Effects of Lipopolysaccharide on Pharmacokinetics of Drugs

Time‐dependent effects of Klebsiella pneumoniae endotoxin on the pharmacokinetics of chlorzoxazone and its main metabolite, 6‐hydroxychlorzoxazone, in rats: restoration of the parameters in 96 hour in KPLPS rats to control levels

“…The Cyp3a subfamily was decreased significantly in the 24 h and 96 h KPLPS rats but not altered in the 2 h KPLPS rats based on the measurement of benzphetamine N-demethylase activity [8]. Hepatic Cyp1a and 3a subfamilies were decreased significantly (by 73% and 59.1%, respectively) in 24 h KPLPS rats, but returned to controls in 96 h KPLPS rats [22]. Thus, the decrease in hepatic Cyp isozymes mentioned above in KPLPS rats could at least partly affect the formation of OH-CZX in the present study.…”

“…The liver and kidney functions in 24 h and 96 h KPLPS rats were not seriously impaired compared with controls based on the plasma and urinary chemistry data as well as liver and kidney histology [22].…”

Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in rats in vitro and in vivo

“…The present results will play an important role in explaining possible differences in the pharmacokinetic parameters of sildenafil and N ‐desmethylsildenafil in various rat disease models in which CYP2C11 and/or 3A1/2 are changed, such as in rats with protein–calorie malnutrition, 30 acute renal failure induced by uranyl nitrate 31 or diabetes mellitus induced by alloxan or streptozotocin, 32 and in studies of the pharmacokinetic effects of lipopolysaccharide endotoxin induced by Escherichia coli 33 or Klebsiella pneumoniae 34 . These results could also explain possible drug interactions between sildenafil and other drugs that are primarily metabolised via CYP2C11 and/or 3A1/2.…”

Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite, <I>N</I>-desmethylsildenafil, in rats <I>in vitro</I> and <I>in vivo</I>

“…acute renal failure induced by uranyl nitrate [31] or diabetes mellitus induced by alloxan or streptozotocin, [32] and in studies of the pharmacokinetic effects of lipopolysaccharide endotoxin induced by Escherichia coli [33] or Klebsiella pneumoniae. [34] These results could also explain possible drug interactions between sildenafil and other drugs that are primarily metabolised via CYP2C11 and/or 3A1/2. The hepatic CYP isozymes responsible for the metabolism of sildenafil in humans (CYP2C9 and 3A4) and in rats (CYP2C11 and 3A1/2) and formation of N-desmethylsildenafil in humans (CYP2C9 and 3A4) and in rats (CYP2C11) are very similar.…”