Plasma Theophylline Concentrations Research Articles

Dependence of the Renal Excretion of Theophylline on its Plasma Concentrations and Urine Flow Rate in Asthmatic Children

The dependence of the renal excretion of theophylline on its plasma concentration and urine flow rate has been investigated in asthmatic children of either sex. One group (age 12.25 +/- 0.80, mean +/- s.d. n = 8) was given aminophylline intravenously (i.v.), while another (age 10.00 +/- 3.64 n = 14) was given a sustained release preparation of theophylline orally (single dose and repeated doses). Unchanged drug (11.6% +/- 1.75) was excreted in the urine corresponding to a renal clearance of 10.6 +/- 1.6 mL h-1kg-1. Time dependence of the renal clearance of theophylline was found only after i.v. administration. Dependence of the renal clearance on urine flow rate was found both after i.v. administration and at steady state, but not after a single oral dose of theophylline. After oral administration, renal clearance of theophylline was higher at steady state than after a single dose (0.58 +/- 0.06 L h-1 kg-1 vs 0.23 +/- 0.03 L h-1 kg-1), while urine flow rate was lower (1.1 +/- 0.5 mL min-1 vs 1.8 +/- 0.9 mL min-1). High correlation of theophylline plasma concentration and theophylline excretion rate was obtained in 10 of 14 patients after administration of a single oral dose of the preparation (r = 0.8567 to 0.9830). There was no dose dependence of the renal clearance of the drug either after a single dose, or at steady state.

Therapeutic drug and biochemical monitoring in a community pharmacy: Part 2

Abstract Opportunistic blood samples, at appropriate times post-dose, were taken from patients presenting prescriptions at a community pharmacy. Measurement and interpretation of carbamazepine (19 patients), digoxin (23), phenytoin (13) and theophylline (51) plasma concentrations indicated that 63.1 per cent (12 patients), 47.8 (11), 84.6 (11) and 58.6 (30), respectively, of the patients could benefit from a change to their therapeutic management to provide plasma concentrations with the highest probability of efficacy and the smallest possibility of side effects. Changes in the therapeutic management of 22 out of 46 patients (47.8 per cent) were necessary because of their plasma potassium concentrations. Of these, 13 (28.3 per cent of the total) were hypokalaemic and their medication included diuretics with no potassium assistance. Nine patients (19.6 per cent) were hyperkalaemic and were taking either a potassium sparing diuretic or potassium supplements with their diuretics. Thirty three (70.2 per cent) of the 47 patients whose creatinine clearance was determined required a change to their therapy. These patients had some degree of renal impairment and, according to the British National Formulary, a dosage adjustment was justified. We have previously shown (in part 1) that accurate measurements of these therapeutic drugs and biochemical parameters can be made in a community pharmacy from plasma samples. The study reported here shows that community pharmacists can use clinical pharmacokinetic and therapeutic knowledge to recommend optimal therapeutic regimens. Liaison between community pharmacists and general practitioners could provide a therapeutic drug and biochemical monitoring service with patient and economic benefits.

Effects of plasma albumin on theophylline concentration in lung tissue

To study the relationship between plasma and lung tissue theophylline concentrations, we changed the number of binding sites for theophylline on serum albumin. Cefazoline, which competes with theophylline for those binding sites, was given to rats, and free theophylline was separated by ultrafiltration. The dose of cefazoline was directly related to the percentage of free theophylline and was inversely related to the plasma total theophylline concentration. The plasma free theophylline concentration, however, was unchanged at the lower doses of cefazoline and was low only at the highest dose. The concentration of theophylline in lung tissue was inversely related to the dose of cefazoline. The concentration of 1, 3-dimethyluric acid, a major metabolite of theophylline, was also inversely related to the dose of cefazoline, which suggests that the metabolic rate of theophylline did not increase. Excretion of theophylline via the urine might be accelerated by its diuretic action. We conclude that when the binding of theophylline to plasma proteins is altered in rats, the concentration of free theophylline in plasma does not reflect the concentration of theophylline in lung tissue. Instead, the total theophylline concentration in plasma can be used as an index of the concentration in lung tissue.

Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of intravenous theophylline in rats: the role of CYP2E1 induction in 1,3-dimethyluric acid formation.

In rats with acute renal failure induced by uranyl nitrate, the hepatic microsomal cytochrome P450 (CYP) 2E1 and CYP3A23 increased 2-4- and 4-times, respectively, CYP2C11 decreased to 80% of control, but the levels of CYP1A2 and CYP2B1/2 were not changed. It has been reported that theophylline was metabolized to 1,3-dimethyluric acid by CYP1A2 and CYP2E1 and 1-methylxanthine via CYP1A2, which was metabolized further to 1-methyluric acid via xanthine oxidase in rats. Hence, it was expected that the formation of 1,3-dimethyluric acid would show an increase in rats with renal failure as a result of induction of CYP2E1. The pharmacokinetics of theophylline were compared in control rats and rats with renal failure after intravenous administration of aminophylline, 5 mg kg(-1) as theophylline. In rats with renal failure, the plasma concentrations of theophylline were considerably lower and the resultant total area under the plasma concentration-time curve from time zero to time infinity (AUC(0- infinity )) of theophylline was significantly smaller (2,200 vs 1,550 microg min mL(-1)) compared with control rats. In rats with renal failure, the plasma concentrations of 1,3-dimethyluric acid were considerably higher and the resultant AUC(0-6 h) of 1,3-dimethyluric acid was significantly greater (44.4 vs 456 microg min mL(-1)) compared with control rats. Moreover, the AUC(0-6 h, 1,3-dimethyluric acid)/AUC(0- infinity, theophylline) ratio increased from 2.02% in control rats to 29.4% in rats with renal failure. The in-vitro intrinsic 1,3-dimethyluric acid formation clearance was significantly faster in rats with renal failure (734 vs 529 10(-6) mL min(-1)) compared with control rats using hepatic microsomal fraction. The results led us to conclude that in rats with uranyl nitrate-induced renal failure after the administration of aminophylline, 5 mg kg(-1) as theophylline, there was an increase in the formation of 1,3-dimethyluric acid as a result of an increase in CYP2E1 expression.

Novel chronotherapeutic rectal aminophylline delivery system for therapy of asthma

The aim of this study was to develop a new chronotherapeutic pharmaceutical preparation as a sustained-release suppository for prevention and therapeutic use against bronchial asthma in the early morning. Sustained-release hollow-type (SR-HT) suppositories using sodium alginate (Alg-Na), sodium polyacrylate (PANa) or polyacrylate-PANa co-polymer (PA-PANa) as gelling polymers (gel agent) were prepared and pharmaceutical characteristics of these suppositories were investigated. Type A SR-HT suppositories comprised a suppository shell prepared with oleaginous base and containing aminophylline only or aminophylline with Alg-Na or PANa in the cavity (hollow space). Type B SR-HT suppositories comprised a suppository shell prepared with oleaginous base and gel agent (30%), with aminophylline in the hollow space. In drug-release studies, the acrylate polymer-containing suppositories showed linearity of delayed release rate, providing significantly decreased the highest concentration of theophylline in plasma ( C max) and delayed the time required to reach C max ( t max) and the mean residence time ( MRT) after rectal administrated in rabbits. In particular, suppositories containing PA-PANa maintained significantly higher theophylline concentrations than control suppositories at 12 h after rectal administration. Furthermore, histopathological examination indicated that these suppositories using acrylate polymers did not result in rectal lesions. The SR-HT suppository, particularly using PA-PANa as a gel agent, may thus be useful against nocturnal symptoms of asthma. In this study, we confirmed new formulation of sustained-release suppository for chronotherapy of theophylline using oily base material in combination with polymer such as PA-PANa. The hollow-type suppository containing oleaginous base and hydrophilic polymer in the shell could be useful device for rectal administration of various drugs with prolongation of plasma concentration.

