Time-Dependent Effects of Klebsiella Pneumoniae Endotoxin (KPLPS) on the Pharmacokinetics of Theophylline in Rats: Return of the Parameters in 96-Hour KPLPS Rats to the Control Levels

Abstract

ABSTRACT:It has been reported that theophylline is primarily metabolized via hepatic CYP1A1/2, 2B1/2, and 3A1/2, and 1,3-dimethyluric acid (1,3-DMU) is primarily formed via CYP1A1/2 in rats. Compared with control rats, the expression of CYP1A subfamily, 2B1/2, and 3A subfamily significantly decreased 24 h (24-h KPLPS rats) after intravenous administration of lipopolysaccharide derived from Klebsiella pneumoniae (KPLPS) to rats but returned to that in control rats after 96 h (96-h KPLPS rats). After intravenous or oral administration of theophylline to 24-h KPLPS rats, the values for the total area under the plasma concentration-time curve from time zero to time infinity of theophylline and 1,3-DMU became significantly greater (46.5 and 34.0% increase after intravenous and oral administration, respectively) and smaller (36.3 and 21.6% decrease, respectively), respectively. Because theophylline is a low hepatic extraction ratio drug in rats, the above results could have been due to significantly slower CL int for the disappearance of theophylline and for the formation of 1,3-DMU (37.1 and 60.6% decrease, respectively). However, in 96-h KPLPS rats, the pharmacokinetic parameters of theophylline and 1,3-DMU returned fully or partially to those in control rats. These findings indicate the existence of time-dependent effects of KPLPS on the pharmacokinetics of theophylline and 1,3-DMU in rats.Theophylline, a bronchodilator, has widely been used for the management of acute bronchospasm associated with asthma or chronic obstructive pulmonary disease. It is metabolized to 1-methylxanthine (MX), 3-MX, and 1,3-dimethyluric acid (1,3-DMU), and 1-MX is further metabolized to 1-methyluric acid via xanthine oxidase in rats (McManus et al., 1988). Recently, Yang et al. (2008) reported that theophylline is primarily metabolized via hepatic microsomal cytochrome P450 (P450) 1A1/2, 2B1/2, and 3A1/2 (but not via CYP2C11, 2D6, and 2E1), and 1,3-DMU was primarily formed via CYP1A1/2 in male Sprague-Dawley rats.Lipopolysaccharide (LPS) is an active component in the outer membrane of Gram-negative bacteria. There have been several studies on changes in the expression of hepatic P450 isozymes in rats pretreated with LPS derived from Klebsiella pneumoniae (KPLPS) (Nadai et al., 1998;Ueyama et al., 2005). However, to our knowledge, no studies on changes in the expression of hepatic CYP1A subfamily, 2B1/2, and 3A subfamily in rats pretreated with KPLPS after 24 h (24-h KPLPS) and 96 h (96-h KPLPS) based on Western blot analysis have yet been reported. It has been reported that inflammation is triggered in rats by a small dose of LPS (Deng et al., 2006), bacterial infection is an important factor in bronchial asthma (Oehling, 1999), and Gram-negative bacterial infections are common in patients with chronic obstructive pulmonary disease combined with pneumonia (Yi et al., 2003). Thus, we examined theophylline in this study.The aim of this study was to investigate changes in pharmacokinetics of theophylline and 1,3-DMU after intravenous or o...

Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus

“…[4,186,189] The metabolism of drugs that were mainly metabolized via the kidney was also dependent on drugs in DMIA or DMIS rats; the metabolism of DA-1131 and rR-RAGE was not altered, but rhIGF-1 increased compared with controls. [57,95,196] The values for CL R of intravenous cefazolin, cefradine, atenolol, and DA-7867 were faster and the values for the AUC of subcutaneous cefotaxime, and oral sodium tungstate and DA-7867 were smaller in DMIA and DMIS rats. [46,54,201,205,210,212] The biliary CL values of intravenous cefoperazone, ouabain, taurocholate, and PAEB were faster and the value for the AUC of oral zopolrestat was smaller in DMIA and DMIS rats.…”

“…[93] In male Sprague-Dawley rats, the formation of 1,3-DMU was primarily mediated via hepatic CYP1A1 and 1A2 and less via CYP3A1 and 3A2 (not via CYP2B1/2, 2C11, 2D1, and CYP2E1). [94,95] The protein expression and mRNA levels of hepatic CYP1A1, 1A2, 3A1, and 3A2 increased in male DMIA and DMIS rats (Table 1), which should have increased the formation of 1,3-DMU. [13,[16][17][18][19]21,22] In fact, after the intravenous administration of 5 mg/kg theophylline to male Sprague-Dawley DMIA rats on the fourth day and DMIS rats on the seventh day, their AUC 1,3-DMU / AUC theophylline ratios became greater (by 184 and 111%, respectively) than those of the controls.…”

Effects of endotoxin derived from Escherichia coli lipopolysaccharide on the pharmacokinetics of drugs

“…The timedependent changes in the hepatic CYP isozymes based on the various enzyme activity tests in ECLPS rats (Gorodischer et al, 1976;Monshouwer et al, 1996;Sewer et al, 1996;Roe et al, 1998;Sewer and Morgan, 1998) are listed in Table II. The changes in the hepatic CYP isozymes in PALPS rats (Ueyama et al, 2005) and in KPLPS rats (Nadai et al, 1998;Ueyama et al, 2005;Yang et al, 2008) have also been reported.…”

“…The changes in the hepatic CYP isozymes have been reported in rat models of KPLPS, ECLPS, and PALPS (Nadai et al, 1998;Ueyama et al, 2005;Yang et al, 2008). The pharmacokinetic changes of drugs in KPLPS rats have been reviewed (Yang and Lee, 2007) and the data on PALPS rats are scarce.…”

Pharmacokinetics of drugs in mutant Nagase analbuminemic rats and responses to select diuretics

“…Theophylline (5 mg/kg [19] ) CYP1A1/2, 2B1/2 and 3A1/2 [24,27] Significantly faster CLNR (by 49.3%) [19] 6…”