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document
Dose dependent pharmacokinetics of theophylline : Michaelis-Menten parameters for its major metabolic pathways . Dose Dependency for pharmacokinetics of theophylline and the formation of its major metabolites , 3-methylxanthine ( 3-MX ) ; 1-methyluric acid ( 1-MU ) ; 1,3-dimethyluric acid ( DMU ) , were examined by administering three single oral doses ( 250 , 375 , 500 mg ) of theophylline to six healthy adult volunteers . The serum and urine concentrations of theophylline and the metabolites in serum and urine were determined by high-performance liquid chromatography . Total clearance of theophylline decreased and its half life increased over the range of doses administered ( p < 0.01 ) . There was a significant dose related decrease in the fractional recovery of 3-MX and 1-MU ( p < 0.001 ) and a dose related increase in fractional excretion of DMU and unchanged theophylline ( p < 0.01 and p < 0.001 respectively ) . No significant dose related changes were observed in the renal clearance of 3-MX , 1-MU and DMU , indicating linear urinary excretion kinetics of the metabolites . Theophylline metabolic clearance to 3-MX as well as to 1-MU decreased with increasing dose but clearance to DMU remained unnaffected by the size of dose . The individual Michaelis-Menten parameters Km and Vmax were estimated for six subjects receiving three different single doses . The Km values for theophylline metabolism to 3-MX , 1-MU and DMU were 2.4+/-0.6 , 5.1+/-1.8+/- and 112.3+/-36.8 mg/L respectively and the Vmax values were 3.5+/-0.7 , 7.5+/-2.6 and 112.3+/-36.8 mg/hr respectively . The Km values for the N-demethylation pathways ( 3MX and 1-MU ) were lower corresponding to therapeutic serum concentrations of drug . These results suggest that the elimination kinetics of theophylline is nonlinear in the human in the therapeutic range of serum concenntrations and can be explained by saturable formation kinetics of 3-MX and 1-MU . In contrast to previous studies we did n't find obvious indication for nonlinear formation of DMU at therapeutic concentration range .
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Intervention_Pharmacological
theophylline
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Intervention_Pharmacological
theophylline
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Intervention_Pharmacological
theophylline
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Intervention_Pharmacological
theophylline
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Intervention_Pharmacological
Theophylline
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Intervention_Pharmacological
theophylline
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Intervention_Pharmacological
theophylline
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Outcome_Other
Total clearance
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Outcome_Mental
fractional excretion of DMU
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Outcome_Mental
renal clearance of 3-MX
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Outcome_Mental
1-MU
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Outcome_Mental
DMU
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Outcome_Mental
Theophylline metabolic clearance to 3-MX
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Outcome_Other
Michaelis-Menten parameters Km and Vmax
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Outcome_Other
Km values for theophylline metabolism to 3-MX
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Outcome_Mental
1-MU
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Outcome_Mental
DMU
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Outcome_Other
Vmax values
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Outcome_Other
Km values for the N-demethylation pathways ( 3MX and 1-MU )
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Outcome_Physical
serum concenntrations
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Participant_Sample-size
six
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Participant_Age
adult