Theophylline Half-life Research Articles

Effects of enoxacin and ciprofloxacin on the theophylline metabolism in humans.

Some kinds of newer fluoroquinolone antibiotics are known to interact with theophylline, which is widely used as a potent bronchodilator in asthma or chronic obstructive lung disease. To evaluate the effect of enoxacin and ciprofloxacin on the metabolism of theophylline, aminophylline was administered intravenously in bolus (6 mg/kg) over 30 minutes to 6 healthy volunteers (age: year, body weight: , height: , female 3, male 3) before and after per oral 5-day medication of enoxacin and ciprofloxacin, respectively and we measured the level of theophylline in serum. The results were as follows: 1) Enoxacin and ciprofloxacin did not influence the volume of distribution significantly. 2) Enoxacin decreased the clearance of theophylline significantly (from to : p: p>0.005). 3) Enoxacin increased the elimination half life of theophylline significantly (from to : p: p>0.05). These results suggested that enoxacin influenced clearance and elimination half life significantly and thorough monitoring of the level of theophylline in patients with coadminstration of enoxacin and theophylline was necessary. In case of ciprofloxacin, the influence on the metabolism of theophylline was not statistically significant, but one exceptionally large decrease of the clearance and increase of the elimination halflife of theophylline suggested the necessity of monitoring of theophylline level during coadministration of ciprofloxacin and theophylline.

Theophylline Pharmacokinetics: Effect of Continuous Versus Intermittent Cimetidine IV Infusion

The comparative effects of continuous versus intermittent cimetidine infusion on theophylline pharmacokinetics were evaluated in 12 nonsmoking healthy male volunteers. Each subject received aminophylline 0.9 mg/kg/hr over 6 hours alone (control) and in random order at 1 week intervals, in combination with intermittent cimetidine (300 mg IV over 15 minutes every 6 hours) and continuous cimetidine (50 mg/hr IV) infusions. Both cimetidine regimens were administered for a total of 50 hours. Serial plasma samples were obtained and assayed for theophylline by HPLC. No significant differences existed in mean theophylline clearance and mean volume of distribution among control, intermittent or continuous cimetidine regimens; the power was greater than 80% to detect a 30% change in clearance. Only a minor difference in theophylline half-life between control and continuous cimetidine infusion (7.59 +/- 2.52 vs. 9.05 +/- 3.17 hr; P less than .05) was observed. These findings do not support a clinically significant interaction between IV aminophylline and cimetidine administered IV either as a low dose continuous infusion or as an intermittent infusion.

The Effect of Multiple-Dose Oral Lomefloxacin on Theophylline Metabolism in Man

Single-dose plasma pharmacokinetics of theophylline (6 mg/kg intravenously) and renal excretion of theophylline and its metabolites, resulting from 8-oxidation and N-demethylation, were investigated in eight healthy volunteers before and at day 3 of concomitant oral administration of the quinolone derivative lomefloxacin (400 mg twice daily). Plasma samples were collected until 24.5 h, and urine samples were collected until 72 h after theophylline administration. The concentrations of theophylline and the major metabolites, resulting from N-demethylation and 8-oxidation, were measured utilizing a high-pressure liquid chromatography (HPLC) technique. No significant changes in theophylline half-life, volume of distribution, protein binding, total body clearance, or renal clearance were noted. In addition, renal excretion of unchanged theophylline, the products of the N-demethylation, 3-methylxanthine, and 1-methyluric acid, and the product of the 8-oxidation, 1,3-dimethyluric acid, were not altered by simultaneous administration of lomefloxacin. Orally administered lomefloxacin is absorbed quickly and to a high extent. During administration of 400 mg twice daily, plasma concentrations reached are well above minimum inhibitory concentration (MIC) values of pathogens that are frequently isolated in lower respiratory tract infections. This study shows that lomefloxacin in a twice daily dose of 400 mg does not effect theophylline metabolism. Lomefloxacin and theophylline can be coadministered without concern about effects of lomefloxacin on theophylline pharmacokinetics.

