Theophylline Half-life Research Articles

Chronopharmacokinetics of theophylline after sustained release and intravenous administration to adults.

The influence of time of drug administration on pharmacokinetics of theophylline was studied both after ingestion of a sustained-release tablet, containing choline theophyllinate ( Zy 15061-S. R.; Teovent ; Sabidal ; ZYMA S.A.) and after intravenous infusion of aminophylline to eight healthy volunteers. Both drugs were administered in the morning (10 a.m.) and on a separate occasion in the evening (10 p.m.) after a 12 h period of fasting. After oral administration of a dose of 540 mg theophylline, the drug was steadily absorbed, both during day-time and during night-time. In some subjects absorption was slower in the evening. Maximum theophylline plasma concentrations were reached after 3.3 +/- 0.4 h (mean +/- SD) and 3.9 +/- 1.4 h respectively (not significantly different p greater than 0.05). The maximum plasma concentrations were almost identical after administration in the morning and in the evening (12.6 +/- 3.3 mg X l-1 and 13.1 +/- 1.4 mg X l-1 respectively). There was also no significant difference (p greater than 0.05) between the areas under the plasma concentration-time curves after oral and intravenous administration, both at day-time and at night-time. This finding indicates complete bioavailability of the sustained release tablets on both occasions. After administration of the tablets in the morning the plasma concentration 12 h post dosing was significantly lower than after administration in the evening: c1 12 accounted for 6.0 +/- 2.0 mg X l-1 after intake at 10 a.m. and for 7.9 +/- 2.1 mg X l-1 after ingestion at 10 p.m. (p less than 0.01). A similar observation was done after intravenous administration of the drug: c12 was 6.6 +/- 1.6 mg X l-1 after starting the infusion in the morning and 8.0 +/- 1.8 mg X l-1 after infusing the drug in the evening (p less than 0.01). This phenomenon could be explained by the finding of a significantly prolonged half-life of theophylline during night-time, provided that the plasma concentrations were in the range of 5 to 15 mg X l-1 (which coincides approximately with the therapeutic range of the drug).(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine inhibition of theophylline clearance.

The effects of morphine on the single dose pharmacokinetics of theophylline were examined in two groups (6 rats/group) of male Sprague-Dawley rats after the administration of theophylline (6.25 mg/kg) alone and in conjunction with a 5 mg /kg I.V. dose of morphine sulfate. Concomitant morphine administration resulted in a 55 % reduction in theophylline clearance (0.14 ± 0.04 vs. 0.31 ± 0.061 · h(-1) kg(-1); p. < 0.0005). The reduction in theophylline clearance with morphine administration was accompanied by a significant prolongation in theophylline half-life (3.5 ± 1.5 vs. 1.4 ± 0.35 h; p < 0.02). No changes in the volume of distribution of theophylline occurred with co-administration of morphine. The mechanism of this pharmacokinetic interaction may be partially related to competition between theophylline and morphine for enzymes which metabolize these compounds.

Depression of theophylline elimination following BCG vaccination.

This study investigated the effects of BCG vaccination on the elimination of a single dose of theophylline in twelve healthy female volunteers. Two weeks following BCG vaccination the mean serum theophylline half-life was increased significantly in subjects with a positive Mantoux test compared to the mean half-life determined prior to vaccination. The mean volume of distribution for theophylline was unchanged following vaccination. In two subjects with negative Mantoux tests theophylline half-life was unchanged after vaccination. It is therefore suggested that immunostimulation following BCG vaccination may impair the capacity of the liver to eliminate theophylline.

Increased serum theophylline clearance with orally administered activated charcoal.

The purpose of this study was to determine whether the oral administration of activated charcoal would increase the clearance of theophylline. Seven normal subjects received aminophylline intravenously (8 mg/kg) on 2 separate days. On Day 1 at 2-h intervals starting immediately after the completion of the aminophylline infusion, subjects ingested 4 doses of a slurry of activated charcoal (30 g each). On Day 2 they received no charcoal. The order of the days the subjects received charcoal or no charcoal was randomized. Plasma theophylline levels were determined by an enzyme immunoassay (Syva) every 2 h after the completion of the intravenous infusion. The theophylline half-life was reduced with charcoal from 10.2 to 4.6 h (p less than 0.001), and clearance increased from 35.6 to 72.6 ml/kg/h (p less than 0.001). In a patient with an initial serum theophylline concentration of 31.0 micrograms/ml and signs of toxicity (arrhythmias and seizures), the administration of charcoal (4 doses of 30 g every 2 h) reduced the half-life from 34.4 to 5.7 h concomitant with rapid resolution of signs of toxicity. We conclude that orally administered activated charcoal significantly enhances the clearance of theophylline and offers a new therapeutic modality in the treatment of theophylline toxicity.