Predicting Food Effects on Drug Release from Extended-Release Oral Dosage Forms Containing a Narrow Therapeutic Index Drug

INTRODUCTION With the various types of oral extended-release (ER) dosage forms available, it is a challenge to accurately predict their in vivo behavior. If therapeutically appropriate, an oral ER dosage form should provide consistent drug release over the entire dosing interval, regardless of when it is given in relation to meal intake. Experience has shown, however, that this cannot be generally assumed to be the case. Substitution of one ER formulation for another or administering the same formulation under varying dosing conditions (e.g., fasted versus fed state) can have unexpected results. Unwanted effects that have been described during the last decades range from “dose-dumping” to sub-therapeutic plasma levels (1–3). As these unwanted side effects may result in severe risks for the patients, it would be highly desirable to be able to forecast the in vivo release rates under various dosing conditions using in vitro data. The aim of these experiments was to develop an in vitro test method that can discriminate dissolution performance among ER dosage forms of a given drug, with view to predicting in vivo differences. Theophylline is a particularly suitable example for this purpose. This drug represents one of the cornerstones in the management of both the acute and chronic phases of reversible airway obstruction (4). However, because the drug has a narrow therapeutic index, the efficacy and toxicity of the active drug are highly dependent on plasma theophylline concentration (5). Optimum therapeutic serum level concentrations are generally considered to range from 8 to 15 μg/mL (6–8). The incidence of serious side-effects (ranging from nausea, vomiting, abdominal cramps, and diarrhea to arrhythmias, tremor, agitation, and convulsions) increases with concentration, particularly beyond the upper end of the usual therapeutic plasma theophylline range (5, 8). Toxic symptoms commonly occur at serum concentrations greater than 25 μg/mL but are typically not noted below 15 μg/mL (8). Thus, it is very important to maintain serum drug levels in the therapeutic range. When given as a solution or an immediate-release (IR) dosage form, theophylline is rapidly and completely absorbed along the small intestine and the colon (9–12). As the elimination half-life of theophylline is short (4–9 h), 4to 6-hourly administration of IR dosage forms is required to maintain the serum concentration within the therapeutic range (12). With such a regimen, lack of patient compliance is a serious problem, and low trough levels in the morning, with a possible risk of breakthrough of symptoms, can occur (13). Accordingly, ER dosage forms are the formulations most favored for the long-term management of chronic bronchospasm. Given only once or twice daily, they should result in more constant plasma levels, increase patient compliance, and avoid therapeutic gaps while preventing serious side effects. An ideal ER product should demonstrate complete bioavailability, minimal fluctuations in drug concentration at steady state, reproducibility of release characteristics independent of food, and minimal diurnal variation. However, with the first ER formulations, it became clear that not all meet the requirements of an ideal theophylline ER product. It was shown that in many cases, drug release from various theophylline ER formulations could be influenced (either increased or decreased) by concomitant intake of food (1, 3, 14–18). Although in maintenance therapy of chronic obstructive lung disease, most drugs are given in conjunction with food, the recent literature contains very few in vivo studies (1, 5, 13, 18–20) and next to no in vitro investigations (21) of the influence of food on the bioavailability of theophylline from ER formulations. Food intake can influence the rate of drug release from the dosage form, the rate of drug absorption, the amount of drug absorbed, or all of these parameters simultaneously. The rate of drug release of various ER formulations can be affected by the composition of the intraluminal contents, which itself is at least partly determined by the size and the composition of the co-administered meal. Depending on the type of dosage form and the intraluminal conditions, a co-administered meal can result in both so-called “positive” and “negative” food effects. Positive food effects typically come along with an increase in drug release from ER formulations and in the worst case, can represent a great risk for the patient, particularly when a large amount of the dose is dumped within a short period of time (22, 23). Such positive food effects are often the result of the loss of the integrity of matrices or coatings (i.e., devices that control drug release of ER dosage forms). It has been observed that fats, high concentrations of bile components, and pH changes (18, 22) are typical triggers for increased drug-release rates.