Lowering of theophylline clearance by isoniazid in slow and rapid acetylators [see comments

The effect of isoniazid (INH) pretreatment (400 mg daily for 2 weeks) on the elimination kinetics of theophylline (given intravenously as aminophylline equivalent to 151.2 mg theophylline) was investigated in 13 healthy male non-smokers. Amongst the 13 subjects studied, seven were rapid and six were slow acetylators. The mean clearance of theophylline was significantly lowered after INH (2.20 +/- 0.24 l h-1) (mean +/- s.e. mean) compared with the baseline value (2.80 +/- 0.24 l h-1). The volume of distribution at steady state was also lowered significantly after INH (0.42 +/- 0.01 l kg-1 vs 0.47 +/- 0.02 l kg-1). Consequently, there was no significant prolongation of theophylline half-life after INH (7.0 +/- 0.3 h vs 6.7 +/- 0.4 h control). The lowering of theophylline clearance by INH may be related to acetylator status since slow acetylators showed a greater interaction than rapid acetylators. However, this difference was not statistically significant.

Childhood Asthma in Thailand

Asthma is common in Thai children with a prevalence of about 4%. A prospective study of 2,000 Thai asthmatic children showed boys to be more frequently affected than girls, and fifty percent of patients experienced their first attack within the first 2 years of life. Attacks usually occurred in winter and the rainy season. 63.15% of patients had asthma associated with other allergic diseases and 79.25% had a family history of allergic diseases. Positive skin tests to important antigens were noted in 93.7% of cases, and house dust was the most common. Pharmacokinetic studies of theophylline were made in Thai asthmatic children after oral administration revealed that the elimination half-life of theophylline was longer than that observed in subjects in Western countries. Long-term follow up of 247 Thai asthmatic children revealed that in 37.2% of patients, symptoms ceased at the age of 15 years. The factors which indicated a favorable prognosis included male sex, mild or moderate illness, negative skin tests or positive skin tests to only a few allergens.

Effect of nifedipine on antipyrine and theophylline disposition

On the basis of reports that some calcium channel blockers impair the elimination of some drugs, the effect of nifedipine on the disposition of antipyrine and theophylline was assessed in healthy volunteers. Antipyrine half-life of 10.04 +/- 1.43 h (mean +/- SD) after a week intake of nifedipine (20 mg twice daily) was not significantly different from the control value of 10.64 +/- 2.15 h; nor was that of 10.02 +/- 1.49 h after 2 weeks pretreatment with the calcium channel blocker in eight healthy volunteers. Control antipyrine clearance (ml min-1) of 44.40 +/- 10.58 was not significantly different from that of 45.66 +/- 9.34 and 46.87 +/- 9.63 after nifedipine pretreatment of 1 and 2 weeks, respectively. Similarly volume of distribution was unaltered: 0.601 +/- 0.074, 0.591 +/- 0.078 and 0.602 +/- 0.051 l kg-1, respectively. A week pretreatment with nifedipine did not significantly alter either of theophylline half-life (7.32 +/- 0.81 h (control) to 7.50 +/- 0.80 h) or clearance (42.10 +/- 5.84 ml min-1 (control) to 43.77 +/- 4.00 ml min-1) in six volunteers. However the change in volume of distribution: 0.451 +/- 0.053 l kg-1 (control) to 0.483 +/- 0.062 l kg-1 was significant (p less than 0.025). Generally, theophylline plasma levels were lower after nifedipine pretreatment and the difference was significant at 2 and 4 h post-dosing (p less than 0.05). It is suggested that nifedipine, unlike diltiazem and verapamil, is unlikely to interfere with the functional integrity of the hepatic mixed-function oxygenase enzymes, but might displace theophylline from plasma protein.

Lack of Effect of Piroxicam on Theophylline Clearance in Healthy Volunteers

This study was conducted to determine if piroxicam alters the clearance or metabolism of theophylline in healthy adults. Six male volunteers were given aminophylline 6 mg/kg iv before and after piroxicam treatment. Piroxicam 20 mg/d po was administered for seven days. Serum samples were collected before and for 24 hours after each aminophylline dose. Theophylline serum concentrations were determined using the Abbott TDx automated immunoassay system. Theophylline and its 1,3-dimethyluric acid metabolite were measured in 24-hour urine collections. Serum theophylline concentration versus time curves were plotted and pharmacokinetic parameters determined for each subject. None of the derived parameters differed as a result of piroxicam exposure. Theophylline metabolites, clearance, half-life, and volume of distribution were compared during the baseline and piroxicam phases and were found to be similar. It was concluded that piroxicam does not alter the clearance, distribution, volume, or metabolism of theophylline in healthy adult volunteers.

