Lowering of theophylline clearance by isoniazid in slow and rapid acetylators [see comments] (original) (raw)
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Temporal variation in the disposition of theophylline and its metabolites
Clinical Pharmacology and Therapeutics, 1985
The temporal aspects of theophylline disposition are of interest, as there are predictable time-dependent fluctuations in the pulmonary function of patients with asthma and theophylline serum concentrations may vary throughout a 24-hour period. We studied the extent to which there are significant temporal changes in theophylline kinetics and the relative contribution of distribution, metabolism, and excretion to this phenomenon. Eight healthy men received an intravenous dose (6 mg/kg) of theophylline at 8 AM and 8 Pm at 1-week intervals. Serum and urine were analyzed for theophylline and its three major metabolites by HPLC. Distribution volumes and total body and nonrenal clearances showed no differences between morning and evening dosing. The elimination rate was 12% greater after morning dosing. Renal clearance was 24% greater after morning dosing and was accompanied by an increased excretion fraction of unchanged theophylline. Based on total urinary metabolite excretion and the metabolite serum AUCs, there was no evidence of time-dependent variation in theophylline biotransformation. Although theophylline renal clearance is greater after morning dosing, it is only a small fraction of the overall drug elimination and does not change the total body clearance after morning or evening dosing. (CLINT PHARMACOL THER 38:89-95, 1985.)
European Journal of Drug Metabolism and Pharmacokinetics, 2001
Dose Dependency for pharmacokinetics of theophylline and the formation of its major metabolites, 3-methylxanthine (3-MX); 1methyluric 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 llife increased over the range of doses administered (p<O.OI).There was a significant dose related decrease in the fractional recovery of 3-MX and I-MU (p<O.OOI)and a dose related increase in fractional excretion of DMU and unchanged theophylline (p<O.OI and p<O.OOl respectively). No significant dose related changes were observed in the renal clearance of 3-MX, I-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~and Vmaxwere estimated for six subjects receiving three different single doses. The K m values for theophylline metabolism to 3-MX, 1-MU and DMU were 2.4±O.6,5.1±1.8± and 112.3±36.8 mg/L respectively and the Vmaxvalues were 305±O.7, 705±2.6 and 112.3±36.8 mg/hrrespectively. The K m values for the N-demethylation pathways (3MX and I-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.
A Single-Blind Crossover Study of Two Different Slow Release Theophylline Preparations
Journal of International Medical Research, 1988
In a single-blind crossover study, two slow release theophylline preparations were evaluated in 18 patients with chronic bronchitis or asthma without cardiac, renal or liver disease. After randomization into two groups, patients were treated, in a crossover study design, with 600 mg choline theophyllinate or 300 mg anhydrous theophylline administered orally every 12 h for 7 days. A 2-day washout period separated the two periods of treatment evaluation. Blood samples in which plasma theophylline concentration was to be measured were taken at 7.30 a.m., 2.00 p.m. and 7.30 p.m. during the last 5 days of therapy with each drug. The mean fluctuation in plasma theophylline concentration was ≤40% in all 18 patients taking choline theophyllinate yet in only 15 (83%) patients administered anhydrous theophylline. Salbutamol inhaler was more frequently required for the relief of bronchospasm when taking anhydrous theophylline than when taking choline theophyllinate (total of 41 vs 25 puffs, re...
Impact of ciprofloxacin on theophylline clearance and steady-state concentrations in serum
Antimicrobial Agents and Chemotherapy, 1988
The effect of a multiple-dose regimen of oral ciprofloxacin (750 mg every 12 h for 11 doses) on the clearance and steady-state concentrations of theophylline in trough (predose) serum was evaluated in nine healthy male subjects, each serving as his own control. Theophylline was taken as a sustained release tablet per os in a dose of 200 mg every 12 h for 19 doses. Theophylline concentrations in serum were measured immediately before each theophylline dose. Ciprofloxacin was administered on study day 4 through the first dose of study day 8. Theophylline concentrations in serum were also measured on study days 3, 6, 8, and 10 at the following times after the first dose of each day: 0, 0.25, 0.50, 1, 2, 4, 6, 8, 10, and 12 h. Steady-state theophylline concentrations in trough serum were significantly higher during ciprofloxacin treatment (day 8) than before (day 3) or after (day 10) ciprofloxacin administration (P less than 0.01). Likewise, theophylline clearance was significantly slow...
