Theophylline-salbutamol interaction: bronchodilator response to salbutamol at maximally effective plasma theophylline concentrations.

1 The effect of inhaled salbutamol following a maximally effective dose of theophylline given by intravenous infusion was determined in 12 patients with chronic bronchitis. 2 An initial single intravenous dose study was performed to estimate each patient's theophylline kinetics and to identify those patients who would respond to theophylline. 3 Pulmonary function was assessed at hourly intervals during four to five incremental steady state theophylline infusions over the concentration range 5-25 mg/l. 4 Inhaled salbutamol (400 micrograms) was administered after the maximum effect from theophylline had been achieved or when theophylline concentrations reached 25 mg/l without maximum effect: pulmonary function was again assessed. 5 Ten patients achieved a further significant improvement in pulmonary function after salbutamol: in five, predicted values for FVC were exceeded. 6 Patients with chronic bronchitis may benefit from the combination of theophylline and salbutamol if steady state theophylline concentrations of 15-20 mg/l are achieved.     

Pharmacokinetic interaction between theophylline and erythromycin.

1 The pharmacokinetics of a single intravenous dose of theophylline alone and during the fifth day of treatment with 500 mg erythromycin every 8 h was studied in six healthy subjects. 2 At the same time the pharmacokinetics of erythromycin at steady-state on the fourth day of the treatment (alone) and the fifth day (during the theophylline co-administration) were also studied. 3 Mean +/- s.d. theophylline clearance was decreased from 62 +/- 15.4 to 53 +/- 10.3 ml min-1 (P less than 0.05) and elimination half-life rose from 7.1 +/- 1.9 to 7.7 +/- 2 h (P less than 0.05) when erythromycin was co-administered. 4 Mean +/- s.d. erythromycin area under the curves (0-8 h) and (0-oc) were reduced from 6.09 +/- 3.2 to 3.8 +/- 2.5 micrograms ml-1 h and 7.2 +/- 3.6 to 5.0 +/- 2.9 micrograms ml-1 h (P less than 0.05) in the presence of theophylline. Mean steady state and maximum steady state concentrations were also reduced from 0.75 +/- 0.4 to 0.47 +/- 0.3 microgram ml-1 (P less than 0.05) and 1.45 +/- 0.87 to 0.85 +/- 0.51 microgram ml-1 (P less than 0.05) respectively. 5 The potential clinical implications of this indication should be considered.     

Toxicity of theophylline depends on plasma concentration by single and also repeated dosing in rats.

The purpose of this study was to evaluate the relationship between the in vivo toxicity and plasma concentration of theophylline. Theophylline was administered intravenously in single doses ( 50, 100, 150 and 200 mg kg(-1)once a day) or repeated doses (12.5, 25 and 90 mg kg(-1)/day for 28 days) in rats. Plasma concentrations of theophylline increased dose-dependently in both single and repeated doses, and there were no differences due to effects of 28-times repeated administration. Neither single dose at 50 mg kg(-1)nor repeated dose at 12.5 mg kg(-1)/day injections of theophylline showed toxic signs, in which plasma concentrations of theophylline were less than 110 and 22.5 microg ml(-1), respectively. Theophylline induced myocardial fibrosis in 25 mg kg(-1)/day and more treated groups: in which plasma concentrations of theophylline were more than 50 microg ml(-1). At doses of 100 mg kg(-1)(single) and 90 mg kg(-1)/day (repeated), theophylline caused tachypnea and excitement of movement. Each theophylline concentration in plasma was more than 194 microg ml(-1)in single 100 mg kg(-1)and 162 microg ml(-1)in repeated 90 mg kg(-1)/day injections, respectively. Death was observed at a dose of 200 mg kg(-1), in which the plasma concentration of theophylline was more than 264 microg ml(-1). Moreover, the recovery period from signs of toxic poisoning to normality in the 200 mg kg(-1)treated group was greater than that in the 150 mg kg(-1)and less treated groups. The results indicated that the in vivo toxicity of theophylline is highly dependent on plasma concentrations in rats which received single and also repeated doses of theophylline.     

Reproducibility of saliva and plasma theophylline levels following single dose administration of two sustained release preparations.

1 Concomitant saliva and plasma theophylline concentrations were measured in six healthy male volunteers following single dose administration of two sustained release preparations (Nuelin SA and Phyllocontin Continus). 2 Using mean values, a good correlation was obtained between saliva and plasma drug concentrations. Prediction of plasma values using individual saliva was poor and varied widely. The ratio of saliva to plasma concentrations in the same individual, assessed under standardised conditions, was not always reproducible.     

Determinants of the plasma protein binding of theophylline in health.