Effects of hemodialysis on theophylline kinetics.

Difficulties encountered in controlling theophylline blood concentrations in an asthmatic patient on hemodialysis prompted us to study the effect of hemodialysis on theophylline kinetics. Plasma theophylline extraction ratios, clearances, and half-lives were determined during dialysis for 11 adults given an intravenous infusion of 4 mg/kg aminophylline. For comparison, eight of these patients were evaluated for theophylline half-lives when not dialyzed. Extraction ratios of theophylline during dialysis ranged from 0.22 to 0.51 (0.35 +/- 0.08) for these patients, indicating that a mean of 36 per cent plasma theophylline was removed during each pass through the dialyzer. This compares with a mean extraction ratio of urea of 0.63 +/- 0.07. Plasma clearance of theophylline during dialysis ranged from 52 to 124 ml/min (83 +/ 20 ml/min). Plasma theophylline half-lives during dialysis ranged from 1.6 to 3.4 hours (2.3 +/- 0.5 hours). Theophylline half-lives when not on dialysis ranged from 3.5 to 8.2 hours (5.0 +/- 1.7). Theophylline clearance was significantly faster in every patient during dialysis. Asthmatics requiring hemodialysis should receive additional theophylline during dialysis if therapeutic blood levels are to be maintained. Routine hemodialysis will significantly increase clearance in a toxic patient in whom life-threatening toxicity is occurring and charcoal hemoperfusion is unavailable.

Comparative Pharmacokinetics of Theophylline in Peritoneal Dialysis and Hemodialysis

Dialysis clearance and drug recovery of theophylline were investigated in three peritoneal dialysis patients and the results were compared with those obtained from five hemodialysis patients. Peritoneal clearance averaged 9.5 ml/min, in contrast with the hemodialysis clearance of 84.8 ml/min, indicating a relative inefficiency of peritoneal dialysis with regard to theophylline removal. Theophylline half-life was reduced substantially during hemodialysis, 2.0 to 3.2 hours, in comparison with the normal half-life range of 4.7 to 6.8 hours during peritoneal dialysis. The fraction of theophylline recovered by peritoneal dialysis approximated 3.2 per cent of dose, while hemodialysis recovered up to 40 per cent of the administered dose. The overall observations of half-life, dialysis clearance, and drug recovery suggest a clear advantage of hemodialysis over peritoneal dialysis for theophylline detoxification. However, peritoneal dialysis may be preferred to hemodialysis for uremic patients requiring theophylline therapy. Since the removal of theophylline by peritoneal dialysis is minimal, an undesirable alteration of the theophylline dosage regimen in association with dialysis therapy can thus be avoided.

Pharmacokinetic studies of theophylline in cats.

The pharmacokinetics of theophylline were determined in adult cats and the data were fitted to a two-compartment model. Single intravenous and multiple oral doses of aminophylline were used. The mean plasma theophylline half-life (t1/2) following the single intravenous dose was 7.8 h and the mean apparent specific volume of distribution (V'd(area] was 0.46 1/kg. The absorption half-life (t1/2ab) was 0.5 h and the bioavailability was 96% following oral administration. There was excellent agreement between the predicted and observed plasma theophylline concentrations following multiple oral doses.

Reduced theophylline half-life induced by carbamazepine therapy

Reduced theophylline half-life induced by carbamazepine therapy

Personality traits and theophylline metabolism.

The objectives of this study were to investigate the relationship between personality trait variables and theophylline disposition in asthmatic patients. Twenty-five patients admitted to a hospital who required intravenous theophylline for bronchodilation were studied. Data on theophylline half-life, and the patients' histories on congestive heart failure, liver disease, and smoking behaviour were abstracted. Eysenck's personality inventory was administered to obtain a score on the two personality traits: neuroticism and extraversion. High neurotic patients showed a significantly (p less than 0.005) lower theophylline half-life. Neuroticism appeared to be, in this patient population, a more important determinant of theophylline half-life than variables such as congestive heart failure, liver disease, or smoking behaviour.

Interaction between nutrition and theophylline metabolism in children.

The influences on theophylline metabolism are multifactorial, resulting in significant inter- and intrapatient variability in drug responsiveness. Clinical investigations with adult patients have demonstrated the influence of diet on theophylline metabolism following a single drug dose. We have undertaken this study to examine the effect of nutritional factors on theophylline pharmacokinetics in 14 asthmatic children receiving the drug on a chronic basis. For 12-day periods each patient received three separate diets with different proportions of protein and carbohydrate but with constant fat and caloric intake. Significant differences were detected for theophylline half-life, apparent volume of distribution, and metabolic clearance rate. The high-protein diet markedly shortened the drug-elimination half-life relative to a normal diet, and high carbohydrate significantly increased it (both p less than 0.001). Other kinetic parameters confirmed this pattern. Our findings in children clearly establish that nutritional factors have a significant environmental influence on theophylline metabolism during the drug's steady-state pharmacokinetics.

