Pharmacokinetic studies and renal dehydropeptidase stability of the new beta-lactamase inhibitor BRL 42715 in animals

Abstract

. Agents Chemother. 33:1580Chemother. 33: -1587Chemother. 33: , 1989. The pharmacokinetics of BRL 42715 were studied following oral and parenteral administration in inice, rats, rabbits, beagle dogs, and cynomolgus monkeys. The elimination half-life (tQ12) of BRL 42715 following intravenous administration was 7 min in rats, 6.2 min in rabbits, 11 min in dogs, and 18 min in cynomolgus monkeys; and interspecies scaling indicated a tj12 of 31 min in humans. Urinary recovery was 24 to 43% in the three species studied. A linear relationship was observed between the dose and the theoretical concentration in blood at time zero and between the dose and area under the concentration-time curve following intravenous administration to mice. Extravascular dosing in mice, rats, and dogs resulted in an increase in t1/2, suggesting a depot effect.BRL 42715 was absorbed in mice following an oral dose (bioavallability of 0.2), but was not absorbed in rats, dogs, or cynomolgus monkeys to any significant extent. The binding of BRL 42715 in serum was 27 to 38% in mouse, rat, and dog sera but was somewhat higher (68 to 70%) in primate and human sera. BRL 42715 was not readily hydrolyzed by the renal dehydropeptidase enzymes of any of the five species studied.BRL 42715 is a penem derivative which is a potent inhibitor of a broad range of ,B-lactamases, including the chromosomally mediated enzymes of Enterobacter, Citrobacter, and Pseudomonas species, against which all other Plactamase inhibitors have poor activity (9). The pharmacokinetics of BRL 42715 were studied in laboratory animals, and these data are reported here.The enzyme renal dehydropeptidase I (RDHP) is known to be a major cause of metabolic inactivation of carbapenems such as imipenem in both laboratory animals and humans. Inhibition of this enzyme by the RDHP inhibitor cilastatin resulted in a six-to eightfold increase in the urinary recovery of imipenem and reduced nephrotoxic potential (12). Certain penem antibiotics are also known to be hydrolyzed by RDHP (11), and it was considered necessary in the early stages of evaluation to determine the stability of BRL 42715 compared with those of the Schering penems SCH 29482 and SCH 34343 and the carbapenems BRL 13902 (3) and imipenem in various kidney homogenates. The results of that study are also reported here. MATERIALS AND METHODSTest compounds. BRL 13902 and BRL 42715 were prepared by SmithKline Beecham Pharmaceuticals. Cilastatin and imipenem were gifts from Merck Sharp & Dohme, Rahway, N.J. SCH 29482 and SCH 34343 were gifts from Schering-Plough Corp., Bloomfield, N.J.Binding of drug to serum. Duplicate samples of BRL 42715 were diluted in pooled fresh serum to a final concentration of 100 ,ug/ml, and the solution was left at room temperature for 15 min, following which samples were centrifuged in an Amicon micropartition system at 1,500 x g for 20 min. BRL 42715 was assayed by high-pressure liquid chromatography using a Waters MicrobondaPak C18 RP column in an RCM-* Corresponding author. 100 unit and was eluted with ...

Kinetic study of interaction between BRL 42715, beta-lactamases, and D-alanyl-D-alanine peptidases

“…However, thanks to its superior intrinsic activity, it remains the most active inhibitor against whole cells. In contrast to other penems, it is not readily hydrolyzed by the renal dehydropeptidase (6).…”

Activity of Amoxicillin-Clavulanate against Penicillin-Resistant Streptococcus pneumoniae in an Experimental Respiratory Infection Model in Rats

“…In studies (23) with cefuroxime axetil (Glaxo), cefpodoxime proxetil (Roussel), and cefixime (Lederle), clavulanate did not enhance the efficacies of these ␤-lactams against rat respiratory tract infections caused by S. pneumoniae N1387, whereas some enhancement was observed for cefprozil (cefprozil monohydrate, kindly supplied by Bristol-Myers Squibb, Hounslow, United Kingdom) and occasionally for cefaclor (Lilly). These studies require confirmation, but the overall results indicate that clavulanate can influence the outcome of experimental infections, despite the absence of ␤-lactamase, as was evidenced by the studies with nitrocefin and with an alternative ␤-lactamase inhibitor, BRL 42715, which has an inhibitory profile similar to that of clavulanic acid (9).…”

“…saline (pH 8.0). The ␤-lactamase inhibitor BRL 42715 is an alkylidine penem that has an inhibitory profile similar to that of clavulanic acid (9).…”

“…The rats received 0.5-ml oral doses of amoxicillin trihydrate or ampicillin trihydrate alone or in combination with the ␤-lactamase inhibitor clavulanic acid. BRL 42715 was dosed by the subcutaneous route because of its inadequate absorption from the gastrointestinal tract (9). Doses were selected to produce areas under the serum concentration-time curves (AUCs) for amoxicillin and clavulanic acid similar to those produced in human serum following the administration of standard oral doses of amoxicillin-clavulanate (Augmentin), i.e., amoxicillin-clavulanate doses of 100/50, 200/50, and 350/50 mg/kg in rats are equivalent to oral Augmentin doses of 250/125, 500/125, and 750/125 mg, respectively (Table 2) (1,16).…”

Studies on monobactams I. Synthesis and β-lactamase inhibitory activity of 4-substituted 3-[(N-methyl-1,2,3-triazol-4-yl)-methylene]-2-azetidinone-1-sulfonates

“…Due to the widespread use of third-generation cephalosporins, resistance caused by chromosomally-mediated class I cephalosporinase is increasing rapidly and may pose a threat in the future. A major breakthrough on this aspect has been the synthesis of BRL-42,715 [8][9][10], which is a potent inhibitor of most bacterial l~-lactamases including the class I cephalosporinase. This penem derivative I bearing the N-methyltriazolylmethylene group at C-6 position had good synergistic activity with amoxycillin in vitro and in vivo [11]; however, there is little information about the further development of this compound.…”