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 CLint 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.
Footnotes
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This study was supported in part by a grant from the Seoul City Collaborative Project among the Industry, Academy, and Research Institute, Korea.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.018499.
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ABBREVIATIONS: KPLPS, lipopolysaccharide induced by Klebsiella pneumoniae; HPLC, high-performance liquid chromatography; AUC, total area under the plasma concentration-time curve from time zero to time infinity; MRT, mean residence time; CL, time-averaged total body clearance; CLR, time-averaged renal clearance; CLNR, time-averaged nonrenal clearance; Vss, apparent volume of distribution at a steady state; Ae0-24 h, percentage of the dose excreted in the 24-h urine; GI24 h, percentage of the dose recovered from the entire gastrointestinal tract (including its contents and feces) at 24 h; Vmax, maximum velocity; Km, apparent Michaelis-Menten constant; CLint, intrinsic clearance; Cmax, peak plasma concentration; Tmax, time to reach Cmax; F, extent of absolute oral bioavailability; 1,3-DMU, 1,3-dimethyluric acid; MX, methylxanthine; P450, cytochrome P450; LPS, lipopolysaccharide.
- Received August 24, 2007.
- Accepted February 21, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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