Effect of hemodialysis on the pharmacokinetics of theophylline in chronic renal failure.

We studied theophylline elimination in 8 patients with chronic renal failure to determine the effect of hemodialysis on the pharmacokinetics of theophylline. Each subject was studied twice, once on a nondialysis day and again during dialysis. Total body theophylline clearance on the nondialysis day was similar to that reported for patients with normal renal function (57.4 +/- 27.2 ml/kg/h). Hemodialysis accelerated theophylline elimination and shortened serum theophylline half-life in all patients (nondialysis t 1/2 = 7.3 h +/- 2.3 vs. dialysis t 1/2 = 2.7 +/- 0.9 h, p less than 0.01). Dialysis clearance averaged 59.7 +/- 16.4 ml/kg/h with a fraction of drug removed of 0.4 liters in 4 h. Guidelines for theophylline management during hemodialysis are suggested.

Effect of erythromycin on theophylline kinetics

The effect of erythromycin base on theophylline kinetics was studied in eight informed, nonsmoking, adult males who received a 15-min infusion of theophylline (aminophylline) 5 mg/kg, prior to (control) and after (experimental) a 7-day course of 1 gm daily ervthromycin base (E-Mycin). Each subject acted as his own control. Multiple serum samples were collected for 24 hr after each dose and were analyzed for theophylline by high-pressure liquid chromatography. The mean ± SD pharmacokinetic parameters for each phase of study were as follows: apparent volume of distribution (L/kg) 0.45 ± 0.05 (control), 0.41 ± 0.05 (experimental); clearance (ml · min/kg) 0.83 ± 0.17 (control), 0.60 ± 0.11 (experimental). elimination half-life (hr) 6.65 ± 1.88 (control), 8.10 ± 1.58 (experimental). Erythromycin significantly affected the elimination half-life and clearance of theophylline (p < 0.05). The apparent volume of distribution was unaffected (p > 0.05). Therefore patients being administered theophylline appear to be at added risk for the development of toxicity when erythromycin is added to the therapeutic regimen.

Pharmacokinetics of theophylline in swine: a potential model for human drug bioavailability studies.

The pharmacokinetics of theophylline in swine were investigated following the oral and intravascular administration of single doses of theophylline free base. The mean half-life of theophylline following intravascular administration was 11.0 h, and the apparent specific volume of distribution was 0.61 liter/kg. Following oral administration, theophylline in solution was absorbed quite rapidly with a bioavailability of 79%. The similarity of the pharmacokinetics of theophylline in swine and humans suggests that swine may provide a useful model for the study of the bioequivalency of theophylline dosage forms intended for human use. The pharmacokinetic characteristics of theophylline also favor its consideration for usage as a therapeutic agent in swine.

Elimination kinetics and protein binding of theophylline in the rabbit

The detailed elimination kinetics of theophylline were studied in 27 rabbits. Each received a 10 mg/kg intravenous bolus of aminophylline. The theophylline half-life ( T 1 2 ) was 3.8 ± 0.63 hr. The apparent volume of distribution (V D) and total body clearance (TBC) for theophylline were 439 ± 60 ml/kg and 81.0 ± 17.3 ml/kg·hr respectively. Theophylline protein binding was determined in 10 animals. The mean bound fraction was 74.3 ± 3.9% (range, 68.3–78.0%); the fraction bound was concentration indifferent over a serum concentration range of 5–20 μgm/ml.

Cimetidine impairs the elimination of theophylline and antipyrine

In 7 healthy subjects theophylline and antipyrine elimination were determined before and during a course of oral cimetidine in a dose of 1 g/day. Plasma clearance of theophylline was reduced from 71.2 ± 10.1 ml/min to 56.0 ± 18.5 ml/min and the plasma clearance of antipyrine from 53.7 ± 14.2 ml/ min to 48.1 ± 11.7 ml/min. Elimination half-life of theophylline was prolonged from 5.1 ± 1.6 to 8.1 ± 1.4 h. All these changes were statistically significant. Volume of distribution of theophylline (31.7 ± 8.4 L before and 39.2 ± 5.6 L during cimetidine administration) and plasma binding of theophylline (44.7 ± 3.8% before and 44.3 ± 3.1% during cimetidine administration) were not significantly different. Similarly, volume of distribution of antipyrine (45.8 ± 14.0 vs. 47.6 ± 17.9) was not significantly affected by cimetidine administration. We conclude that cimetidine impairs the elimination of theophylline and antipyrine in healthy subjects.

Pharmacokinetic studies of theophylline in dogs.

