Pharmacokinetics and tissue distribution of a new carbapenem DA-1131, after intravenous administration to mice, rats, rabbits and dogs

Biopharm Drug Dispos. 1998 May;19(4):219-29. doi: 10.1002/(sici)1099-081x(199805)19:4<219::aid-bdd95>3.0.co;2-f.

Abstract

The pharmacokinetic parameters including tissue distribution and/or biliary excretion of DA-1131, a new carbapenem, were evaluated after intravenous (iv) administration to mice, rats, rabbits, and dogs. After i.v. administration to mice (20, 50, 100, and 200 mg kg-1), rats (50, 100, 200, and 500 mg kg-1), rabbits (20, 50, 100, and 200 mg kg-1), and dogs (10, 20, 50, 100, and 200 mg kg-1), the pharmacokinetic parameters of DA-1131 seemed to be independent of DA-1131 doses studied in all four animal species. However, the renal clearance of percentage of i.v. dose of DA-1131 excreted in 24 h urine as unchanged drug decreased significantly in rabbits (from 200 mg kg-1) and dogs (from 100 mg kg-1) due to reduced kidney function induced by DA-1131. The creatinine clearance decreased significantly in rabbits at 200 mg kg-1 compared with that in the control rabbits (0.466 versus 4.31 mL min-1 kg-1). Renal active secretion of DA-1131 was observed in rabbits and was less considerable in rats, but renal active reabsorption of DA-1131 was observed in dogs. Although DA-1131 was widely distributed in all tissues studied in mice (20-200 mg kg-1), rats (200 mg kg-1), rabbits (50 mg kg-1), and dogs (50 mg kg-1) affinity of DA-1131 for tissues was low: the tissue-to-plasma concentration ratios were greater than unity only in the kidney and/or liver. The low affinity of DA-1131 for tissues was also supported by relatively low values of the apparent volume of distribution at steady state in rats (147-187 mL kg-1), rabbits (91.7-148 mL kg-1), and dogs 243-298 mL kg-1). The contribution of biliary excretion of unchanged DA-1131 to nonrenal clearance of DA-1131 seemed to be minor in rats (200 mg kg-1) and dogs (50 mg kg-1); the percentages of i.v. dose excreted in 8 h bile as unchanged DA-1131 were 1.76 and 2.71% after i.v. administration of the drug to rats and dogs, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile / metabolism
  • Biliary Tract / metabolism
  • Carbapenems / blood
  • Carbapenems / pharmacokinetics*
  • Dogs
  • Injections, Intravenous
  • Male
  • Mice
  • Mice, Inbred ICR
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution

Substances

  • Carbapenems
  • DA 1131