Pharmacokinetics of sustained release theophylline in low and high multidose regimens.

Koeter, Gh; Jonkman, J. H. G.; Vries, K. de; Schoenmaker, R.; Greving, Je; Zeeuw, Rokus A. de

doi:10.1111/j.1365-2125.1981.tb01283.x

Cited by 20 publications

(5 citation statements)

References 11 publications

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“…Third, a linear correlation was found between dosages from 400 to 1,200 mg and steady-state plasma levels, which is con sistent with the reported dose proportion ality and linear pharmacokinetics of theo phylline [11]. In the majority of patients studied by us a daily dose of 800 mg seems appropriate from a point of view of toler ance and efficacy.…”

Section: Discussionsupporting

confidence: 55%

Once-Daily Dosing of a New Ultrasustained-Release Theophylline Preparation

Brande

Nys²,

Tjandramaga³

et al. 1987

Respiration

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Theophylline plasma levels and profiles were evaluated in patients with chronic obstructive pulmonary disease during once-daily dosing of an ultrasustained-release theophylline preparation (Theo-1; capsules filled with microgranules containing 400 mg anhydrous theophylline). In a first study, 6 patients received a single morning dose of 800 mg (a) in the fasting state, and (b) with a protein-fat-rich breakfast in a random order, and the systemic theophylline availability was evaluated for 48 h. No significant differences were found either in C_max (a: 7.0 ± 3.2 μg/ml; b: 7.6 ± 2.6 μg/ml), or in T_max (a: 11.7 ± 6.1 h; b: 10.2 ± 3.6 h). Elimination half-life was in a 11.4 ± 4.4 h and in b 12.9 ± 4.8 h (p < 0.05). In a second study, the steady-state theophylline levels were measured during a 24-hour dosage interval on day 8 after intake of 800 mg at 8 a.m. in 16 patients and at 8 p.m. in 11 patients. Plateau-shaped plasma concentration-time curves were obtained, with small fluctuations between the peak (C_max) and trough (C_min) levels: [100(C_max-C_min)/C_min] was 83 ± 40% after morning dose, and 54 ± 26% after evening dose (p < 0.05). C_max was 12 ± 5 and 11 ± 4 μg/ml, respectively (NS). T_max was 9 ± 3 and ± 3 h, respectively (NS). The FDA fluctuation for the 37 patients was 48 ± 20%. In a third study, the dose-plasma concentration relationship was evaluated in steady state in 6 patients receiving 400, 800 and 1,200 mg for 3 days each. The trough plasma concentrations were 2.6 ± 0.9, 6.2 ± 2.1 and 10.2 ± 3.1 μg/ml, respectively. Six hours after drug intake the plasma levels were 5.0 ± 1.6, 10.6 ± 2.5 and 15.4 ± 4.2 μg/ml, respectively; and h after drug intake, 4.9 ± 1.4, 11.6 ± 2.4 and 14.5 ± 3.7 μg/ml, respectively. In conclusion, we found in these studies that with once-daily dosing of the ultrasustained-release preparation Theo-1, plateau-shaped 24-hour theophylline plasma levels could be achieved. The relationship between daily dosage and theophylline plasma levels was linear intraindividually but showed an important interindividual variation. No consistent interference by food intake was found and no serious side effects occurred within therapeutic plasma levels

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Section: Discussionsupporting

confidence: 55%

Once-Daily Dosing of a New Ultrasustained-Release Theophylline Preparation

Brande

Nys²,

Tjandramaga³

et al. 1987

Respiration

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“…During repeated administration of the drug when steady state plasma concentrations are achieved, saturation of theophylline metabolism should be observed, particularly if the dose is increased. However, a recent study in a group of healthy adults (Koeter et al, 1981) has shown that theophylline followed linear pharmacokinetics during 1 week repeated oral administration of Theodur®E (300 and 900 mg/day), a sustained release preparation. This observation is confirmed in our study in which there was no clear evidence that the kinetics of theophylline could be saturated.…”

Section: Discussionmentioning

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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“…Since the constant rate excretion of metabolites could be explained by assuming Michaelis-Menten kinetics for formation or excretion of the metabolites, so further investigations with plasma data based on different doses were required to confirm the findings. Some studies using different doses of theophylline concluded that there was no significant dose dependency in theophylline kinetics in the therapeutic range of serum conncentration (14,23). Gundert-Remy et al could be able to measure DMU, the major mmetabolite of theophylline, in plasma and reported that there is some evidence for saturable formation of DMU even in the therapeutic dosage range (24).…”

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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Pharmacokinetics of sustained release theophylline in low and high multidose regimens.

Cited by 20 publications

References 11 publications

Once-Daily Dosing of a New Ultrasustained-Release Theophylline Preparation

Once-Daily Dosing of a New Ultrasustained-Release Theophylline Preparation

Pharmacokinetics of theophylline: a dose‐range study.

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

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