Pharmacokinetics of an ampicillin/sulbactam (2:1) combination in rabbits E. ESCUDERO* M. S. VICENTE* J. M. SERRANO* ,† & C. M. CA ´ RCELES* * Departamento de Farmacologı ´a, Facultad de Veterinaria, Universidad de Murcia, Campus de Espinardo, 30.071-Murcia, Spain; † Departamento de Farmacologı ´a y Toxicologı ´a, Facultad de Veterinaria, Universidad de Co ´rdoba, Edificio C-1, Campus Agroalimentario de Rabanales, Carretera de Madrid-Ca ´diz, km 396 A, 14071-Co ´rdoba, Spain Escudero, E., Vicente, M. S., Serrano, J. M., Ca ´rceles, A. M. Pharmacokinetics of an ampicillin/sulbactam (2:1) combination in rabbits. J. vet. Pharmacol. Therap. 25, 259–264. The pharmacokinetics of a 2:1 ampicillin–sulbactam combination in six rabbits, after intravenous and intramuscular injection at a single dosage of 20 mg/kg bodyweight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam) were investigated by using a high performance liquid chromato- graphic method for determining plasma concentrations. The plasma concen- tration–time curves were analysed by compartmental pharmacokinetic and noncompartmental methods. The disposition curves for both drugs were best described by an open two-compartment model after intravenous administration and a one-compartment model with first order absorption after intramuscular administration. The apparent volumes of distribution calculated by the area method for ampicillin and sulbactam were 0.62 ± 0.09 and 0.45 ± 0.05 L/kg, respectively, and the total body clearances were 0.65 ± 0.04 and 0.42 ± 0.05 L/kg h, respectively. The elimination half-lives of ampicillin after intravenous and intramuscular administration were 0.64 ± 0.11 and 0.63 ± 0.16 h, respectively, whereas for sulbactam the half-lives were 0.74 ± 0.12 and 0.77 ± 0.17 h, respectively. The bioavailability after intra- muscular injection was high and similar in both drugs (73.34 ± 10.08% for ampicillin and 83.20 ± 7.41% for sulbactam). The mean peak plasma concentrations of ampicillin and sulbactam were reached at similar times (0.20 ± 0.09 and 0.34 ± 0.15 h, respectively) and peak concentrations were also similar but nonproportional to the dose of both products administered (13.07 ± 3.64 mg/L of ampicillin and 8.42 ± 1.74 mg/L of sulbactam). Both drugs had similar pharmacokinetic behaviour after intramuscular administra- tion in rabbits. (Paper received 9 March 2001, accepted for publication 20 April 2002) Dr Elisa Escudero, Farmacia, Farmacologı ´a y Terape ´utica, Facultad de Veterinaria, Universidad de Murcia, Campus de Espinardo, 30.071-Murcia Spain. E-mail: escudero@um.es INTRODUCTION Production of b-lactamases is the most common mechanism by which Gram-negative bacteria express resistance to b-lactam antibiotics. One successful method of circumventing the threat of plasmid-encoded b-lactamases is to combine inhibitors of these enzymes with penicillin (Lister, 2000). Ampicillin is a broad spectrum aminopenicillin which is extensively used in the treatment of bacterial diseases in animal species. However, this antibiotic has the disadvantage of inactivation by bacterial b-lactamases or penicillinases. The addition of a penicillinase inhibitor, such as sulbactam, results in a drug combination that broadens the antibacterial spectrum of ampicillin. Sulbactam is a semisynthetic compound which inhibits b-lactamases irrevers- ibly. Sulbactam has been shown to extend the in vitro spectrum of b-lactam antibiotics to a number of resistant bacteria, although it has little intrinsic antibacterial activity. The primary objective of sulbactam in such a combination is to prevent the degradation of ampicillin by the bacterial b-lactamases and so to restore the previous susceptibility of the bacteria to the antibiotic (English et al., 1978). This strategy could contribute to the renaissance of well known b-lactam antibiotics such as ampicil- lin in the management of different infections. However, an essential prerequisite for the therapeutic efficacy of sulbactam is the concomitant administration of ampicillin and confirmation that the pharmacokinetics of the two compounds in the animals are similar (Alexov et al., 1996). Ampicillin is combined with sulbactam at a 2:1 ratio in commercial preparations (Unasyn Ò Pfizer, Bacimex Ò Alter Laboratories, Madrid, Spain). Combina- tions of ampicillin and sulbactam showed increased effectiveness J. vet. Pharmacol. Therap. 25, 259–264, 2002. ANTIINFECTANTS Ó 2002 Blackwell Science Ltd 259