Verapamil‐Induced Inhibition of Theophylline Elimination in Healthy Humans

The interaction between theophylline and verapamil was investigated in 7 healthy volunteers. Oral administration of verapamil in a dose of 120 mg t.i.d. for 7 days caused a significant inhibition of the elimination of theophylline (5 mg/kg intravenously). Theophylline clearance was reduced from 45.2 to 36.1 ml/hr/kg (20.1%; P less than 0.005). The apparent steady-state volume of distribution of the drug was not influenced. The terminal half-life of theophylline was increased from 6.80 to 8.23 hr (21.0%; P less than 0.001). Increased steady-state plasma theophylline concentrations may thus be expected when verapamil is added to a drug regimen which includes theophylline.

Comparison of Inhibitory Effects of New Quinolones on Drug Metabolizing Activity in the Liver

The effects of three new quinolones (enoxacin (ENX), norfloxacin (NFLX) and ofloxacin (OFLX)) on acetaminophen-induced liver injury in rats were examined and compared with their effects on the elimination half-life (T1/2) of theophylline (in vivo) and on the 7-ethoxycoumarin (7-EC) O-deethylase activity in liver microsomes (in vitro). ENX, NFLX and OFLX (75 or 300 mg/kg) were administered orally to rats 1 hr before, simultaneously with, and 1 hr after the acetaminophen injection (800 mg/kg). Biochemical liver function tests, drug metabolizing activity in liver microsomes, the total glutathione content of the liver and histological changes were examined 5 hr after the acetaminophen injection. ENX markedly reduced acetaminophen-induced liver injury and NFLX slightly but significantly did so, but no protective effect was observed with OFLX treatment. ENX markedly and NFLX slightly prolonged the T1/2 of theophylline, but OFLX did not affect it. In addition, ENX markedly and NFLX slightly inhibited the 7-EC O-deethylase activity in liver microsomes, but OFLX again had no effect. These findings indicated that ENX markedly inhibited the activity of cytochrome P-450 in liver microsomes and NFLX did so slightly, while OFLX had no such effect. Slight variations in the structures of these quinolones might explain the differences in their effects on cytochrome P-450 activity.

Theophylline and Antiparasitic Drug Interactions: A Case Report and Study of the Influence of Thiabendazole and Mebendazole on Theophylline Pharmacokinetics in Adults

To determine a change in theophylline pharmacokinetics during concomitant thiabendazole or mebendazole therapy, we studied six normal, healthy male volunteers. Aminophylline was administered intravenously, followed by a 30-h blood sampling period. Subjects were randomized to receive thiabendazole or mebendazole, then crossed over to receive the other therapy. Theophylline concentrations were measured utilizing an HPLC technique and a one-compartment model was fit to the data. Theophylline pharmacokinetic parameters were significantly different during thiabendazole therapy. Mean theophylline half-life increased, clearance decreased and elimination rate constant decreased. Two subjects experienced severe nausea and vomiting during thiabendazole therapy. There were no significant differences in theophylline pharmacokinetic parameters during mebendazole therapy. Thiabendazole administration results in a significant decrease in theophylline clearance and beta elimination rate constant. The theophylline half-life increased significantly. Concomitant administration of theophylline and thiabendazole resulted in severe nausea and vomiting. Mebendazole administration did not seem to alter theophylline pharmacokinetics.

Effect of lomefloxacin on theophylline pharmacokinetics.

A study involving 25 health male volunteers was conducted to evaluate the effect of lomefloxacin on the pharmacokinetics of theophylline. The mean age was 22.4 +/- 3.0 years, and the mean weight was 77.3 +/- 7.7 kg. A single 6-mg/kg aminophylline dose was given intravenously on study days 1 and 15. The subjects received a 400-mg lomefloxacin dose (four 100-mg capsules) on study days 9 through 15. No treatment was given on study days 2 through 8. Thirteen blood samples were collected within 24 h after each aminophylline dose. Theophylline concentrations in serum were measured by enzyme immunoassay (EMIT). The mean aminophylline dose was 437 +/- 36 mg, equivalent to 344 mg of theophylline. Multiple doses of lomefloxacin had no effect on the area under the concentration-time curve from 0 h to infinity, maximal concentration, or clearance of theophylline from serum. There was a slight increase in the theophylline half-life from 6.72 +/- 1.63 to 7.02 +/- 1.37 h after lomefloxacin dosing (P = 0.04); however, the change was clinically insignificant. No change in theophylline dose is required when lomefloxacin therapy is instituted in a patient receiving theophylline.

