PAPERS & ARTICLES Pharmacokinetics of amoxycillin and the rate of depletion of its residues in pigs M. R. MARTINEZ-LARRANAGA, A. ANADON, M. A. MARTINEZ, M. J. DIAZ, M. T. FREJO, V. J. CASTELLANO, G. ISEA, C. 0. DE LA CRUZ Six pigs were used in a two-period crossover study to investigate the pharmacokinetics of amoxycillin after single intravenous and oral doses of 20 mg/kg bodyweight. Twelve pigs were used to study the residues of the drug in muscle, kidney, liver and fat after they had received daily oral doses of 20 mg/kg amoxycillin for five days. The mean (sd) elimination half life (tV/20) and mean residence time of amoxycillin in plasma were 3-38 (0.30) and 3.54 (0.43) hours, respectively, after intravenous administration and 4.13 (0.50) and 4.47 (0.30) hours, respectively, after oral administration. After oral administration, the maximum plasma concentration (Cmax) was 7.37 (0-42) pg/mI and it was reached after 0-97 (0.29) hours. Six days after the last oral dose, the mean concentration of amoxycillin in the pigs' kidneys was 21.38 ng/g and in the liver it was 12*32 ng/g, but no amoxycillin could be detected in fat or muscle; the concentrations of amoxycillin in edible tissues were less than the European Union maximal residue limit of 50 pg/kg. Veterinary Record (2004) 154, 627-632 M. R. Martinez- Larrafnaga, DSc, PhD, BPharm, DipECVPT, A. Anad6n, DVM, PhD, DipECVPT, M. A. Martinez, BPharm, PhD, M. J. Diaz, DSc, PhD, M. T. Frejo, DVM, PhD, V. J. Castellano, DVM, G. Isea, DVM, C. 0. De La Cruz, DVM, Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Complutense University, 28040 Madrid, Spain AMOXYCILLIN (D- [ - ] a-amino-p-hydroxybenzylpenicillin) is a semisynthetic penicillin with a broad spectrum of anti- bacterial activity (Gram-positive and Gram-negative organ- isms) similar to that of ampicillin (Sutherland and Rolinson 1970), over which it has been shown to have important advantages. In particular, when given orally in a number of species, its bioavailability is approximately twice that of ampi- cillin and much higher serum concentrations are obtained (Yeoman 1977). The influence of food on the oral absorption of aminopenicillins has been reviewed by Eshelman and Spyker (1978), and it has been shown that the absorption of ampicillin, but not of amoxycillin, is reduced in the presence of food. It has also been shown that certain important Gram- negative bacilli (including Escherichia coli) are destroyed more rapidly by amoxycillin and that experimental infections respond more quickly to amoxycillin than to ampicillin (Hunter and others 1973, Comber and others 1975, Rolinson and others 1977). In human respiratory disease in particu- lar, amoxycillin appears to penetrate more effectively to the intrabronchiolar site and produce a more complete and rapid curative effect than ampicillin (May and Ingold 1972, Bergogne-Berezin and others 1978, Hagstad 1984, Valcke and others 1990). Amoxycillin is the most frequently prescribed agent for the oral treatment of respiratory tract infections (Woodhead and others 1987) and is generally highly effective against Streptococcus pneumoniae and non-,B-lactamase- producing Haemophilus influenzae. Amoxycillin possesses high in vitro activity against the major respiratory tract pathogens of pigs, such as Haemophilus parasuis, Pasteurella multocida, Mannheimia haemolytica and Actinobacillus pleuropneumoniae, but not against mycoplasmas, and is also a likely candidate for the treatment of respiratory infections in the species (Palmer and others 1976, Cox and others 1989, Pijpers and others 1989b). In pigs, Agerso and Friis (1998a) observed tissue to plasma ratios (based on area under curve [Auc] values) of 0 3 for both bronchial secretions and bronchial mucosa, the primary sites of bacterial invasion in acute pneumonia (Dom and others 1994), which suggests a therapeutically active plasma concentration of 0 3 ptg/ml. The therapeutic usefulness of amoxycillin for respiratory infections, bacterial enteritis (colibacillosis) and epidemic streptococcal meningitis in pigs, and the selection of a suit- able dose, requires detailed information on its pharmaco- kinetic properties in relation to its potency against common pathogens. The aim of this study was to investigate the plasma disposition of amoxycillin after its intravenous and oral administration to healthy pigs and to determine the rate of depletion of its residues in their tissues. MATERIALS AND METHODS Pigs Eighteen healthy male Landrace x Large White pigs weigh- ing 78 to 82 kg were used. They were obtained from a breed- ing farm and housed in separate pens with ad libitum access to water, and they were fed 0 75 kg of pelleted, antibiotic-free food twice daily. They were acclimatised for seven days in a house maintained at 25 ± 2°C and 45 to 65 per cent relative humidity. Two days before the pharmacokinetic studies, catheters were placed in the pigs' left and right jugular veins to facilitate the administration of the drug and the collection of blood samples. The catheters were inserted under anaes- thesia by the method described by Pijpers and others (1989a), and they were fixed to the dorsum in the cervical area. Drugs and chemicals Sodium amoxycillin (assigned potency 93 5 per cent) for intravenous administration and amoxycillin trihydrate (assigned potency 85-9 per cent) for oral administration were supplied by SmithKline-Beecham. All other chemicals were obtained from commercial sources and were of analytical grade. Study protocol The pigs were randomly allotted to two groups: group A (six pigs) was used to investigate the pharmacokinetic character- istics of amoxycillin after single intravenous and oral admin- istrations of 20 mg/kg bodyweight. The pharmacokinetic study used a cross-over design with an interval of one week between the two stages. Group B (12 pigs) was used to study the tissue residues of amoxycillin after the pigs had been given oral doses of 20 mg/kg amoxycillin daily for five consecutive days; all the doses were given between 08.00 and 09.00. A freshly prepared solution of sodium amoxycillin (320 mg/ml) in sterile distilled water was used for the intravenous injec- tions, administered via the catheter in the left jugular vein. After the administration of the drug, the catheter was flushed with 10 ml of 09 per cent sodium chloride solution. The oral doses were given with each morning meal. Food but not water was withheld overnight and the pigs were dosed with the antibiotic mixed with 200 g of food which was consumed within five minutes; food was withheld for two hours after dosing. From the pigs in group A, heparinised blood samples were collected through the catheter placed in the right jugular vein, before and 15 and 30 minutes and one, two, three, four, six, eight, 12 and 24 hours after the administration of the drug. The Veterinary Record, May 15, 2004 627 group.bmj.com on April 18, 2012 - Published by veterinaryrecord.bmj.com Downloaded from