1 The plasma protein binding of theophylline was determined after addition of [14C]-theophylline (15 micrograms/ml) to plasma from 24 healthy drug-free volunteers and equilibrium dialysis for 2 h at 37 degrees C. 2 The percentage of drug unbound was 60.0% +/- 2.2% (s.d.) with very little variation between individuals. The binding ratio of theophylline was not significantly related to the plasma albumin or alpha 1-acid glycoprotein (AAG) concentrations but was significantly, although weakly, negatively related to the logarithm of the non-esterified fatty acid concentration (NEFA) (r = 0.443, P less than 0.05). 3 Intravenous administration of heparin (1000 units) caused a significant rise in plasma NEFA concentration and in the percentage of drug unbound in plasma after equilibrium dialysis. 4 In human serum albumin solutions, the binding ratio of theophylline was significantly related to the albumin concentration and at the albumin concentration seen in the 24 normal subjects, the percentage of drug unbound was almost identical. Addition of AAG in physiological concentrations did not enhance theophylline binding but oleic acid, and to a lesser extent palmitic acid, reduced binding significantly. 5 The percentage of theophylline unbound in plasma varied markedly with pH so that at pH7 the percentage unbound was 52% greater than at pH 8. There was no evidence of concentration dependence of binding up to 140 micrograms/ml theophylline. 6 Theophylline appears to bind almost exclusively to albumin and its plasma protein binding varies little in healthy subjects, showing no concentration-dependence over the therapeutic range of concentrations. The binding is affected by pH and by NEFA concentration, however, and these factors may be of greater importance in disease states. Caution should be employed in the use of heparin in studies of plasma protein binding of theophylline.     

Estimating the clearance of amylobarbitone from a single plasma measurement.

Amylobarbitone sodium (200 mg) was given by intravenous injection to nine healthy, young adults (four males). Subjects were drug-free and nonsmokers. Serial blood samples were drawn for 48 h following the infusion, and multiple sample and single sample estimates of clearance were calculated. The mean (+/- s.d.) values for clearance (CL) and apparent volume of distribution (V) were 0.032 (+/- 0.007) 1 h-1 kg-1 and 1.08 (+/- 0.16) 1 kg-1, respectively. The mean (+/- s.d.) single sample estimate of clearance, CL, based on just the 48 h plasma concentrations of amylobarbitone was 0.033 (+/- 0.006) 1 h-1 kg-1. The 48 h single sample CL value was shown to reliably reflect the value of CL with little bias and good precision. Values of the 48 h CL when compared to CL exhibited a mean prediction error (mpe) of 1.2% with 95% confidence limits of -6.3% to 9.4%, and a root mean squared error (rmse) of 9.4%. It is concluded that amylobarbitone's clearance can be estimated in a single dose, single sample protocol permitting its use as a single dose, single sample probe for studying host factor influences on drug metabolism.     

Theophylline-rifampicin interaction: non-selective induction of theophylline metabolic pathways.

The effect of rifampicin pre-treatment (600 mg daily for 6 days) on theophylline disposition at steady state was investigated in six healthy males. Following rifampicin treatment total plasma clearance of theophylline increased by 82%. Theophylline clearance through each metabolic pathway was increased, 1-demethylation by (116 +/- 34%) (mean +/- s.e. mean), 3-demethylation by (91 +/- 16%) and 8-oxidation by (81 +/- 17%). Renal clearance of unchanged drug was not altered. Previous studies have suggested that two forms of cytochrome P-450 are involved in theophylline metabolism, one mediating the N-demethylations and the other 8-oxidation. Thus, unlike the selective inductive effect of rifampicin on antipyrine metabolic pathways, rifampicin does not differentially affect those forms of cytochrome P-450 involved in theophylline metabolism. The extent to which theophylline metabolism is induced by rifampicin is likely to have important clinical consequences.     

The interaction of erythromycin with theophylline

Summary The pharmacokinetics of the antikaliuretic amiloride has been studied in healthy controls and in patients with chronic renal failure or hepatitis. It was 40% bound to protein.In healthy volunteers 49% of an oral dose was recovered unchanged in the urine. The renal clearance of amiloride was about 3 times the creatinine clearance, which means that it was predominantly excreted via tubular secretion.Renal impairment reduced the clearance of amiloride, causing a prolongation of the t_1/2 and drug accumulation in plasma. In hepatitis the t_1/2 of amiloride was prolonged and the AUC increased. Urinary recovery (Ae) of amiloride was greater in hepatitis patients than in controls.     

