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. 1991 Sep;35(9):1748–1752. doi: 10.1128/aac.35.9.1748

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

K Coleman 1, D R Griffin 1, P A Upshon 1
PMCID: PMC245262  PMID: 1952842

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.

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Selected References

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  1. Allen G. D. MODFIT: a pharmacokinetics computer program. Biopharm Drug Dispos. 1990 Aug-Sep;11(6):477–498. doi: 10.1002/bdd.2510110603. [DOI] [PubMed] [Google Scholar]
  2. Basker M. J., Boon R. J., Box S. J., Prestige E. A., Smith G. M., Spear S. R. Properties of MM 13902 and other carbapenem antibiotics in vitro and in vivo. J Antibiot (Tokyo) 1983 Apr;36(4):416–422. doi: 10.7164/antibiotics.36.416. [DOI] [PubMed] [Google Scholar]
  3. Basker M. J., Boon R. J., Hunter P. A. Comparative antibacterial properties in vitro of seven olivanic acid derivatives: MM 4550, MM 13902, MM 17880, MM 22380, MM 22381, MM 22382 and MM 22383. J Antibiot (Tokyo) 1980 Aug;33(8):878–884. doi: 10.7164/antibiotics.33.878. [DOI] [PubMed] [Google Scholar]
  4. Bolton G. C., Allen G. D., Filer C. W., Jeffery D. J. Absorption, metabolism and excretion studies on clavulanic acid in the rat and dog. Xenobiotica. 1984 Jun;14(6):483–490. doi: 10.3109/00498258409151435. [DOI] [PubMed] [Google Scholar]
  5. Boxenbaum H. Interspecies pharmacokinetic scaling and the evolutionary-comparative paradigm. Drug Metab Rev. 1984;15(5-6):1071–1121. doi: 10.3109/03602538409033558. [DOI] [PubMed] [Google Scholar]
  6. Brown A. G., Butterworth D., Cole M., Hanscomb G., Hood J. D., Reading C., Rolinson G. N. Naturally-occurring beta-lactamase inhibitors with antibacterial activity. J Antibiot (Tokyo) 1976 Jun;29(6):668–669. doi: 10.7164/antibiotics.29.668. [DOI] [PubMed] [Google Scholar]
  7. Chung M., Radwanski E., Loebenberg D., Lin C. C., Oden E., Symchowicz S., Gural R. P., Miller G. H. Interspecies pharmacokinetic scaling of Sch 34343. J Antimicrob Chemother. 1985 Jun;15 (Suppl 100):227–233. doi: 10.1093/jac/15.suppl_c.227. [DOI] [PubMed] [Google Scholar]
  8. Coleman K., Griffin D. R., Page J. W., Upshon P. A. In vitro evaluation of BRL 42715, a novel beta-lactamase inhibitor. Antimicrob Agents Chemother. 1989 Sep;33(9):1580–1587. doi: 10.1128/aac.33.9.1580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gootz T., Girard D., Schelkley W., Tensfeldt T., Foulds G., Kellogg M., Stam J., Campbell B., Jasys J., Kelbaugh P. Pharmacokinetic studies in animals of a new parenteral penem CP-65,207 and its oral prodrug ester. J Antibiot (Tokyo) 1990 Apr;43(4):422–432. doi: 10.7164/antibiotics.43.422. [DOI] [PubMed] [Google Scholar]
  10. Kahan F. M., Kropp H., Sundelof J. G., Birnbaum J. Thienamycin: development of imipenen-cilastatin. J Antimicrob Chemother. 1983 Dec;12 (Suppl 500):1–35. doi: 10.1093/jac/12.suppl_d.1. [DOI] [PubMed] [Google Scholar]
  11. Wright W. E., Line V. D. Biliary excretion of cephalosporins in rats: influence of molecular weight. Antimicrob Agents Chemother. 1980 May;17(5):842–846. doi: 10.1128/aac.17.5.842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Yamaoka K., Nakagawa T., Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm. 1978 Apr;6(2):165–175. doi: 10.1007/BF01117450. [DOI] [PubMed] [Google Scholar]

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