BACKGROUND: Since up to 90% of a theophylline dose is biotransformed, probably by interaction with one or more the variants of the cytochrome P-450 drug metabolism system, anti-tuberculosis agents including drugs influencing microsomal enzyme systems, such as isoniazid and rifampicin, may be affect the elimination of theophylline. METHODS: The effect of combination therapy with isoniazid(INH), rifampicin(RFP), ethambutol(EMB) and pyrazinamide(PZA) on the pharmacokinetics of theophylline was evaluated by a computer program using Bayesian method. Three group were divided as follows. Group lis control, Group II is treated with INH, RFP, EMB and PZA and Group lll is treated with INH, RFP and EMB. All of them were non-smoker who were normal in liver and renal functions, and not administered drugs affecting on the clearance of theophylline with exception of anti-tuberculous agents. RESULTS: When it compared control with test groups, the clearance of theophylline in Group ll and Group lll was significantly decreased(p<0.001), and half life in Group ll and Group lll showed significant elevation(p<0.001). However there were no significant differences in clearance and half life between the Group ll and Group lll. CONCLUSION: These results suggest that theophylline dose may be need of readjustment in concurrent medica fion of anti-tuberculous agents including INH, RFP, and EMB.
Bayes Theorem ; Cytochrome P-450 Enzyme System ; Ethambutol* ; Half-Life ; Isoniazid* ; Liver ; Metabolism ; Pharmacokinetics* ; Pyrazinamide ; Rifampin* ; Theophylline*

BACKGROUND: Theophylline is a weak bronchodilator with a narrow therapeutic window. Much of its clinical benefit derives from effects other than bronchodilaton; therapeutic doses of theophylline increase ventilatory drive, enhance diaphragmatic contractility and increase cardiac output. About 20% of COPD patients respond to theophylline with improved airflow, exercise tolerance and quality of life. Generally it is prescribed as a twice-daily equal-dose regimen so as to produce nearly constant blood level throughout each 24 hour. We compared 12-hour and 24-hour sustained-release theophyllines in the management of chronic obstructive pulmonary disease. METHODS: A crossover study was conducted with 27 adult chronic obstructive pulmonary disease requiring daily bronchodilator therapy. The study group included nineteen males and eight females ranging in age from 48 to 71 years. The overall approach was to place the patients first on the twice-daily preparation (Etheophyl(R)) for 28 days at 8 AM and 8 PM and pulmonary function tests and theophylline level were measured on the 28th day. The patients were subsequently switched to the once-daily preparation (Uniphyl(R)) in the same daily dose at 8 PM on the 29th day and the same parameters were measured on the 56th day. RESULTS: The mean serum levels of theophylline were 8.80+/-2.64 microgram/mL in the Etheophyl(R)-treated and 8.48+/-2.08 microgram/mL in the Uniphyl(R)-treated period. And the FEV1 showed 63.72+/-8.63% in the Etheophyl(R)-treated and 62.81+/-9.81% in the Uniphyl(R)-treated period. CONCLUSION: The results suggested that there was little clinical differences between the two medications. The two drugs were equally effective in clinically controlling COPD over the four weeks of treatment.
Adult ; Cardiac Output ; Cross-Over Studies ; Exercise Tolerance ; Female ; Humans ; Male ; Pharmacokinetics ; Pulmonary Disease, Chronic Obstructive* ; Quality of Life ; Respiratory Function Tests ; Theophylline

Diagnostic and therapeutic use of radioiodine in the management of thyroid disorders depends on the ability of thyroid cells to concentrate radioiodine, a process that is regulated by the intracellular increase in cAMP. We hypothesized that theophylline, a drug known to increase intracellular cAMP via inhibition of phosphodiesterase, could increase thyroidal radioiodine uptake. We tested this effect in vivo, using C57BL/6j mice, and in vitro, using Fisher rat thyroid (FRTL-5) cells. One mouse received 2.5mg theophylline i.p., whereas a control mouse received only saline. Twenty-hours after theophylline, mice were injected with 10mu Ci Na(125)I in 0.1 mL saline through the tail vein. Mean thyroidal (125)I activity was 3.3-fold higher in theophylline-treated mice than in their respective controls. Radioiodine uptake and intracellular cAMP production of FRTL-5 cells were increased by a relatively low concentration of theophylline (1mu M). Intracellular cAMP increased up to 30 min and then declined in response to 1mu M theophylline. Sera from theophylline-treated mice stimulated (125)I uptake and intracellular cAMP production by FRTL-5 cells. These findings show that theophylline can enhance radioiodine uptake by thyrocytes in vivo and in vitro. The in vitro effects of theophylline on both radioiodine uptake and cAMP production in a dose-dependent manner are consistent with an action mediated by phosphodiesterase inhibition.
Animals ; Blood Proteins/pharmacology ; Cells, Cultured ; Cyclic AMP/metabolism ; Female ; Iodine Radioisotopes/*diagnostic use/pharmacokinetics ; Mice ; Mice, Inbred C57BL ; Theophylline/*pharmacology ; Thyroid Gland/cytology/*metabolism ; Vasodilator Agents/*pharmacology

Administration, Inhalation ; Adrenal Cortex Hormones ; pharmacology ; Asthma ; drug therapy ; metabolism ; Child ; Child, Preschool ; Drug Interactions ; Drug-Related Side Effects and Adverse Reactions ; Female ; Humans ; Male ; Theophylline ; pharmacokinetics ; pharmacology ; Treatment Outcome

CYP1A2, CYP2D6 and N-acetyltransferase activities were estimated in 100 patients with bladder cancer and 84 control subjects from measurements of theophylline, metoprolol and isoniazid and their metabolites in urine, respectively. The frequency of occurrence of slow acetylators of isoniazid and poor metabolizers of metoprolol were 16.7% and 1.2% in the control group and 16.3% and 2.0% in the cancer patient group. These differences were not significant. The recovery ratio of 1-methyluric acid(1-MU) from theophylline was significantly higher in patients with bladder cancer than in control subjects(0.340 +/- 0.016 versus 0.260 +/- 0.020, p< 0.05). The 1-MU recovery ratio was a significant, independent risk factor among the metabolic capacities tested as shown by logistic regression analysis, controlling for N-acetylation of isoniazid, hydroxylation of metoprolol, age, sex, and smoking. We concluded that the capacity for 3-demethylation of theophylline, as a reflection of CYP1A2 activity, is significantly associated with increased risk of nonoccupational urinary bladder cancer.
Acetylation ; Adult ; Aged ; Amines/metabolism ; Bladder Neoplasms/enzymology/*epidemiology ; Carcinoma, Transitional Cell/enzymology/*epidemiology ; Case-Control Studies ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP2D6 ; Cytochrome P-450 Enzyme System/metabolism/*urine ; Disease Susceptibility ; Enzyme Induction ; Female ; Human ; Isoniazid/*pharmacokinetics ; Korea/epidemiology ; Logistic Models ; Male ; Methylation ; Metoprolol/*pharmacokinetics ; Middle Age ; Mixed Function Oxygenases/metabolism ; Mixed Function Oxygenases/metabolism ; Oxidoreductases/*urine ; Smoking ; Support, Non-U.S. Gov't ; Theophylline/*pharmacokinetics ; Uric Acid/analogs & derivatives/urine