Plasma theophylline and caffeine and plasma clearance of theophylline during theophylline treatment in the first year of life

Plasma concentrations of caffeine and theophylline were simultaneously determined in 17 preterm infants after oral administration of aminophylline for treatment of apnoea. The ratio of caffeine/theophylline concentration in plasma increased during the first 2 weeks of treatment, owing to the longer time required for caffeine than for theophylline to reach steady state. The caffeine/theophylline ratio at steady state was 0.57 +/- 0.03 (mean +/- SE). Thus, caffeine contributed significantly to the total methylxanthine load in the infants. The plasma clearance of theophylline was calculated from the plasma steady state concentrations. In 3 preterm infants treated with oral aminophylline, repeated sampling showed an approximately linear increase in clearance with time from 16.8 +/- 0.4 (mean +/- SE) at a postnatal age of 6-11 days to 30.9 +/- 2.5 ml/kg/h at 64-69 days. In 1 full-term infant treated with oral theophylline from 3.5 to 11.5 months of age, the plasma clearance of theophylline increased in a roughly linear manner, reaching a plateau of about 100 ml/kg/h at 6-7 months of age. This corresponds to the clearance found in 1-4 year old infants.     

Influence of food on the bioavailability of theophylline from a sustained-released theophylline preparation.

In a single-dose cross-over study with 12 healthy male volunteers the relative bioavailability of theophylline (CAS 58-55-9) in a dosage of 700 mg (sustained-release preparation) under fasting- and non-fasting conditions was investigated. The areas under the plasma concentration-time curves AUC amounted to 184.2 +/- 42.7 micrograms.h/ml (fasting) and 157.9 +/- 32.9 micrograms.h/ml (non-fasting, p = 0.031). The bioavailability was reduced by approx. 15% by concomitant food intake. The 95% confidence intervals for AUC and Cmax were 76-99% and 78-105%, respectively, and therefore narrowly outside the usual 80-120% limits. There were no therapeutically relevant changes with regard to the parameters Cmax, tmax and MRT. The MRT values of 13.4 and 13.9 h respectively showed furthermore that theophylline represents a twice-daily formulation. No "dose-dumping effect" was observed.     

Food induced changes in theophylline absorption from a once-a-day theophylline product.

Bioavailability and the absorption pattern of theophylline from the sustained release theophylline (SRT) product, Uniphyllin, were studied in eight adults and eight children under fasting conditions in the morning, after a standardised breakfast in the morning, and under fasting conditions in the evening (adults only). Theophylline given intravenously was used as a reference. The extent of absorption of theophylline was complete for all administrations of SRT both in adults and children. In adults the absorption profiles after the three administrations of SRT were very similar and at no time point was there any difference in serum theophylline concentration or fraction absorbed between the three regimens. In addition, inter and intra individual variations in absorption were small. In children food caused a substantial change in the absorption pattern of theophylline so that the profiles became rather unpredictable with delays in absorption and periods of rapidly increasing serum drug concentrations. In three of the patients the dose dumping phenomenon resulted in toxic serum drug concentrations. Dumping of the dose could take place at any time interval between 3 and 15 h post dosing. Cmax was about 50% higher after fed than after fasting medication (P less than 0.01). It is concluded that children should not take SRT in large doses in combination with food.     

A study of the interaction of viloxazine with theophylline

The effect of viloxazine on the pharmacokinetics of theophylline was studied in eight healthy volunteers. Theophylline 200 mg/day (théophylline Bruneau 100 mg tablets) was administered on day 1; after a 3-day washout period, viloxazine 300 mg/day (Vivalan 100 mg tablets) was administered orally from days 5 to 7. On day 8, theophylline 200 mg and viloxazine 100 mg were concomitantly administered. The pharmacokinetic parameters of theophylline alone and after coadministration of viloxazine were determined. Viloxazine significantly increased the plasma concentrations (p less than 0.01) and the area-under-the-curve values (p less than 0.01) of theophylline and decreased its body clearance (p less than 0.05). Our results suggest that the dosage of theophylline should be decreased and its plasma concentrations monitored when viloxazine is prescribed.     

A serious interaction of dantrolene and theophylline

Dantrolene and theophylline have in common pronounced actions on several muscular systems. Therefore we investigated the interaction of these 2 drugs in rats. Normal cases of dantrolene (4 or 2 mg/kg) caused an increase in the lethality produced by theophylline, but without showing the expected seizures of theophylline toxicity. This may be caused by a synergistic action on the heart or blood vessels. On the other hand, a small dose of dantrolene decreased theophylline-induced seizures and death. This may be due to the effect of dantrolene on calcium release in skeletal muscles. The dosage of dantrolene should be decreased when used with theophylline.