The effect of coenzyme Q10 on the pharmacokinetic parameters of theophylline

Interaction of a drug with other drugs and dietary supplements is becoming an emerging issue for patients and health insurance authorities due to awareness of adverse drug event. In this study, we examined the effects of coenzyme Q10 (CoQ10), one of the most popular dietary supplements, on the pharmacokinetic parameters of theophylline in rats. The pharmacokinetic parameters of theophylline changed significantly when the drug was administered after five consecutive days of pretreatment with CoQ10. Time to reach maximum plasma concentration of theophylline delayed when the drug was administered after the pretreatment with CoQ10. Maximum plasma concentration and area under the curve of theophylline were about two-fold increased and other pharmacokinetic parameters such as half-life and volume of distribution were also changed significantly. Therefore, although CoQ10 is generally considered a safe dietary supplement, it appears that patients on theophylline therapy should use caution when they take CoQ10.

In Vitro and In Vivo Evaluations of Cytochrome P450 1A2 Interactions with Duloxetine

To determine whether duloxetine is a substrate, inhibitor or inducer of cytochrome P450 (CYP) 1A2 enzyme, using in vitro and in vivo studies in humans. Human liver microsomes or cells with expressed CYP enzymes and specific CYP inhibitors were used to identify which CYP enzymes catalyse the initial oxidation steps in the metabolism of duloxetine. The potential of duloxetine to inhibit CYP1A2 activity was determined using incubations with human liver microsomes and phenacetin, the CYP1A2 substrate. The potential for duloxetine to induce CYP1A2 activity was determined using human primary hepatocytes treated with duloxetine for 72 hours. Studies in humans were conducted using fluvoxamine, a potent CYP1A2 inhibitor, and theophylline, a CYP1A2 substrate, as probes. The subjects were healthy men and women aged 18-65 years. Single-dose duloxetine was administered either intravenously as a 10-mg infusion over 30 minutes or orally as a 60-mg dose in the presence or absence of steady-state fluvoxamine (100 mg orally once daily). Single-dose theophylline was given as 30-minute intravenous infusions of aminophylline 250 mg in the presence or absence of steady-state duloxetine (60 mg orally twice daily). Plasma concentrations of duloxetine, its metabolites and theophylline were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods and evaluated using mixed-effects ANOVA. Safety measurements included vital signs, clinical laboratory tests, a physical examination, ECG readings and adverse event reports. The in vitro results indicated that duloxetine is metabolized by CYP1A2; however, duloxetine was predicted not to be an inhibitor or inducer of CYP1A2 in humans. Following oral administration in the presence of fluvoxamine, the duloxetine area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and the maximum plasma drug concentration (C(max)) significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In the presence of fluvoxamine, the oral bioavailability of duloxetine increased from 42.8% to 81.9%. In the presence of duloxetine, the theophylline AUC(infinity) and C(max) increased by only 13% (90% CI 7, 18) and 7% (90% CI 2, 14), respectively. Coadministration of duloxetine with fluvoxamine or theophylline did not result in any clinically important safety concerns, and these combinations were generally well tolerated. Duloxetine is metabolized primarily by CYP1A2; therefore, coadministration of duloxetine with potent CYP1A2 inhibitors should be avoided. Duloxetine does not seem to be a clinically significant inhibitor or inducer of CYP1A2; therefore, dose adjustment of CYP1A2 substrates may not be necessary when they are coadministered with duloxetine.

Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers

Danshen extract is widely used for the treatment and prevention of coronary heart disease and other diseases of senility in Asia. Danshen extract and theophylline may be prescribed together to treat patients with asthma. In human, theophylline with low therapeutic index is mainly metabolized by CYP1A2. In vitro findings have shown that human CYP1A2 is inhibited by the ethyl acetate extract of danshen and danshen pharmaceutical product. There may be drug interactions between danshen extract and theophylline (CYP1A2 substrate). This study concerned drug interactions between danshen extract and theophylline in Chinese volunteers. Long-term oral intake of danshen extract does not change the basic pharmacokinetic parameters of theophylline. Dose adjustment of theophylline thus may not be necessary in patients receiving concomitant therapy with danshen extract. To examine the potential effect of danshen extract on the pharmacokinetics of theophylline. In a sequential cross-over study with two phases, 12 volunteers took 100 mg theophylline on day 1 and day 15. From day 2 to day 15, volunteers received danshen extract tablets three times daily, four tablets each time for 14 days. On day 15, they received four danshen extract tablets with 100 mg theophylline. Plasma concentrations of theophylline were measured on days 1 and 15 periodically for 24 h. The 90% confidence interval of C(max), t(1/2) and CL/F of theophylline with 14-day danshen extract tablets vs. without comedication were (101.42, 121.36) (84.57, 106.72) and (88.82, 105.72), respectively. The time to peak plasma theophylline concentration was unchanged by danshen (P > 0.05). The pharmacokinetics parameter of theophylline was unaffected by danshen extract. Danshen extract does not influence the metabolism of theophylline in healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with danshen extract tablets.

