Quantitative evaluation of effect of renal failure on the pharmacokinetics of panipenem in rats.
The pharmacokinetics of panipenem in experimental renal failure animal models was investigated in order to identify the appropriate covariates affecting the pharmacokinetic behavior. Panipenem and betamipron were administered intravenously to rats with a variety of renal failures, such as nephritis induced by glycerol, gentamicin, uranium and antiserum against glomerular basement membrane as well as 5/6 subtotal nephrectomy. Panipenem in plasma and urine was determined and pharmacokinetic analysis was performed using a one-compartment open model. The elimination half-life prolonged and total body clearance, renal clearance (CL(R)) and renal excretion ratio were decreased according to the renal function, i.e. control>glycerol>anti-GBM=gentamicin>nephrectomy=uranium in order. However, distribution volume was consistent in all models. CL(R) showed strong positive correlation with the glomerular filtration rate in spite of a weak correlation with the reciprocal of blood urea nitrogen. However, no obvious correlation was observed with secretory clearance of N-1-methylnicotinamide. This preliminary information based on animal model might be useful for designing pharmacokinetic studies in special population at early stage of new drug development.
Tajima
Naoyuki
N
Clinical Pharmacology and Biostatistics Department, Sankyo Co., Ltd, Japan. tajima_naoyuki@sankyo.co.jp
Soma
Masako
M
Ishizuka
Hitoshi
H
Naganuma
Hideo
H
D000818:Animals; D000900:Anti-Bacterial Agents; D019540:Area Under Curve; D001323:Autoantibodies; D001485:Basement Membrane / Q000276:immunology; D001806:Blood Urea Nitrogen; D002851:Chromatography, High Pressure Liquid; D005839:Gentamicins; D005919:Glomerular Filtration Rate; D005990:Glycerol; D006207:Half-Life; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000276:immunology; D008297:Male; D009393:Nephritis / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D013056:Spectrophotometry, Ultraviolet; D013845:Thienamycins / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014501:Uranium
D000900:Anti-Bacterial Agents; D001323:Autoantibodies; D005839:Gentamicins; D013845:Thienamycins; D014501:Uranium; D005990:Glycerol; C039536:panipenem