The disposition and renal handling of enprofylline in endotoxemic rats by bacterial lipopolysaccharide (LPS).
The effects of lipopolysaccharide (LPS), isolated from Klebsiella pneumoniae (O3:K1-), on the pharmacokinetic behavior and renal handling of enprofylline, which is mainly excreted into the urine by an active tubular secretion mechanism, were investigated in rats. LPS (50 and 250 micrograms/kg) was infused for 20 to 30 min 2 hr before an intravenous administration of enprofylline (2.5 mg/kg). LPS induced a decrease in the systemic clearance and an increase in the volume of distribution at the steady state of enprofylline without any histological changes in the kidneys. No changes in the protein-binding parameters of enprofylline were observed between the control and LPS-pretreated groups, although LPS slightly decreased the albumin concentration in plasma. LPS caused decreases in the apparent maximum capacity of transport (Vmax) from 71.24 to 15.02 micrograms/min, in the Michaelis-Menten constant (KM) from 3.04 to 1.42 micrograms/ml, and in the glomerular filtration rate as estimated for inulin clearance from 3.10 to 1.87 ml/min. These results indicate that LPS decreases both the affinity and capacity of the tubular transport system, and in turn decreases the tubular secretory intrinsic clearance of enprofylline as shown by Vmax/KM. The mechanism for inducing changes in the pharmacokinetic behavior and renal handling of enprofylline by LPS may be related to the effects of LPS on tubular secretion of enprofylline and its distribution in the organs and peripheral tissues.
Nadai
M
M
Department of Hospital Pharmacy, Nagoya University School of Medicine, Japan.
Hasegawa
T
T
Kato
K
K
Wang
L
L
Nabeshima
T
T
Kato
N
N
D000818:Animals; D001993:Bronchodilator Agents / Q000493:pharmacokinetics*; D004347:Drug Interactions; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007711:Klebsiella pneumoniae / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014970:Xanthines / Q000493:pharmacokinetics*
D001993:Bronchodilator Agents; C043237:Klebsiella O3 lipopolysaccharide; D008070:Lipopolysaccharides; D014970:Xanthines; C034347:enprofylline