Lack of effect of amoxicillin on theophylline pharmacokinetics.

The effect of the antibiotic drug amoxicillin on steady state pharmacokinetics of theophylline was studied in healthy adults by comparing the pharmacokinetic parameters as found during a 9 day course of theophylline alone and as obtained during comedication with amoxicillin. Theophylline plasma concentrations were measured by means of h.p.l.c. analysis. On the ninth day of each of the two periods of drug administration a concentration-time curve was evaluated. It showed no influence of amoxicillin on absorption, elimination and volume of distribution of theophylline, as a result of which mean steady state plasma concentrations were not significantly different during both treatments. It is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.     

No effect of influenza vaccination on theophylline pharmacokinetics as studied by ultraviolet spectrophotometry, HPLC, and EMIT assay methods

The effect of influenza vaccination on steady-state pharmacokinetics of theophylline was studied in six healthy young adults by comparing pharmacokinetic parameters found on days 4 and 5 during a 5-day course of theophylline alone with those obtained after influenza vaccination on day 4 of a second study phase. Theophylline plasma concentrations were measured by means of high-pressure liquid chromatography (HPLC) analysis and, in part, with a manual ultraviolet spectrophotometric method and with an EMIT assay. On the fourth and fifth days of each of the two periods of drug administration, theophylline plasma concentration-time curves were evaluated, and the following pharmacokinetic parameters were compared: trough plasma concentration (cmin), peak plasma concentration (cmax), time to peak (tmax), and the area under the curve during a dosing interval (AUC). None of these pharmacokinetic parameters of theophylline before and after vaccination were found to be significantly different with any of the analytical methods.     

Patient compliance with oral theophylline therapy.

Day-to-day variations in plasma theophylline concentrations at steady-state have been assessed in 29 hospital inpatients who required theophylline for obstructive airways disease. Plasma concentrations were measured at 09.00h and 14.00h for four consecutive days in the equilibrium state in 13 patients taking 350 mg/day and 16 patients taking 700 mg/day. Analysis of variance gave 95% confidence limits for day-to-day variation of +/- 2.9 micrograms/ml at 350 mg/day and +/- 4.8 micrograms/ml at 700 mg/day. In a separate study, compliance with sustained-release theophylline therapy has been assessed in a group of 63 patients receiving the drug in general practice but not attending hospital. Compliance was estimated by comparing plasma theophylline concentrations before and after a 7-day period of measured theophylline consumption and by tablet counting. Of the 63 patients, 16 had discontinued their theophylline prior to being contacted and two did so during the first week: these were considered non-compliant. Three patients had plasma concentrations which increased by more than the day-to-day variation for their dose level during monitored intake and one other took less than 80% of his tablets. These patients were also considered non-compliant. A further four patients in whom plasma theophylline levels were zero on at least one occasion during the study were also adjudged non-compliant. Thus non-compliance with prescribed theophylline dosage occurred in 26 (41.3%) of the patients studied. In the majority of these, treatment had been discontinued and the non-compliance was gross.(ABSTRACT TRUNCATED AT 250 WORDS)     

A theophylline dosage regimen which reduces round-the-clock variations in plasma concentrations resulting from diurnal pharmacokinetic variation

Summary Slower drug absorption at night can leave residual drug from an evening dose of a sustained-release product remaining to be absorbed at the time of the next morning's dose, thereby giving higher plasma concentrations of the drug during the day than the night.When a capsule product releasing theophylline over 12 h after a morning dose was given repetitively at 8 a.m. and 8 p.m. for 4 days, daytime plasma concentrations from 4 h to 8 h after the dose were about 40% greater than corresponding night-time concentrations, and the mean steady-state concentration during the night-time interval was only 81% of that during the daytime interval.Altering the regimen to one capsule at 12 noon and one at 10 p.m. eliminated all significant differences between a.m. and corresponding p.m. plasma concentrations of theophylline and between the mean steady-state concentrations for each of the interdose intervals within a day.     

