title: Pharmacokinetic studies and renal dehydropeptidase stability of the new beta-lactamase inhibitor BRL 42715 in animals.
abstract: BRL 42715 is a novel, highly potent beta-lactamase inhibitor with good activity against a broad range of beta-lactamases, including the class I enzymes of Enterobacter and Citrobacter spp. (K. Coleman, D.R.J. Griffin, J.W.J. Page, and P.A. Upshon, Antimicrob. Agents Chemother. 33:1580-1587, 1989). The pharmacokinetics of BRL 42715 were studied following oral and parenteral administration in mice, rats, rabbits, beagle dogs, and cynomolgus monkeys. The elimination half-life (t1/2) 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 t1/2 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 (bioavailability 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.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Betchworth, Surrey, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Coleman
authors.forename: D R
authors.initials: DR
authors.lastname: Griffin
authors.forename: P A
authors.initials: PA
authors.lastname: Upshon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D046508:Culture Techniques; D004150:Dipeptidases / Q000378:metabolism; D004285:Dogs; D005260:Female; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D007769:Lactams; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D007769:Lactams; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C061593:C6-(N1-methyl-1,2,3-trazolylmethylene)penem; D004150:Dipeptidases; C038937:dipeptidase