Clinical Pharmacokinetics of Theophylline and Levels of α1-Acid Glycoprotein in Smokeless Tobacco Users

Elimination half-life and apparent volume of distribution of theophylline were determined in ten healthy volunteers who used smokeless tobacco (snuff or chewing tobacco) regularly but did not smoke cigarettes. Serum concentrations of the acute phase reactant alpha 1-acid glycoprotein (AAG) were also measured. The elimination half-life of theophylline was 9.32 +/- 3.40 hours (mean +/- standard deviation), the apparent volume of distribution was 0.45 +/- 0.03 L/kg, and AAG concentrations were 63.8 +/- 15.76 mg/dL. All these values are comparable to values reported for nonsmokers. These results suggest that nonsmoking users of ST should be considered to be tobacco nonusers for purposes of planning theophylline dosing and monitoring strategies.

Maturational changes of theophylline pharmacokinetics in preterm infants

The pharmacokinetics of theophylline were studied at steady state by stable isotope methodology in nine individual preterm infants. Maturational variables such as postnatal age, postconceptional age, gestational age, duration of treatment, and body weight at the time of the study were analyzed for their influence on theophylline kinetics during the first 6 months of life. The strongest statistical correlations were found between the logarithm of theophylline half-life (t1/2) and the postnatal age (r = 0.98; p less than 0.001) and the postconceptional age (r = 0.96; p less than 0.001). Step-wise multiple regression analysis revealed postnatal age as the most powerful predictor for theophylline t1/2 in the neonatal period (partial correlation coefficients were 0.78 for postnatal age, 0.19 for postconceptional age, and 0.10 for gestational age). Gestational age, duration of treatment, and weight did not correlate significantly with any pharmacokinetic parameters. We propose that theophylline metabolizing function of the liver increases in a logarithmic fashion during the first 6 months of life.

Inhibition of theophylline elimination in rabbits by verapamil.

Single intravenous dose pharmacokinetics of theophylline in 10 rabbits were investigated before and after 5 days oral administration of verapamil in daily doses of 6 mg/kg. Verapamil caused a significant inhibition of theophylline elimination. Theophylline clearance was reduced from 126 to 98 ml/hr/kg (22.2%) whereas the steady state volume of distribution of the drug increased from 461 to 550 ml/kg (19.3%). The terminal half-life of theophylline increased from 2.7 to 4.0 hr (49.8%).

Sex-related differences in theophylline pharmacokinetics.

Theophylline pharmacokinetic parameters were compared in healthy males and healthy premenopausal females who were matched for age and smoking status. Twenty-four subjects (including five smokers and seven non-smokers of each sex) received a single dose of aminophylline 6 mg.kg-1, orally or by intravenous infusion. Theophylline half-life was significantly shorter in female non-smokers (FNS) versus male non-smokers (MNS), (FNS = 6.0 h; MNS = 9.3 h), and in female smokers (FS) versus male smokers (MS), (FS = 4.6 h; MS = 6.3 h). Total body clearance was significantly different in FNS versus MNS, (FNS = 43.8 ml.min-1.-1(1.73) m-2; MNS = 37.4 ml.min-1.1.73 m-2), but did not reach statistical significance in FS vs. MS, (FS = 64.2 ml.min-1.1(-1).1.73 m-2; MS = 53.1 ml.min-1.1.73 m-2). Volume of distribution did not differ significantly between groups. Sex differences in theophylline pharmacokinetics exist and may reflect differences in drug metabolism.

Attenuation of rifampicin-induced theophylline metabolism by diltiazem/rifampicin coadministration in healthy volunteers.

