Alterations in renal uptake kinetics of the xanthine derivative enprofylline in endotoxaemic mice.
The pharmacokinetics and renal uptake of enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg-1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of enprofylline after constant infusion for 1 h. The renal uptake rate of enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (Vmax) from 17.3 to 32.2 micrograms h-1 g-1 of kidney and in the Michaelis-Menten constant (Km) from 2.7 to 21.7 micrograms mL-1 and decrease in the nonsaturable uptake rate constant (K4) from 0.87 to 0.43 mL h-1 g-1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of enprofylline by inducing a decrease in the renal uptake ability.
Nadai
M
M
Department of Hospital Pharmacy, Nagoya University School of Medicine, Japan.
Hasegawa
T
T
Wang
L
L
Haghgoo
S
S
Okasaka
T
T
Nabeshima
T
T
Kato
N
N
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D019446:Endotoxemia / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D007711:Klebsiella pneumoniae; D008297:Male; D051379:Mice; D014970:Xanthines / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014970:Xanthines; C034347:enprofylline