Changes in the steady-state pharmacokinetics of theophylline during treatment with dirithromycin

The steady-state plasma concentrations and pharmacokinetic characteristics of theophylline were studied during intermittent treatment with dirithromycin. The addition of dirithromycin (500 mg orally once daily at 7:00 AM) to a sustained-release theophylline dosing regimen (200 mg every 12 hours) elicited small changes in the steady-state pharmacokinetics of theophylline. Mean steady-state plasma theophylline trough concentrations (Cmin) were invariant before, during, and after dirithromycin treatment; however, mean average steady-state plasma theophylline concentrations (Cav) declined by 18% during dirithromycin treatment (P less than .05), and mean peak plasma concentrations (Css,max) declined by 26% (P less than .01). Theophylline clearance (CL/F) exhibited an increase of comparable magnitude during dirithromycin treatment, although the increase in CL/F was not statistically significant (.05 less than P less than .1). Dirithromycin treatment alters the steady-state pharmacokinetics of theophylline; however, the magnitude of the changes is small and is not likely to modify treatment outcomes.     

Theophylline binding to plasma proteins in patients with chronic obstructive pulmonary disease

The binding of theophylline to plasma proteins was studied in samples from healthy adults at different pH values and drug concentrations and in samples from patients with chronic obstructive pulmonary disease (COPD). Binding determinations were performed by ultrafiltration and drug concentrations were measured by high performance liquid chromatography. Total plasma levels of theophylline did not influence the degree of the binding. The percentage of bound theophylline was positively correlated with pH both in vitro (r = 0.998, p less than 0.005) and in vivo (r = 0.579, p less than 0.005). Mean theophylline binding values in vivo (mean 56.3 +/- 12.5) and in vitro (mean 48.3 +/- 9.4) were significantly different. The increase in theophylline free levels detected in COPD patients was partially dependent on low pH values but the influence of other factors must also be considered. The therapeutic implications of altered theophylline binding are discussed.     

Theophylline-terbutaline, a steady state study on possible pharmacokinetic interactions with special reference to chronopharmacokinetic aspects.

1. The pharmacokinetic interaction of terbutaline and theophylline and chronopharmacokinetics of both drugs were studied in a three-way crossover study with repeated administration of terbutaline (Bricanyl Depot) 7.5 mg twice daily, theophylline (Theo-Dur) 300 mg twice daily alone or the combination of both for 7 days to 12 healthy volunteers (six male and six female). 2. After the morning dose on day 7, blood and urine were sampled for 12 h, and after the evening dose on day 7, blood and urine were sampled for 48 h. Theophylline concentrations in plasma and concentrations of unchanged drug and metabolites in urine were determined by two selective high performance liquid chromatography methods. Terbutaline concentrations in plasma and urine were measured with a gas chromatography-mass spectrometry method. Area under the plasma concentration-time curve, fluctuations in plasma concentration, mean residence time, elimination half-life, renal clearance as well as maximal, minimal and average plasma concentration at steady state were evaluated. 3. The addition of terbutaline to the repeated administration of theophylline lowered the relative bioavailability of theophylline by approximately 11% during the night interval. The rate of elimination of theophylline and mean residence time were influenced accordingly. No significant changes in excretion of the theophylline metabolites were observed, but the excretion of 3-methylxanthine was slightly reduced by the concomitant terbutaline administration. None of the observed changes should be of any clinical importance. 4. The addition of theophylline did not influence any of the calculated pharmacokinetic parameters of terbutaline. 5. It can be concluded that no dosage adjustment is necessary when terbutaline and theophylline are given together.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative investigation of the influence of nizatidine, ranitidine, and cimetidine on the steady-state pharmacokinetics of theophylline in COPD patients.