The pharmacokinetics of theophylline were investigated in dogs following intravenous, single oral, and multiple oral doses of aminophylline. Mean half-life (t1/2) of theophylline following single intravenous administration was 5.7 h and the apparent specific volume of distribution (V'd area) was 0.82 litre/kg. The bioavailability of theophylline was high (91%) following oral administration of aminophylline tablets and the absorption half-life (t1/2ab) was 0.4 h. Theophylline plasma concentrations observed following repeated oral administration of aminophylline tablets were somewhat greater than predicted. This suggests that theophylline plasma concentrations should be monitored and the dosage regimen individually adjusted in critically ill animals.

Effect of Caffeine on Circulating Theophylline Levels in Beagle Dogs

The pharmacokinetic interactions of caffeine with theophylline were examined in two beagle dogs by administering 100mg of aminophylline intravenously, 3 weeks before and immediately after repeated oral doses of caffeine. Serial plasma samples were analyzed for caffeine and theophylline simultaneously by high-performance liquid chromatography. Upon multiple oral dosing, 100mg every 12hr for 7 days, the caffeine half-life increased slightly in one dog but decreased in the other. As predicted from single-dose data, caffeine accumulation in plasma after repeated doses was slight, while plasma levels of the N- demethylated metabolite, theophylline, rose to about three times the initial values. After rapid intravenous doses of aminophylline, the theophylline half-life was 5-7 hr, which decreased slightly when the drug was administered concomitantly with caffeine during steady state of caffeine. The theophylline volume of distribution (0.75 liter/kg) was unaffected by caffeine. On the other hand, an acute aminophylline injection prolonged the elimination half-life and increased the apparent volume of distribution of caffeine, causing little overall change in its plasma clearance. The results suggested that interactions between theophylline and caffeine may be attributed to changes in drug distribution and drug elimination characteristics.

Inhibition of theophylline metabolism by long-term allopurinol administration.

Administration of an oral dose of allopurinol (300 mg every 12 hr) for 14 consecutive days increased the mean theophylline area under the curve (AUC) 27% and mean theophylline half-life (t1/2) 25%, whereas the mean theophylline clearance (Cl) decreased 21%. Allopurinol did not alter either apparent volume of distribution (aVd) or gastrointestinal absorption (Cmax and tmax) of theophylline. After 28 consecutive days of allopurinol administration, theophylline disposition was the same as that on day 14. Thus, given in a dose of 300 mg every 12 hr for 14 or 28 days, allopurinol inhibits theophylline metabolism, despite the failure of allopurinol in lower doses given for only 7 days to alter theophylline disposition. These results emphasize the need to investigate several different doses and durations of administration within therapeutic ranges before firm conclusions can be drawn concerning the influence of one drug on the disposition of another.

Pharmacokinetics and relative Bioavailability of Oral Theophylline Capsules

The oral bioavailability of liquid-filled theophylline capsules relative to a nonalcoholic aminophylline solution was determined in normal volunteers. In addition, theophylline absorption and elimination kinetics were reexamined. There were no statistically significant differences between the bioavailability of capsules and liquid as measured by the area under the curve (AUC) from time 0 -→ ∞ (p > 0.05). The bioavailability parameters of Cmax, tmax, and AUC were determined from actual serum theophylline concentration-time data and from a nonlinear least-squares fit of the serum concentration-time data. Theophylline absorption from the capsules was noticeably faster than from the liquid in most subjects, although the differences in absorption rates were not significantly different (p > 0.05). The determined apparent volume of distribution, elimination half-life, and plasma clearance of theophylline were similar to values reported by other investigators. Marked inter- and intraindividual variations in the elimination half-life were noted.

Plasma theophylline levels after sustained-release aminophylline.

Healthy adult subjects were given oral sustained-release (SR) aminophylline tablets 225 mg 12-hourly (n = 12) or 450 mg 12-hourly (n = 6) for 5 doses, and all were given aminophylline 225 mg intravenously on a separate occasion to determine individual kinetic parameters. The mean plasma theophylline half-life ( 1 1/2) from the intravenous study was 5.8 hr (SD +/- 1.9). During the 12 hr after the fifth dose of SR aminophylline, the maximum and minimum mean (SD) plasma theophylline levels were 9.7 (3.2) mug/ml and 4.9 (2.0) mug/ml for the 225-mg dose, and 21.1 (2.2) mug/ml and 11.6 (4.4) mug/ml for the 450-mg dose. Side effects were generally mild in the low-dose study, but in the high-dose study 3 subjects reported headache and 1 was withdrawn after 3 doses. Two subjects also noted nausea, and 3 reported insomnia and anxiety in the high-dose study. It was concluded that there was a considerable range of doses needed to achieve adequate plasma levels, and that the formulation studied was capable of producing reasonably stable and satisfactory plasma theophylline levels once individual dose requirements had been established.