Dose-dependent elimination of theophylline in rats

Teunissen, M. W. E.; Brorens, Irinka O. N.; Geerlings, J. M.; Breimer, D. D.

doi:10.3109/00498258509045346

Cited by 52 publications

(24 citation statements)

References 23 publications

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“…Recent studies on the metabolic inhibition of enoxacin in rats, however, suggested that quinolones may affect the pathway of theophylline metabolism for oxidation in addition to affecting N demethylation (6,20). Further detailed studies concerning whether quinolones selectively act in the metabolic pathway of theophylline in humans are necessary, although the pathways of theophylline metabolism in humans and rats are considered to be quite similar (3,27).…”

Section: Discussionmentioning

confidence: 99%

Effect of a new quinolone, sparfloxacin, on the pharmacokinetics of theophylline in asthmatic patients

Takagi

Yamaki

Nadai

et al. 1991

Antimicrob Agents Chemother

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Recently, it has become evident that some quinolones affect the processing of theophylline in the human system. The effect of a new quinolone, sparfloxacin, on the pharmacokinetics and metabolism of theophyUine was investigated in six asthmatic patients receiving chronic theophylline therapy (a sustained-release theophylline tablet formulation of 200 to 300 mg twice daily at 12-h intervals). To these patients, sparfloxacin (200 mg once daily) was coadministered for 1 week. Plasma and urine samples were analyzed by highperformance liquid chromatography for theophyiline and its metabolites. Plasma theophyiline concentrationtime curves and the urinary excretion of theophyline and its major metabolites before and after coadministration of sparfloxacin were compared. The total body clearance of theophylline after coadministration of sparfloxacin, 42.81 + 6.64 mI/h/kg (mean ± standard error of the mean), was not significantly different from that after the administration of theophylline alone, 47.11 ± 7.61 mW/kg. Also, no significant change in the urinary excretion of theophylline and its metabolites was observed for subjects receiving or not receiving sparfloxacin. These findings indicate that a once-daily dose of 200 mg of sparfioxacin has no significant effect on the pharmacokinetics and metabolism of theophylline and that it would be safe to coadminister this quinolone to asthmatic patients receiving chronic theophylline therapy.Theophylline is widely used in the treatment of patients with reversible obstructive airway diseases. In treating asthma, however, theophylline is commonly prescribed in combination with various other drugs. Many articles have been published on the interactions of theophylline with other drugs (13,15,17,18,31). Some quinolone antimicrobial drugs (ciprofloxacin, enoxacin, pefloxacin, and tosufloxacin), when coadministered with theophylline, may create clinical problems due to an inhibition of theophylline clearance, thus increasing the risk of the development of serious side effects (7,8,22,24,29,30).The mechanism of the decrease in theophylline clearance due to quinolones has generally been considered to be an inhibition of theophylline metabolism. However, the precise mechanism of the interaction between theophylline and quinolones is not yet fully understood. Therefore, interest remains in determining the pharmacokinetic interactions between theophylline and quinolones.A large number of new quinolone antimicrobial drugs with broad-spectrum activity have been developed in the past few years. Sparfloxacin (Fig. 1) has broad antibacterial activity against both gram-positive and gram-negative bacteria. This study was conducted as part of a program directed to the development of guidelines for the safe use of quinolone drugs in combination with theophylline in asthmatic patients. We investigated the possibility that multiple oral doses of sparfloxacin may affect the pharmacokinetics of theophylline in asthmatic patients receiving chronic theophylline therapy. MATERIALS AND METHODSPatients. Six...

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Section: Discussionmentioning

confidence: 99%

Effect of a new quinolone, sparfloxacin, on the pharmacokinetics of theophylline in asthmatic patients

Takagi

Yamaki

Nadai

et al. 1991

Antimicrob Agents Chemother

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“…Many investigators have reported the dose-dependent metabolic disposition of theophylline in humans [19][20][21][22] and in rats [23]. Therefore, in the present study, we used both a single low dose of 5 mg/kg of theophylline and multiple high doses of 50 mg/kg of the drug twice daily for 3 days, which has been reported to indicate linear and nonlinear pharmacokinetics, respectively [23], and investigated the ef fect of combination of ofloxacin, enox acin and cimetidine on the pharmacoki netics of theophylline.…”

Section: Discussionmentioning

confidence: 99%

Lack of Effect of Ofloxacin on Theophylline Pharmacokinetics in Rats

Okazaki

Miyazaki²,

Tachizawa³

1987

Chemotherapy

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Effect of ofloxacin, a new quinolone antibacterial agent, on the pharmacokinetics of theophylline was studied in rats in comparison with that of enoxacin and cimetidine. Ofloxacin by pretreatment with five oral doses of 50 mg/kg did not increase serum concentrations of theophylline (5 mg/kg, i.v. single) and showed no significant effect on total body clearance, serum half-life (TV,) and AUC of theophylline, while enoxacin by the same pretreatment increased significantly serum theophylline concentrations and resulted in significant effect on all the pharmacokinetic parameters. Coadministration of ofloxacin (80 mg/kg, p.o. twice) did not induce a significant effect on the pharmacokinetic parameters of theophylline at repeated doses (50 mg/kg, i.v., twice daily for 3 days). On the contrary, coadministration of enoxacin and cimetidine at the same dose as ofloxacin remarkably increased serum concentrations of theophylline at the same repeated doses, and caused a significant decrease in clearance and an increase in T_½ and AUC. The three drugs had no influence on rat serum protein binding of theophylline. Ofloxacin exhibited a weak inhibitory effect on rat hepatic microsomal cytochrome P-450-dependent monooxygenases, whereas enoxacin and cimetidine induced a significant inhibition of the enzymes. Thus, it is concluded that ofloxacin has no significant effect on the pharmacokinetics of theophylline in rats, and that enoxacin raises serum theophylline concentrations and results in a significant effect on the theophylline pharmacokinetics by inhibition of the hepatic microsomal monooxygenases in rats.

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“…Many investigators reported dose-dependent metabolic disposition of theophylline in humans (Lesko, 1979;Massey et al, 1984) and rats (Teunissen et al, 1985). Thus, theophylline at a dose of 5 mg/kg, which has been reported to be in the ranges of dose-independent metabolic disposition of theophylline in rats (for up to 10 mg/kg) (Teunissen et al, 1985), was administered intravenously or orally to rats.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, theophylline at a dose of 5 mg/kg, which has been reported to be in the ranges of dose-independent metabolic disposition of theophylline in rats (for up to 10 mg/kg) (Teunissen et al, 1985), was administered intravenously or orally to rats. The expression of hepatic CYP1A subfamily, 2B1/2, and 3A subfamily in three groups of rats is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Yang

Jung²,

Lee³

et al. 2008

Drug Metab Dispos

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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...

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Dose-dependent elimination of theophylline in rats

Cited by 52 publications

References 23 publications

Effect of a new quinolone, sparfloxacin, on the pharmacokinetics of theophylline in asthmatic patients

Effect of a new quinolone, sparfloxacin, on the pharmacokinetics of theophylline in asthmatic patients

Lack of Effect of Ofloxacin on Theophylline Pharmacokinetics in Rats

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

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