The influence of usual regimens of the H2 blocking drugs, cimetidine, ranitidine, and nizatidine on the steady-state plasma concentrations and pharmacokinetic characteristics of theophylline was studied in seventeen patients with chronic obstructive pulmonary disease (COPD). Patients were dosed to steady-state with an oral, sustained-release formulation of theophylline given in therapeutic doses twice daily for 2 weeks. Over the next 4 weeks, each patient received a week-long regimen of each H2 blocker concomitantly with theophylline, and a week-long regimen of theophylline alone (control). At the end of each of the latter 4 weeks the steady-state pharmacokinetics of theophylline were assessed. Neither ranitidine nor nizatidine treatment altered the steady-state pharmacokinetics of theophylline relative to the control phase (i.e. no H2 blocker treatment). Values for theophylline C(ave), Cssmax, AUC0-12, and CLoral were significantly different during cimetidine treatment compared with all other treatments (ranitidine, nizatidine, and control). Cimetidine increased theophylline Cssmax, AUC0-12 and Cave by approximately 32%, and decreased theophylline oral clearance by approximately 23%. The authors conclude that cimetidine alters the steady-state pharmacokinetics of theophylline in COPD patients, whereas ranitidine and nizatidine are without effect.     

Aging,cigarette smoking and oral theophylline requirement

Summary In a prospective study in 73 patients with obstructive pulmonary disease, aged 63.5±13.5 years (SD), it was found that theophylline dose, cigarette smoking and age were all significant determinants of the steady-state trough plasma theophylline level during oral administration of the drug. As the predictive efficiency of the three factors combined amounted only to 25%, firm dosage recommendations cannot be made. Even among elderly patients, tobacco smokers had significantly lower plasma concentrations of theophylline. It is suggested that in order to obtain trough plasma concentrations of 50 µmol/l (9 µg/ml), a non-smoking 50 year-old patient would require 9.8 mg/kg/day of oral theophylline, the dose increasing to 14.2 mg/kg/day in smokers of the same age. These doses should probably be reduced by 15–20% in 75 year-old patients.     

Plasma theophylline concentrations following the oral administration of microcrystalline theophylline and a new sustained-release theophylline preparation to normal subjects

Summary Plasma theophylline concentrations have been measured in 14 normal subjects following the oral administration of a microcrystalline theophylline preparation (MT) 187.5 mg every 6 h and a sustained-release theophylline preparation (SRT) 375 mg every 12 h for 5 days. During the 5 days, blood samples were drawn before and 2 h after each morning dose with MT, and before and 4.5 h after each morning dose of SRT. On days 1 and 5, more frequent samples were taken during the dose interval. With both preparations, steady-state plasma concentrations were achieved by the third day. The trough levels were significantly higher with SRT than with MT on days 3 and 4, and the levels at 4.5 h after SRT were significantly higher than those measured 2 h after MT on days 3, 4 and 5. Over the terminal 3 days of the study, mean theophylline concentrations with SRT ranged between 11.2 and 15.5 µg/ml at measured trough and peak times, whereas the mean trough levels with MT were always below 10 µg/ml. With adjustment for the dosage differences, the mean ratio of the areas under the plasma concentration/time curves for the final dosage interval for the two formulations (AUC_SRT/AUC_MT) was 1.29±0.56, suggesting that the SRT preparation was well absorbed. The mean steady-state plasma theophylline concentrations (AUC/dose interval) on day 5 were 11.5±4.7 µg/ml with MT and 13.7±5.7 µg/ml with SRT. Nine subjects experienced a total of 35 side-effects whilst taking MT, compared with 10 subjects complaining of 23 side-effects on SRT. These results indicate that, in normal subjects, SRT 375 mg every 12 h exhibited satisfactory sustained-release properties and achieved adequate mean plasma theophylline concentrations during chronic administration. It produced higher plasma levels and a lower incidence of side-effects than the same daily dose of MT.     

Is diurnal variation in absorption of slow-release aminophylline an age-related phenomenon?

