Effects of acute renal failure on the pharmacokinetics of telithromycin in rats: negligible effects of increase in CYP3A1 on the metabolism of telithromycin

2008

Pharm Res

Self Cite

Section: Introductionmentioning

confidence: 99%

Telithromycin Pharmacokinetics in Rat Model of Diabetes Mellitus Induced by Alloxan or Streptozotocin

2008

Pharm Res

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“…Although the exact values of hepatic and intestinal first-pass effects were not measured separately in NARs, the total percentages of both first-pass effects were supposed to be increased in NARs and this could result in a smaller F in NARs. Similarly, it has been also reported that hepatic and intestinal first-pass effects of several drugs were subjected to significant changes in various disease states in accordance with their specific CYP isozyme changes [33,34].…”

Section: Discussionmentioning

confidence: 79%

Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein binding

Jung

Kim

et al. 2009

Biopharm & Drug Disp

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It is well known that there are various changes in the expression of hepatic and intestinal CYPs in mutant Nagase analbuminemic rats (NARs). It has been reported that the protein expression of hepatic CYP1A2 was increased, whereas that of hepatic CYP3A1 was not altered, and it was also found that the protein expression of the intestinal CYP1A subfamily significantly increased in NARs from our other study. In addition, in this study additional information about CYP changes in NARs was obtained; the protein expression of the hepatic CYP2D subfamily was not altered, but that of the intestinal CYP3A subfamily increased in NARs. Because omeprazole is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats, it could be expected that the pharmacokinetics of omeprazole would be altered in NARs. After intravenous administration of omeprazole to NARs, the Cl(nr) was significantly faster than in the controls (110 versus 46.6 ml/min/kg), and this could be due to an increase in hepatic metabolism caused by a greater hepatic CYP1A2 level in addition to greater free fractions of the drug in NARs. After oral administration of omeprazole to NARs, the AUC was also significantly smaller (80.1% decrease) and F was decreased in NARs. This could be primarily due to increased hepatic and intestinal metabolism caused by greater hepatic CYP1A2 and intestinal CYP1A and 3A levels. In particular, the smaller F could mainly result from greater hepatic and intestinal first-pass effect in NARs than in the controls.

“…The lower CL NR might result from a decrease in the expression of hepatic CYP3A (Fig. 1) in ECLPS rats, because telithromycin was metabolized via CYP3A1/2 in rats (15). Decreased expression of rat hepatic 3A2 has also been reported (24,25).…”

Section: Figmentioning

confidence: 80%

“…After centrifugation of the blood sample, a 100-l aliquot of plasma sample was stored at Ϫ70°C until it was used for the HPLC analysis of telithromycin. The preparation and handling of urine samples and gastrointestinal tract samples (including contents of the tract and feces) taken at 24 h were similar to reported methods (14,15).…”

Section: Treatment With Eclpsmentioning

confidence: 92%

“…The protocol for this animal study was approved by the Institutional Animal Care and Use Committee of Seoul National University, Seoul, South Korea. Male Sprague-Dawley rats, 6 to 8 weeks old and weighing 240 to 300 g, purchased from Taconic Farms, Inc. (Samtako Bio Korea, O-San, South Korea), were maintained according to previously reported methods (14,15).…”

Section: Chemicalsmentioning

confidence: 99%

See 1 more Smart Citation

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

Antimicrob Agents Chemother

Cho

Jung

et al. 2008

Self Cite

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...