On the basis of reports that diltiazem binds to the hepatic microsomal enzymes and inhibits the metabolism of coadministered drugs, we investigated the effect of a 240 mg daily dose of the calcium channel blocker for a week on theophylline metabolism in 8 healthy male volunteers aged 20-24 years and weighing 56-68 kg. None of theophylline half-life (9.7 h), volume of distribution (0.514 l.kg-1) and total clearance (0.63 ml.min-1.kg-1) after pretreatment differed from the respective control value of 9.5 h, 0.519 l.kg-1 and 0.65 ml.min-1.kg-1. In 6 of the volunteers, 600-mg daily dose of rifampicin for a week induced theophylline metabolism. The control half-life of the bronchodilator (9.6 h) was reduced to 5.5 h and its total clearance (0.64 ml.min-1.kg-1) increased to 1.22 ml.min-1.kg-1. There was no change in volume of distribution. In these 6 volunteers, intake of diltiazem (240 mg daily), concurrently with rifampicin for a week, significantly elevated theophylline half-life to 6.2 h as well as reduced its clearance to 1.03 ml.min-1.kg-1. The volume of distribution did not change. Furthermore, diltiazem-induced absolute fall in theophylline clearance correlated significantly with its post-rifampicin value (r = 0.895). It is suggested that diltiazem has no effect on theophylline metabolism in non-induced subjects. However, rifampicin-induced metabolism of the bronchodilator could be attenuated by diltiazem when the two drugs are given concurrently.

Caffeine Pharmacokinetics in Preterm Infants Older than 2 Weeks

We studied 17 preterm infants receiving caffeine, and measured their plasma levels of caffeine and the theophylline metabolite by high-pressure liquid chromatography. The half-life was calculated by computer analysis using the least-square method. The mean gestational age of our patients was 29.7 +/- 1.9 weeks (mean +/- SD) and they were studied at 20.7 +/- 6.6 days (mean +/- SD) postnatal age. The caffeine half-life was 52.03 +/- 23.87 h (means +/- SD) and the theophylline half-life was 77.04 +/- 65.01 h (mean +/- SD).

Lack of effect of ponsinomycin on the plasma pharmacokinetics of theophylline.

The influence of ponsinomycin on the pharmacokinetics of theophylline has been studied in 12 young healthy volunteers. They received 10 doses of theophylline 200 mg every 8 h p.o., successively in the absence and then in the presence of ponsinomycin. This new macrolide, structurally related to midecamycin, was given in the therapeutic dose of 800 mg b.d. for 5 days, starting 2 days before the second phase of treatment with theophylline. The pharmacokinetic parameters of theophylline, calculated from its plasma concentration at steady-state, were not affected by the co-treatment. In particular, there was no significant difference between the peak and trough plasma levels, apparent clearance or apparent elimination half-life of theophylline in the absence and the presence of ponsinomycin. Only renal clearance was slightly (27%) but significantly increased by the co-treatment. The results suggest that ponsinomycin would be a good choice if a macrolide antibiotic were needed in patients being treated with theophylline.

EFFECT OF TE-031, A NEW MACROLIDE ANTIBIOTIC, ON SERUM THEOPHYLLINE CONCENTRATION

Effect of TE-031, a new macrolide antibiotic, on theophylline kinetics was studied in asthmatic children.In the first study, 18 patients were taking sustained-release theophylline orally for 4 weeks, and TE-031 was given in a dose of 600mg/day for 7 days on the 3rd week of the study. Blood samples were collected at the same time (7:20 a.m. and 2 p.m.) on 8 days and 1 day prior to TE-031 administration, on the 3rd and 7th day after TE-031 administration and on the 7th day after the termination of TE-031. The mean serum theophylline concentration on the 7th day after administration was more significant than on other days (p<0.01).In the second study, an investigation regarding the effect of TE-031 on intravenously given theophylline was carried out in three patients. Among these patients, one of them had a significantly prolonged theophylline half-life and her clearance decreased after TE-031 administration.The results of these two studies indicate that TE-031 may affect the theophylline kinetics and its serum concentration. Patients receiving therapeutic doses of theophylline are at a considerably higher risk of theophylline toxicity if TE-031 is co-administered. Thus, it is advised to monitor theophylline concentration during administration of these two drugs together.

Interaction between phenytoin and theophylline in healthy volunteers.

1. The effect of phenytoin, 100 mg thrice daily for 3 weeks, on theophylline disposition was studied in eight healthy volunteers. 2. The anticonvulsant significantly reduced the half-life of theophylline and this was associated with an increase in the rate of theophylline clearance. The volume of distribution was not significantly altered. 3. There was no correlation between initial theophylline clearance and its percentage increase after phenytoin pretreatment. 4. Coefficients of variation in theophylline clearance before and after phenytoin pretreatment were similar. 5. It is suggested that phenytoin induces theophylline metabolism, that initial theophylline metabolism is not a determinant of the extent of such induction, and that there is a similar potential for induction among healthy volunteers.