Summary To specifically assess the possible influence of ageing on the changes in theophylline absorption, the plasma concentration-time profiles of sustained-release aminophylline were studied in 8 young and 8 elderly subjects after 9 a.m. and 9 p.m. administration.After 9 p.m. administration, in elderly subjects, maximum plasma theophylline concentrations (C_max) were decreased, time to maximum concentration (t_max) was increased, and area under plasma concentration-time curve (AUC) was decreased compared to 9 a.m. dosing. This was true for single dose and at steady-state and suggests delayed and diminished absorption at night. No statistically significant changes were seen in the young subjects.This study therefore suggests that time related changes in absorption may be more significant in elderly subjects, possibly due to postural differences after 9 p.m. dosing, and this should be borne in mind when prescribing.     

Influence of pentoxifylline on steady-state theophylline serum concentrations from sustained-release formulations

This clinical study assessed the influence of pentoxifylline and its metabolites on steady-state serum theophylline concentrations. Nine healthy volunteers took sustained-release formulations of pentoxifylline, theophylline, and a combination of both agents each for 7 days at standard therapeutic doses in a randomized order. Serum theophylline concentrations were analyzed using fluorescence-polarization immunoassay (TDx) technique. During the pentoxifylline treatment phase, serum theophylline concentrations were undetectable, demonstrating the lack of assay interference from pentoxifylline and its metabolites. Mean trough steady-state serum theophylline concentrations were 30% higher (p less than 0.05) during the combination treatment phase compared to theophylline administration alone, and varied considerably. Although side effects were more frequent during the combination phase, differences in the number of adverse reactions did not achieve statistical significance. This study demonstrates an interaction between theophylline and pentoxifylline, and indicates that close monitoring of serum theophylline concentrations during combination therapy is warranted.     

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.     

Lack of Effect of Olanzapine on the Pharmacokinetics of a Single Aminophylline Dose in Healthy Men

Study Objective . To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate. Design . Two-way, randomized, crossover study. Setting . Clinical research laboratory. Subjects . Nineteen healthy males (16 smokers, 3 nonsmokers). Interventions . Because the a priori expectation was no effect of olanzapine on theophylline pharmacokinetics, a parallel study using cimetidine was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg after 9 consecutive days of either olanzapine or placebo. In group 2, seven healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo. Measurements and Main Results . Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma concentrations of olanzapine and its metabolites were measured for 24 hours after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. However, cimetidine significantly decreased theophylline clearance and the corresponding formation of its metabolites. Urinary excretion of theophylline and its metabolites was unaffected by olanzapine but was reduced significantly by cimetidine. Steady-state concentrations of olanzapine (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4′-N-desmethyl olanzapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and were unaffected by coadministration of theophylline. Conclusion . As predicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and should not affect the pharmacokinetics of other agents metabolized by the CYP1A2 isozyme.     

Influence of sulbactam plus ampicillin on theophylline clearance

The effect of sulbactam/ampicillin (500 mg/1000 mg) every 12 hours taken for seven days on the steady-state pharmacokinetics of theophylline was studied among 12 patients suffering from chronic obstructive pulmonary disease. Theophylline concentrations were measured serially for 12 h by the method of polarized immunofluorescence (Abbott TDx system). No influence of sulbactam/ampicillin was detectable on the theophylline half-life, clearance or volume of distribution. It was concluded that both drugs could be administered concomitantly without any dosage adjustment of theophylline.     

Experience with a computer-based technique for estimating pharmacokinetic constants from limited data

