Effects of Escherichia coli Lipopolysaccharide on Telithromycin Pharmacokinetics in Rats: Inhibition of Metabolism via CYP3A

Abstract

It has been reported that telithromycin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP) 3A1/2 in rats and that the expression of hepatic and intestinal CYP3A decreases in rats pretreated with Escherichia coli lipopolysaccharide (ECLPS rats; an animal model of inflammation). Thus, it is possible that the area under the plasma concentration-time curve from 0 h to infinity (AUC 0-ؕ ) of intravenous and oral telithromycin is greater for ECLPS rats than for the controls. To assess this, the pharmacokinetic parameters of telithromycin were compared after intravenous and oral administration (50 mg/kg). After intravenous administration of telithromycin, the AUC 0-ؕ was significantly greater (by 83.4%) in ECLPS rats due to a significantly lower nonrenal clearance (by 44.5%) than in the controls. This may have been due to a significantly decreased hepatic metabolism of telithromycin in ECLPS rats. After oral administration of telithromycin, the AUC 0-ؕ in ECLPS rats was also significantly greater (by 140%) than in the controls and the increase was considerably greater than the 83.4% increase after intravenous administration. This could have been due to a decrease in intestinal metabolism in addition to a decreased hepatic metabolism of telithromycin in ECLPS rats.Telithromycin, a ketolide antibiotic, is the first of a new class of semisynthetic agents derived from erythromycin by the replacement of the sugar cladinose at position C-3 with a keto group. This alteration resulted in both improved pharmacokinetic properties and an improved spectrum of activity against community-acquired upper and lower respiratory tract pathogens compared to those of erythromycin (4). Telithromycin inhibits bacterial protein synthesis via two mechanisms, first by directly blocking the translation of mRNA and second by interfering with the assembly of new ribosomal units (5). Telithromycin has potent activities both in vitro and in vivo against common respiratory tract pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and group A beta-hemolytic streptococci, irrespective of their ␤-lactam or macrolide susceptibility (1). Its spectrum of activity also extends to atypical and intracellular pathogens (23). Lotter et al. (17) reported that telithromycin has antiinflammatory properties like those of conventional macrolides due to the inhibition of production of proinflammatory cytokines, which leads to a decreased formation of nitric oxide in Escherichia coli lipopolysaccharide (ECLPS)-treated mice.LPS is an active component in the outer membrane of gramnegative bacteria. ECLPS has been used as a classical inflammatory model for rats (9,27). Changes in the expression and mRNA levels of hepatic microsomal cytochrome P450 (CYP) isozymes have been reported for rats pretreated with ECLPS (ECLPS rats). For example, the expression and mRNA levels of hepatic CYP2C11, -2E1, and -3A2 decreased in male rats of the Fisher 344 or Sprague-Dawley strain 24 h after intraperitoneal injection of ECLP...

The acute phase response induced by Escherichia coli lipopolysaccharide modifies the pharmacokinetics and metabolism of florfenicol in rabbits

“…() demonstrated that an APR induced by the administration of E. coli LPS in rabbits decreased significantly the CYP content measured at 24 h after the first injection of endotoxin. Moreover, a significant decrease in hepatic and intestinal CYP3A was demonstrated in E. coli LPS‐treated rats, in which the endotoxin administration reduced the body clearance of telithromycin (Lee et al ., ). It has been proposed that suppressive effects of LPS on hepatic microsomal CYP are mediated through proinflammatory cytokines, such as TNF‐ α , IL‐1 β and IL‐6 (Monshouwer & Witkamp, ).…”

Plasma concentration and safety of lopinavir/ritonavir in patients with Covid-19: a short communication

“…In cultured human hepatocytes, direct treatments with tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) can reduce the expression of CYP1A2, CYP2C8 and CYP3A4 (13,14). In animals and humans, several studies or reports have shown the role of inflammation in reducing drug metabolism and CYP450 inhibition (15,16). CYP3A4 expression is transcriptionally regulated by pregnane X receptor (PXR), which is a ligand-dependent transcription factor (17).…”

Pharmacokinetics of mirodenafil, a new erectogenic, and its metabolite, SK3541, in rats: involvement of CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 for the metabolism of both mirodenafil and SK3541

“…The present results will play an important role in explaining the possible pharmacokinetic changes of mirodenafil and SK3541 in various rat disease models in which the CYP isoforms mentioned above are changed. For example, in rats with protein-calorie malnutrition (29), acute renal failure induced by uranyl nitrate (30), and diabetes mellitus induced by alloxan or streptozotocin (31), mutant Nagase analbuminemic rats, an animal model for human familial analbuminemia (32), and rats pretreated with lipopolysaccharide endotoxin induced by E. coli (33) or Klebsiella pneumoniae (34). These results could also contribute to explain possible drug-drug interactions between mirodenafil and other drugs which are primarily metabolized via hepatic CYP1A1/2, 2B1/2, 2D subfamily and/or 3A1/2.…”