Frequent Toxicity from IV Aminophylline Infusions in Critically ILL Patients

Use of recommended IV aminophylline dosage regimens in 48 older, acutely ill, hospitalized patients with chronic obstructive pulmonary disease (COPD) resulted in excessive plasma theophylline concentrations in 29 percent of these patients. A mean dose of 0.89 mg/kg/hr produced a plasma concentration which ranged from 7 to 52 mcg/ml with a mean of 21.9 mcg/ml. Plasma theophylline concentration was determined spectrophotometrically from plasma samples drawn at least 12 hours after a loading dose and initiation of a constant infusion. Severity of toxicity strongly correlated with the plasma theophylline concentration in 18 patients. Nausea and/or vomiting preceded life-threatening drug-induced arrhythmias and seizures less than half the time. Tachycardia was found to be the most consistent symptom associated with toxicity. These patients had lower plasma clearances than otherwise healthy younger adult asthmatics and healthy volunteers. Toxicity and identifiable risk factors for excessive plasma levels strongly correlated with reduced plasma clearance. Dosage modifications based upon plasma clearances from COPD patients without concurrent functional abnormalities and those with liver dysfunction and cardiac decompensation ranged from 0.7 to 0.12 mg/kg/hr. This study clearly demonstrates the poor correlation between dose and plasma concentration and the strong relationship between toxicity and plasma concentration. These results as well as those previously reported mandate that the relatively simple, rapid and inexpensive theophylline plasma measurement be used in all patients receiving IV aminophylline for longer than 24 hours in order to prevent toxicity.

Pharmacokinetics of Theophylline after Administration of Suppositories Formulation

Asthma is a public health problem for developed countries. It attacks all age groups but often starts in childhood. Theophylline ethanoate of piperazine in a suppository form is one of the treatments of asthmatic children. The pharmacokinetics of theophylline were evaluated in 24 healthy male subjects after administration of theophylline ethanoate of piperazine suppositories (PR) (Minophylline 500 mg. Alexandria Co.) and single injection intravenous (IV) of theophylline ethanoate of piperazine (Minophylline ampoules 500 mg Alexandria Co.). The theophylline serum levels were determined by an ELISA method. Peak theophylline plasma concentration, Cmax, (mean±S.D) was 21.5±2.10 µg/mL & 14±0.90 µg/mL; AUC(0‐t) values were 80.9 and 67. 4 µg · ml · hr for the reference IV preparation and suppositories, respectively. The median peak time, Tmax, was 0.5 hr for theophylline rectal administration. The above mentioned results demonstrate the possibilities of using theophylline (Minophylline Suppositories—500 mg Alexandria Co.) in asthmatic children in rural and desert areas away from health care personnel.

Population Pharmacokinetics of Caffeine and its Metabolites Theobromine, Paraxanthine and Theophylline after Inhalation in Combination with Diacetylmorphine

The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

Bronchodilating effects of salmeterol, theophylline and their combination in patients with moderate to severe asthma