A computer-based approach for estimating pharmacokinetic data and predicting plasma drug concentrations based on two measurements of plasma drug concentrations was compared with a standard two-point method for estimating aminoglycoside (AG) pharmacokinetic parameters. The computer-based technique was also used to predict a theophylline steady-state nadir from two preceding ones. The computer-based and standard two-point methods provided similar estimates for mean (+/- SD) values of elimination rate constant (lambda) (0.172 +/- 0.103 h-1 and 0.179 +/- 0.010 h-1, respectively) and apparent volume of distribution (V) (22.7 +/- 9.9 L and 23.3 +/- 11.5 L, respectively). The mean (+/- SD) of predicted AG troughs was 1.3 +/- 0.5 mg/L for the standard method and 1.3 +/- 0.6 mg/L for the computer-based method. Neither was significantly different from the actual AG trough mean of 1.3 +/- 0.7 mg/L. Both methods exhibited a slightly negative bias in their predictions of actual AG troughs. When applied to theophylline data from patients or subjects receiving multiple-dose theophylline, the computer-based method effectively predicted trough theophylline concentrations for three formulations of theophylline. Mean prediction errors ranged from 0.1 to 0.5 mg/L, and root mean squared error ranged from 1.1 to 1.2 mg/L. This computer-based technique may be useful in dose individualization since relatively few constraints are placed on the type of data required for its application.     

Influence of allopurinol on drug metabolism in man

1. Elimination rates of phenylbutazone and warfarin after single oral doses in human volunteers, and steady-state plasma concentrations of these drugs in patients have been measured before, during and after administration of allopurinol.2. Allopurinol, in usual clinical doses, had no significant influence on the elimination rate of either drug in the group of volunteers as a whole although in a few individuals an apparent inhibitory effect was observed.3. No significant changes in the steady-state plasma concentrations of either phenylbutazone or warfarin were observed in patients during the administration of allopurinol.4. It is concluded that although allopurinol may have an apparent inhibitory effect on drug elimination in a few individuals, its administration to most patients on anticoagulant therapy is unlikely to alter dose requirements.     

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.     

Absence of a clinically significant interaction between theophylline and furosemide

Summary In new of previous contradictory results, the possible interaction between the loop diuretic furosemide and theophylline was re-evaluated in 12 healthy volunteers with a steady-state plasma theophylline level.Two doses of furosemide 20 mg at a 4 h interval did not influence the steady-state plasma concentration of theophylline despite causing a moderate diuresis. Urinary recovery of theophylline and its metabolites amounted to 106±21% of the dose without furosemide and 96±19% of the dose with furosemide, demonstrating that there was no influence on the enteral absorption of theophylline of the furosemide treatment. After the first dose of furosemide the fractional renal clearance (CL_R1) of theophylline (fractional = hourly sampling period) changed in parallel with the urinary flow rate, without a significant difference between treatment with and without furosemide. After the second dose of furosemide, CL_R1 was increased in the first hour and then it declined to levels far lower than the control value.This unexpected result could explain the unchanged plasma concentration of theophylline during furosemide treatment.     

Diphenhydramine disposition in the sheep maternal-placental-fetal unit: determinants of plasma drug concentrations in the mother and the fetus

The objective of this study was to identify the important factors that determine plasma concentrations of diphenhydramine (DPHM) in the mother and the fetus after maternal as well as fetal steady-state drug administration. Inter-relationships were evaluated between maternal and fetal placental and nonplacental clearances, plasma protein binding, and steady-state plasma concentrations of DPHM among data obtained from 18 pregnant sheep during late gestation. The major determinant of plasma DPHM concentrations in the mother after maternal as well as fetal administration appears to be maternal plasma protein binding and maternal nonplacental clearance. In contrast, the major determinant of fetal plasma DPHM concentrations after maternal drug administration was the extent of fetal first-pass hepatic drug uptake from the umbilical vein. However, after fetal drug administration, the fetal plasma concentrations were related to the extent of fetal plasma protein binding and fetal placental and nonplacental clearances. The index of fetal-to-maternal placental drug transfer after fetal drug administration (steady-state maternal-to-fetal plasma concentration ratio) was related to steady-state fetal plasma unbound fraction and fetal placental and nonplacental clearance. However, this index was not related to the magnitude of the factors operating on the maternal side of the placenta such as maternal plasma protein binding and maternal nonplacental clearance. This might indicate a lack of complete equilibration of the unbound drug concentrations on the two sides of the placenta at the exchange site.