The faster CLNR after intravenous administration was due to increased hepatic CYP3A1/2 in both models of diabetes. The comparable AUC after oral administration was mainly due to decreased intestinal CYP3A1/2 activity. Alloxan and streptozotocin appear to influence some pharmacokinetics of telithromycin in a different fashion.
The pharmacokinetic and pharmacodynamic parameters of torasemide were compared after intravenous administration at a dose of 2 mg/kg to diabetic rats induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. It was reported that torasemide was mainly metabolized via CYP2C11 in rats and the expression and mRNA level of CYP2C11 decreased in DMIA and DMIS rats. Hence, it could be expected that the time-averaged nonrenal clearance (Cl(nr)) of torasemide could be slower in the diabetic rats. As expected, the Cl(nr) values were significantly slower in DMIA (0.983 versus 1.35 ml/min/kg) and DMIS (0.998 versus 1.36 ml/min/kg) rats. However, the time-averaged renal clearance (Cl(r)) values of torasemide were significantly faster in DMIA (0.164 versus 0.0846 ml/min/kg) and DMIS (0.205 versus 0.0967 ml/min/kg) rats due to urine flow rate-dependent timed-interval Cl(r) of torasemide in rats. The comparable time-averaged total body clearance (Cl) values between the diabetic and control rats were due to partially compensated Cl(r) in the diabetic rats. The 8 h urine output and diuretic efficiency increased significantly in the diabetic rats due to significantly greater 8 h urinary excretion of unchanged torasemide and at least partly due to an increase in urine output in diabetes per se (without administration of any drugs).
The pharmacokinetics of diclofenac were compared after intravenous and oral administration at a dose of 5 mg/kg in a rat model of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. Diclofenac was reported to be metabolized via the hepatic microsomal cytochrome P450 (CYP) 2C11 in male rats. The expression and mRNA level of CYP2C11 decreased in rat models of DMIA and DMIS. Hence, the time-averaged nonrenal clearance (Clnr) of diclofenac was expected to be slower in a rat model of diabetes. As expected, after intravenous administration, the Clnr values of diclofenac were significantly slower in rat models of DMIA (11.3 versus 13.6 ml/min/kg) and DMIS (8.06 versus 15.2 ml/min/kg) than those in control rats. As a result, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values were significantly greater in rat models of DMIA (435 versus 367 microg min/ml) and DMIS (540 versus 329 microg min/ml). However, after oral administration, the AUC from time zero to the last measured time, 12 h, in plasma (AUC0-12 h) values were comparable between the rat models of DMIA and DMIS and their control rats, and this could be due to changes in the first-pass effect of diclofenac and was not due to a decrease in the absorption of diclofenac in the rat models of diabetes.
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...
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