Ten patients with moderate to severe asthma (mean FEV1±SD: 57.3±5.8% of predicted) participated in this 4-day single-blind, placebo-controlled, crossover study, aimed to comparatively evaluate the bronchodilating effects of a single dose of inhaled salmeterol (50μg) and oral slow-release theophylline (Theo-Dur, 600mg tablets), used either alone or in combination. In particular, FEV1 was recorded at baseline and 2, 4, 6, 8, 10, and 12h after drug administration; at the same times, with the exception of the 12thh, theophylline plasma concentrations were also measured. When compared to theophylline, bronchodilation induced by salmeterol was characterized by an earlier onset, a greater magnitude, and a longer duration. Given in combination with salmeterol, theophylline elicited a further slight increase in airway calibre with respect to the bronchodilator action of the β2-agonist alone, with FEV1 changes which resulted to be statistically significant at the 4th, 6th and 8thh after administration (p<0.05, p<0.03 and p<0.05, respectively). At the 4thh theophylline reached serum levels included within the therapeutic range, which were persistently maintained at least until the the 10thh. Therefore, our findings suggest that inhaled salmeterol and oral slow-release theophylline, the latter acting within the range of therapeutic plasma concentrations, exert additive bronchodilating effects in asthmatic patients with moderate to severe airflow limitation.

High-Throughput Liquid Chromatography–Tandem Mass Spectrometry Assay for Plasma Theophylline and Its Metabolites

Theophylline is metabolized to 1,3-dimethyluric acid (1,3-DMU), 3-methylxanthine (3MX), and 1-methylxanthine (1MX) mainly by CYP1A2, and 1MX is rapidly converted to 1-methyluric acid (1MU) by xanthine oxidase (1)(2)(3). Individuals differ in terms of their rates of theophylline metabolism and the resulting serum concentrations (1); moreover, some theophylline metabolites, such as 3MX, are known to have bronchodilator activity. Thus, we need to determine the plasma concentrations of theophylline and its metabolites simultaneously to ensure the safe use of theophylline, especially in patients with renal insufficiency, in whom serious side effects can occur if metabolites are allowed to accumulate. Many HPLC methods have been used to measure theophylline and its metabolites. However, most of these techniques require the avoidance of caffeine or require a longer separation time because of the interfering effect of caffeine metabolites such as 1,7-dimethylxanthine (1,7-DMX), 3,7-dimethylxanthine, and theophylline (1,3-dimethylxanthine) (4). Recently, liquid chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods to determine theophylline and caffeine metabolites have been developed (5)(6). However, these methods require two runs per sample, with negative and positive ionization, and the total HPLC run time is ∼60 min. These methods therefore are not suitable for the high-throughput determinations of theophylline and its metabolites required for routine therapeutic drug monitoring. In the present study, we developed a simple and rapid LC-MS/MS method for the simultaneous determination of plasma theophylline and its metabolites and applied this method to phenotyping of CYP1A2. We prepared stock solutions containing 1 g/L theophylline and 100 mg/L each of its metabolites in methanol. We constructed calibration curves with seven concentrations ranging from 0 to 20 mg/L theophylline and 0 to 2 mg/L each of the metabolites. A plasma sample (100 μL) was mixed with 100 μL of internal standard (IS) solution (1 μg of …

An Evaluation of the Dose‐Dependent Inhibition of CYP1A2 by Rofecoxib Using Theophylline as a CYP1A2 Probe

This study was undertaken to determine whether rofecoxib can interfere with CYP1A2 activity in humans using theophylline as a probe substrate. Single oral doses of theophylline were administered to each of three panels of 12 healthy subjects receiving daily doses of rofecoxib for 7 days to examine the effect of rofecoxib administration on the absorption and disposition of theophylline. Each panel was administered doses of 12.5, 25, or 50 mg of rofecoxib or a matching placebo in a two-way, randomized, crossover fashion and administered a single oral 300-mg dose of theophylline on day 7 of rofecoxib or placebo administration. Plasma concentrations of theophylline were monitored for 48 hours postdose to assess differences in pharmacokinetics. All three commercially marketed doses of rofecoxib were found to slow the clearance of theophylline with no detectable effect on absorption. CL/F values for theophylline were estimated from AUC infinity and by point estimates from the concentrations of drug in plasma at 12 and 24 hours postdose. The point estimates of CL/F were found to be in agreement with those derived from AUC.

