposurebefore eggs are free of drug should be noted that some drugs included in this review areprohibited from use in some or all food animals in the US and orthe EU. In the US, extra-label use of fluoroquinolones isprohibited in food animals, and any use of these drugs in amanner not explicitly approved is illegal.

5 If an animal ismistakenly or intentionally treated with a drug that is prohibitedfrom extra-label drug use, then the exposed animal(s) should notenter the food chain unless permission is granted from the properauthorities. In both the US and EU, other drugs, includingchloramphenicol, the nitroimidazoles, and nitrofurans, arecompletely prohibited from use in food animals (Daviset al.,2009; EMEA, 2009). A summary of drugs approved in the US forgame bird species has been published (Needhamet al., 2007),and a recent update on drugs prohibited from extra-label druguse in the US is available (Daviset al.)

6 , 2009). EU approvalstatuses and maximum residue limits for veterinary drugs usedin food-producing animals are described in the EuropeanCommission Regulation 37 2010 (European Commission,2009).Of the three main egg components (yolk, albumen, and shell),the yolk has the longest development time. Precursors to yolklipoproteins are produced in the liver and transported throughcirculation to the yolk follicles in the ovary. In an actively layinghen, several follicles at varying developmental stages residesimultaneously in the ovary. Before an egg is laid, the yolkundergoes a stage of rapid growth, in which it increases in sizeexponentially over 10 days (Etches, 1996).

7 Drugs that deposit inthe yolk will rapidly accumulate during this time and can bepresent in successive eggs for 10 or more days followingtreatment. Following yolk maturation, the albumen or eggwhite is laid down over a period of 2 3 h (Whittow, 2000) andcan also serve as a residue accumulation site. The egg shell isadded after albumen proteins are deposited and diluted withwater (Etches, 1996). The egg development process is similaracross species of poultry and game birds, although the rates ofdevelopment vary (Whittow, 2000). A detailed diagram of achicken egg is shown in Fig.

8 Vet. pharmacol . : ARTICLE 2011 Blackwell Publishing Ltd1 Many drugs deposit preferentially in the yolk or albumen,depending on the drug s physicochemical properties. Somecharacteristics that effect the distribution of residues are thedrug s tendency to bind to plasma proteins, hydrophobicity orhydrophilicity, and the ability to move through different tissuetypes (Martinez, 1998). However, a drug s kinetic propertiescannot always be predicted from its chemical properties (Dono-ghue, 2005). This review presents a compilation of studies foundscattered throughout the literature that address the kinetics ofveterinary drugs in laying OF THE drug ( spectinomycin and apramy-cin) are antimicrobial compounds produced byStreptomycesandMicromonosporaspp.

9 (Botsoglou & Fletouris, 2001). Aminocycl-itols are effective against gram-negative and some gram-positivebacteria, but not anaerobic bacteria, because their mechanism ofaction relies on bacteria s oxygen transport system (Dowling,2006). In poultry, administration is most commonly oral, via thefeed or water. A limited number of studies in chickensdemonstrate that following oral administration there is little orno absorption of the drugs from the gastrointestinal (GI) tract,and therefore when given orally, aminocyclitols are likely to beeffective primarily against GI infections (Bennettet al.)

10 , 2001).The main excretory pathway following oral administration inmammals is the faeces (Brown & Riviere, 1991). Probablybecause of poor GI absorption, spectinomycin residues are notfound in eggs following oral administration (Table 1). Incontrast, orally administered apramycin is found in the eggalbumen for several days following treatment (Romvaryet al.,1991) (Table 1). This difference between the two aminocyclitolscould be attributable to differences in serum protein bindingaffinity:in vitro, chicken serum protein binding of apramycin is26% (Afifi & Ramadan, 1997), compared with 5 6% forspectinomycin (El-Sayedet al.