A Clinical and Pharmacokinetic Basis for the Selection and Use of Slow Release Theophylline Products
Clinical Pharmacokinetics, 1984
In order to achieve the greatest chance for maximum benefit from theophylline in the management of chronic asthma, the serum concentration should be maintained in the therapeutic range of 10 to 20 pg/ml. Conventional rapid release formulations produce excessive fluctuations in serum concentrations that can result in variability in clinical response between doses. In contrast, slow releaseformulations have the potential to achieve relatively constant serum concentrations with i2-hour dosing intervals, thus providing around-the-clock stabilisation of the hyper-reactive airways that characterise chronic asthma. Furthermore, the decreased frequency of dosing with these formulations can improve patient compliance. However, significant differences in rate and extent of absorption exist between the available formulations. Single-dose bioavailability studies comparing a slow release product with an oral solution or plain uncoated tablet in a crossover design permit examination of the rate and extent of absorption. Comparison of a slow release product with an oral reference following multiple doses at steady-state permits examination of the extent but generally not rate of absorption. The mean fraction absorbed-time profile, calculated from a modification of the Wagner-Nelson equation, is a process-independent method of comparing rates of absorption of different products after single doses. A prospective study in i4 children with chronic asthma has demonstrated that this modified equation, when rearranged to iteratively solve for serum concentrations, can accurately predict steady-state serum concentrations for different dosing intervals in patient populations with different rates of elimination. When slow release products are compared in this manner at 8or i2-hour dosing intervals for patients with slow elimination, clinically relevant differences between brands are not apparent. However, in patients with rapid elimination, i.e. children, cigarette smokers, and 25% of non-smoking adults, application of this method shows that only some formulations (i.e. 'Slo-Bid Gyrocaps' and Theo-Dur', which is also marketed under different brand names such as 'Sustaire', 'Pulmi-Dur' and Theolin RetardJ can maintain serum concentrations within the therapeutic range for an entire I2-hour dosing interval. More rapidly absorbed slow release products must be administered at 8-hour dosing intervals in patients with rapid elimination, despite promotional claims to the contrary. Current products promQted for once-a-day administration are clinically inadequate because of incomplete and erratic absorption, and/or excessive serum concentration fluctuations. With one of these formulations, Theo-24 , (also marketed under the name 'Pulmo-TimeletsJ, there is evidence that food induces dose dumping of potentially toxic amounts of the drug.
Effect of cimetidine on the pharmacokinetics of theophylline
General Pharmacology: The Vascular System, 1988
The effect of the therapeutic doses of cimetidine (400 mg/twice daily) on theophylline metabolism in Jordanian volunteers was studied. 2. The administration of the above therapeutic cimetidine dose did not alter theophylline clearance and elimination half-life. 3. Cimetidine administration also failed to alter the elimination of theophylline metabolites in urine.
Stability of theophylline elimination rate
Clinical pharmacology and therapeutics, 1987
The elimination rate for theophylline varies greatly among patients, but recommendations for maintenance dosing schedules have assumed relatively little intrapatient variability even over extended time periods. Reports of large intrapatient variability of theophylline elimination rate and consequent clearance raise concerns regarding this assumption and also challenge the practice of assuming relative constancy of elimination rate in the performance of bioavailability studies of slow-release formulations. We therefore systematically studied under controlled conditions the elimination rate of theophylline in 10 patients over an extended time interval. The initial elimination rate constants ranged from 0.062 to 0.136 hours-1. The changes ranged from -5.9% to 9.4% of the initial value during intervals of 2 to 11 months. Correlation of the first and second values was 0.96. Thus the elimination rate of theophylline generally appears to vary little within individuals over time when studie...
The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects
British Journal of Clinical Pharmacology, 1995
1 The mechanism of the interaction between ciprofloxacin and theophylline was investigated in nine healthy subjects. 2 Subjects were given a single oral dose of theophylline (3.4 mg kg-), before and after 60 h of ciprofloxacin therapy at a dose of 500 mg twice daily. 3 Ciprofloxacin reduced the oral clearance of theophylline by 19% (-7.73 ± 6.42 ml kg-' h-' (95% confidence limits -12.66, -2.79)). Some subjects (group A, n = 4) showed little decrease in clearance (mean 4.4%; -1.6 ± 0.7 ml kg-' h-1 (-2.6, -0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; -12.7 ± 3.7 ml kg-' h-1 (-17.2, -8.1)).