Theophylline

Theophylline poisoning may occur following deliberate overdose or may complicate therapeutic use. It is important to establish at an early stage the precise theophylline product involved, because many formulations are sustained-release. As a consequence, peak plasma concentrations of theophylline are often not attained until 6-12 hours after overdose and the onset of features is correspondingly delayed.

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects with a new asymmetric dosage regimen.

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects was studied. In this study, a new asymmetric dosage regimen was presented to achieve a better accordance with the chronotherapy of asthma. Each of 10 subjects was administered one tablet (equivalent to 0.1 g anhydrous theophylline) in the morning and four tablets in the evening for a consecutive 6 days and blood samples were collected at the predetermined time and analyzed by a validated HPLC method. This new regimen produced a steady and effective level of theophylline in plasma for the whole day, especially in the evening. A lower dose in the morning could reach the effective level (C(min)4.97 +/- 1.60 microg/mL and C(max)10.68 +/- 1.80 micro g/mL over the a.m. dosing interval) and a higher dose in the evening did not result in toxic levels but led to a reasonable concentration range (C(max)9.72 +/- 1.56 microg/mL over p.m. dosing interval), which could maintain a higher plasma theophylline concentration without the risk of serious adverse events and control asthmatic symptoms probably occurring during the night or early in the morning. The results suggested that the proposed asymmetric regimen was necessary, practicable and safe for twice daily sustained-release tablets of theophylline sodium glycerinate and also provides the basis for the clinical dosage regimen of other theophylline formulated products.

Effects of Adding Either a Leukotriene Receptor Antagonist or Low-Dose Theophylline to a Low or Medium Dose of Inhaled Corticosteroid in Patients With Persistent Asthma

To evaluate the effect of adding zafirlukast or low-dose theophylline to a beclomethasone dipropionate (BDP) extra-fine hydrofluoroalkane aerosol on bronchial hyperresponsiveness as the primary outcome variable. Twenty-four patients with mild-to-moderate asthma were studied using a randomized crossover design with the following three treatment blocks: (1) beclomethasone, 100 microg/d, alone for the first 2 weeks followed by 400 microg/d alone for the next 2 weeks; (2) beclomethasone, 100 microg/d, followed by 400 microg/d, with the addition of zafirlukast, 20 mg bid; (3) beclomethasone, 100 microg/d, followed by 400 microg/d, with the addition of theophylline, 200 to 300 mg bid. Measurements were made after 2 and 4 weeks of each treatment and at pretreatment baseline. The mean trough plasma theophylline concentration was 6.7 mg/L, coinciding with the anti-inflammatory target range (ie, 5 to 10 mg/L). The provocative dose of methacholine causing a 20% fall in FEV(1) (as doubling dose difference from baseline) was significantly (p < 0.05) greater with beclomethasone, 100 microg, plus zafirlukast (1.1 doubling dose) but not with beclomethasone, 100 microg, plus theophylline (0.7 doubling dose) compared to beclomethasone, 100 microg alone (0.4 doubling dose), but not compared to beclomethasone, 400 microg alone (1.1 doubling dose). There were also significant (p < 0.05) differences between beclomethasone, 100 microg, plus zafirlukast (but not BDP, 100 microg, plus theophylline) vs beclomethasone, 100 microg, alone in terms of nitric oxide level, midexpiratory phase of forced expiratory flow, and peak expiratory flow. There were no further significant improvements observed with the addition of zafirlukast or theophylline to beclomethasone, 400 microg. A leukotriene receptor antagonist, but not low-dose theophylline, conferred significant additive anti-inflammatory effects to therapy with a low-dose inhaled corticosteroid but not to that with a medium dose of an inhaled corticosteroid. Thus, optimizing the dose of inhaled corticosteroid as monotherapy would seem to be the logical first step, which is in keeping with current guidelines.

