title: Pharmacokinetics and tissue distribution of a new carbapenem DA-1131, after intravenous administration to mice, rats, rabbits and dogs.
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.
authors.affiliation: College of Pharmacy, Seoul National University, Republic of Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: J W
authors.initials: JW
authors.lastname: Kwon
authors.forename: M G
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism; D015780:Carbapenems / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D015780:Carbapenems; C099230:DA 1131