Kinetics of intravenous theophylline

Chrzanowski, Frank A.; Niebergall, Paul J.; Mayock, Robert L.; Taubin, Joel; Sugita, Edwin T.

doi:10.1002/cpt1977222188

Cited by 41 publications

(11 citation statements)

References 8 publications

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“…As a consequence, the monitoring of plasma concentration in patients on theophylline treatment is now current practice (Hendeles et al, 1978;Ogilvie, 1980). After intravenous administration to healthy adults, the pharmacokinetics of theophylline in plasma are best described by a two compartment open model (Mitenko & Ogilvie, 1973a;Chrzanowski et al, 1977); the biphasic disposition of the drug is characterised by a rapid distribution phase (half-life of 30 to 40 min) and a slower elimination phase (half-life of 4 to 12 h). After oral administration, the distribution phase of the drug is masked by the absorption and the kinetics can be adequately studied applying a one compartment model (Upton et al, 1980).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of theophylline: a dose‐range study.

Rovei¹,

Chanoine²,

Benedetti³

1982

Brit J Clinical Pharma

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1 Pharmacokinetics of theophylline were investigated in a group of healthy adult volunteers (non smokers and on xanthine-free diet) following single oral administration of 125, 250, 375 and 500 mg doses as tablets (Theodel(®). 2 Absorption of theophylline was rapid and followed first-order kinetics. Plasma curves were fitted according to a one compartment open model.3 There was a linear relationship (P < 0M.0)) between plasma Cmax or AUC, values and the administered dose. The analysis of variance showed that the pharmacokinetic parameters of theophylline (t,, abs, tmai, t. 3,, CL, CLR, Vd and F) were not modified at any dose.4 Absorption of the drug was complete since the recovery in urine of theophylline (13.7 to 16.8% of the dose) and its major metabolites, 1,3-dimethyluric acid (35 to 42%), 1-methyluric acid (21.3 to 26.7%) and 3-methylxanthine (11.5 to 13.7%), accounted for the administered dose. Some impairment of demethylation to 3-methylxanthine was observed in two subjects, however the percentage of theophylline and its major metabolites excreted in urine was constant for all the four doses. 5 On the basis of these results, after single oral administration, elimination of theophylline followed first-order kinetics in the range of doses investigated (1.62 to 10.42 mg/kg).

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of theophylline: a dose‐range study.

Rovei¹,

Chanoine²,

Benedetti³

1982

Brit J Clinical Pharma

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“…The elimination kinetics of theophylline can be described by linear models at doses which are therapeutic [3,4], Recently, Tang-Liu et al [5] have shown that the formation of 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid from theophylline follows Michaelis-Menten ki netics and becomes capacity-limited within the therapeutic range of theophylline. In a recent investigation of the suppression of ci metidine on theophylline clearance using a single low dose (2 mg/kg) of theophylline, we observed a mean theophylline clearance rate of 0.065 Mi-l *kg_l which approaches the upper limit of clearances reported for healthy, nonsmoking young adults [6].…”

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confidence: 99%

Theophylline Kinetics: Dose Dependency and Single Sample Prediction of Clearance

et al. 1985

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Theophylline clearance was measured at 3 doses (2, 4 and 6 mg/kg) in 10 young, healthy adult subjects. Clearance decreased as the dose of theophylline increased going from 0.064 ± 0.016 to 0.052 ± 0.011 l·h^–1 Kg^–1 at the 2 and 6 mg/kg doses, respectively (p < 0.02). A simplified method for estimating theophylline clearance was tested using single plasma concentrations of theophylline and assuming a constant value (0.5 l/kg) for volume distribution of theophylline. This method gave the best results when samples were drawn at 12 or 24 h after a 2 or 4 mg/kg intravenous dose of theophylline, respectively, and was effectively applied in estimating the quantitative impact of cimetidine administration on theophylline clearance.

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“…Although log-linear decay of theophylline plasma concentration after a single dose have been interpreted to favor the concept of linear kinetics (7,14,(17)(18)(19) dose dependent kinetics of the drug in the therapeutic dose range have been suggested by several innvestigators (2,(8)(9)(10)(11)(12)(20)(21)(22). The finding of dose dependent kinetics was explained by constant excretion rate of 3-MX and 1-MU for some hours after a single oral doe of theophylline (2,12).…”

Section: Discussionmentioning

confidence: 99%

Dose dependent pharmacokinetics of theophylline: Michaelis-menten parameters for its major metabolic pathways

Dadashzadeh

Tajerzaden

2001

Eur. J. Drug Metab. Pharmacokinet.

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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 didn't find obvious indication for nonlinear formation of DMU at therapeutic concentration range.

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Kinetics of intravenous theophylline

Cited by 41 publications

References 8 publications

Pharmacokinetics of theophylline: a dose‐range study.

Pharmacokinetics of theophylline: a dose‐range study.

Theophylline Kinetics: Dose Dependency and Single Sample Prediction of Clearance

Dose dependent pharmacokinetics of theophylline: Michaelis-menten parameters for its major metabolic pathways

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