Preparation and evaluation of press-coated aminophylline tablet using crystalline cellulose and polyethylene glycol in the outer shell for timed-release dosage forms

In an attempt to achieve chronopharmacotherapy for asthma, press-coated tablets (250 mg), which contained aminophylline in the core tablet in the form of low-substituted hydroxypropylcellulose (L-HPC) and coated with crystalline cellulose (PH-102) and polyethylene glycol (PEG) at various molecular weights and mixing ratios in the amounts of PH-102 and PEG as the outer shell (press-coating material), were prepared (chronopharmaceutics). Their applicability as timed-release (delayed-release) tablets with a lag time of disintegration and a subsequent rapid drug release phase was investigated. Various types of press-coated tablets were prepared using a tableting machine, and their aminophylline dissolution profiles were evaluated by the JP paddle method. Tablets with the timed-release characteristics could be prepared, and the lag time of disintegration was prolonged as the molecular weight and the amount of PEG, for example PEG 500,000, in the outer shell were increased. The lag time of disintegration could be controlled by the above-mentioned method, however, the pH of the medium had no effect on disintegration of the tablet and dissolution behavior of theophylline. The press-coated tablet (core tablet:aminophylline 50 mg, L-HPC and PEG 6000; outer shell:PH-102:PEG = 8:2 200 mg) with the timed-release characteristics was administered orally to rabbits for an in vivo test. Theophylline was first detected in plasma more than 2 h after administration; thus, this tablet showed a timed-release characteristics in the gastrointestinal tract. The time (tmax) required to reach the maximum plasma theophylline concentration (Cmax) observed after administration of the press-coated tablet was significantly (p < 0.05) delayed compared with that observed after administration of aminophylline solution in the control experiment. However, there was no difference in Cmax and area under the plasma theophylline concentration-time curve (AUC0-->24) between the press-coated tablet and aminophylline solution. These results suggest that the press-coated aminophylline tablet (with the timed-release characteristic) offers a promising forms of theophylline chronotherapy for asthma.

Pharmacokinetic Profile of Zafirlukast

Zafirlukast is a cysteinyl leukotriene type 1 receptor antagonist that causes bronchodilation and has anti-inflammatory properties. Clinical efficacy has been demonstrated when using oral doses of 20 to 40 mg twice daily. The pharmacokinetics of zafirlukast are best described by a two-compartment model. Maximum plasma concentrations (Cmax) were achieved 3 hours after a single oral dose of 20 or 40 mg to healthy volunteers. The absolute bioavailability of zafirlukast is unknown. However, coadministration of zafirlukast with food reduces bioavailability by approximately 40%. The drug binds to plasma proteins (>99%), predominantly to albumin, and has a mean terminal elimination half-life of approximately 10 hours in both healthy volunteers and patients with asthma. Zafirlukast undergoes extensive hepatic metabolism. Hydroxylation by cytochrome P450 (CYP) 2C9 is the major biotransformation pathway. The metabolites of zafirlukast contribute little to its overall activity. Zafirlukast is mainly eliminated in the faeces, while urinary excretion accounts for <10% of an orally administered dose. Because of its primarily hepatic metabolism, the clearance of zafirlukast is reduced in patients with hepatic impairment. In patients with stable alcoholic cirrhosis, Cmax and area under the plasma concentration-time curve for zafirlukast were increased by 50 to 60% compared with healthy volunteers. Asymptomatic elevations of serum liver enzymes have been reported with high dosages of zafirlukast (80 mg twice daily), returning to normal after cessation of the drug. Inhibition of the CYP2C9 and CYP3A isoenzymes by zafirlukast has been reported in vitro. Zafirlukast interacts with warfarin and produces a clinically significant increase in the prothrombin time, but it does not alter the pharmacokinetics of terfenadine carboxylate, the active metabolite of terfenadine. Plasma concentrations of zafirlukast decreased when the drug was administered concomitantly with erythromycin, terfenadine or theophylline, and increased when it was coadministered with aspirin (acetylsalicylic acid). Theophylline metabolism is unchanged in most cases by zafirlukast, but there is a report of one patient with increased theophylline plasma concentrations when zafirlukast was coadministered. Recently, cases of Churg-Strauss syndrome have been described in patients with asthma receiving zafirlukast treatment. This occurrence in patients being withdrawn from corticosteroid therapy while receiving zafirlukast has been attributed to a previously undiagnosed presence of this syndrome in these patients.