Changes In Theophylline Clearance Research Articles

Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants.

The purpose of this study was to explore clinical markers reflecting developmental changes in drug clearance by preterm infants. Preterm infants administered aminophylline or theophylline to treat apnoea of prematurity were enrolled in this study. Trough and one of 2h, 4h or 6h post-dose blood samples and urine samples were collected during steady state, to determine the concentrations of theophylline and its targeted metabolites. CYP1A2*1C and CYP1A2*1F genotypes were analyzed. Total, renal and nonrenal clearances of theophylline were calculated, and cytochrome P450 1A2 (CYP1A2) activity was obtained from the ratio of 1-methyluric acid and 3-methylxanthine to theophylline in urine. Multiple linear regression analysis was performed to evaluate the relationships between theophylline clearance and the clinical characteristics of preterm infants. A total of 152 samples from 104 preterm infants were analyzed. A strong association between the serum trough and urine theophylline concentrations was found (P<0.001). Total, renal and nonrenal clearances of theophylline were 0.50±0.29mlkg-1 min-1 , 0.16±0.06mlkg-1 min-1 and 0.34±0.28mlkg-1 min-1 , respectively. CYP1A2 activity correlated positively with the postnatal age and postmenstrual age. However, CYP1A2 genotype was not associated with CYP1A2 activity, which was significantly associated with nonrenal clearance. CYP1A2 activity, postnatal age , weight and 24-h urine output were significantly associated with total theophylline clearance. CYP1A2 activity can be monitored using noninvasive random urine samples, and it can be used to assess developmental changes in theophylline clearance by preterm infants.

Effect of Levofloxacin on Theophylline Clearance During Theophylline and Clarithromycin Combination Therapy

OBJECTIVE:To report a case of decreased theophylline clearance by the addition of levofloxacin in a patient receiving theophylline and clarithromycin.CASE SUMMARY:A 59-year-old Japanese man who was receiving theophylline for emphysema experienced stimulation, insomnia, and tachycardia due to theophylline toxicity after clarithromycin and levofloxacin were added to the regimen. The combination of these agents resulted in a decrease in theophylline clearance to approximately 60% of the initial value obtained while the patient was receiving theophylline alone. The adverse effects disappeared after the dosage was reduced and the theophylline serum concentration decreased; however, there was no change in theophylline clearance. After discontinuation of levofloxacin, the theophylline serum concentration decreased, and theophylline clearance returned to the initial level even though clarithromycin was continued.DISCUSSION:Levofloxacin is believed not to influence the clearance of theophylline, although some new fluoroquinolones have been reported to do so. This case indicates that levofloxacin and clarithromycin inhibited theophylline metabolic pathways catalyzed by both CYP1A2 and CYP3A4 and resulted in the decrease in theophylline clearance. The clearance of theophylline, therefore, is not influenced by clarithromycin alone.CONCLUSIONS:Careful monitoring is required when levofloxacin is prescribed for patients who are taking clarithromycin with theophylline.

Increased theophylline metabolism in the menstrual phase of healthy women

Background: We previously reported on a Japanese woman with premenstrual asthma whose serum theophylline concentration was lower before the onset of her menstrual period. We evaluated the clearance of theophylline in each phase of her menstrual cycle and found an increase in clearance in the premenstrual and menstrual phases. Objective: This study was designed to investigate whether changes in theophylline clearance may occur with the menstrual cycle in nonasthmatic women. Methods: Aminophylline, 250 mg, was infused intravenously for 45 minutes, and the clearance of theophylline was calculated in seven healthy, ovulatory women on days 1 or 2, 10, and 20 or 25 of the menstrual cycle. The serum concentration of theophylline was determined with an enzyme immunoassay (homogeneous). Results: Theophylline clearance was significantly higher and its half-life was significantly shorter in the menstrual phase than in the follicular phase. Conclusion: The metabolism of theophylline, and consequently, its clearance were increased in healthy women around the onset of menses. Clinicians must therefore consider the menstrual variation in theophylline metabolism when prescribing this drug to female patients. (J Allergy Clin Immunol 1997;100:39-43.)

乳幼児におけるテオフィリンクリアランスに及ぼす年齢の影響，および投与指針の検討

Theophylline clearance was investigated in 91 hospitalized children (aged 0 to 14 years) with asthma or asthmatic bronchitis, and the change in theophylline clearance with growing larger was evaluated in 12 children. The patients were administered durable intravenous of theophylline intravenously. The mean clearance in children from 0 to 1 year old was significantly decreased (P<0.01) over that in children over 2 years old, and a significant relationship between age and theophylline clearance was confirmed in children from 0 to 36 months old (r=0.647, P<0. 01). The clearance was increased with growing larger in children less than 2 years old. Though, no such changes were observed in children over 2 years old. Since these data revealed that the clearance increases with growing larger in children less than 2 years old, when theophylline is to be administered to children less than 2 years old attention should be given to the effect of age on theophylline clearance. Conversely, to determine the initial optimum dosage in babies and infants, we summarize the theophylline dosage based on the above calculated regression equation, with the dosage in infants aged 6, 12, 18 and 24 months being determined to be 10.7, 12.2, 13.6 and 15.1 mg/kg/day, respectively.

Effect of low-dose methotrexate on the disposition of glucocorticoids and theophylline

Low-dose methotrexate (MTX) therapy has been recently proposed as alternative therapy for patients with severe steroid-requiring asthma. Several questions have been raised regarding the mechanism of action, including alteration of pharmacokinetics of two medications used in these patients, specifically, glucocorticoids and theophylline. To address this question, pharmacokinetic studies were performed at baseline and after 6 weeks of treatment with either intramuscular MTX or placebo (folic acid). Plasma concentrations of theophylline were measured by fluorescence polarization immunoassay (TDx, Abbott Diagnostics, Abbott Park, Ill.). Prednisolone, methylprednisolone, and cortisol concentrations were measured by high-performance liquid chromatography. Fifteen adults were enrolled in the double-blind, placebo-controlled trial. No change in prednisolone pharmacokinetic parameters was found. Theophylline clearance decreased an average of 19% in patients randomized to receive MTX, from 48.0 ± 2.0 ml/hr/kg to 38.9 ± 3.6 ml/hr/kg ( p < 0.05). This change resembles change observed with theophylline and phenobarbital clearance in which a high degree of interpatient variability is observed. The most likely explanation for the change in theophylline clearance is inhibition of hepatic microsomal enzyme activity. Three patients complained of adverse effects, and dosage was reduced in one patient. The variable effect of MTX on theophylline clearance indicates that theophylline concentration monitoring should be performed in patients receiving both drugs.

Effect of Phenobarbital Administration on Theophylline Clearance in Premature Neonates

The effect of phenobarbital administration on theophylline clearance was studied in 24 premature neonates. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose followed by a maintenance dose of 2.5-5 mg/kg/12 h. Of the 24 neonates studied, 12 received a mean phenobarbital dose of 26.34 mg/kg/d (ranging from 2 mg every 24 h to 25 mg every 12 h) and the mean phenobarbital concentration was 56.12 micrograms/ml (range 22-112 micrograms/ml). The remaining 12 patients did not require phenobarbital therapy but did receive aminophylline alone. The two groups were closely matched for gestational age, 5-min Apgar scores, and sex (p greater than 0.2). Steady-state theophylline clearance was determined at least once a week for four or more separate weeks. The study lasted a minimum of 8 wk and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated an increase in mean theophylline clearance over time (from 15.75 and 16.67 ml/h/kg to 30.33 and 35.42 ml/h/kg for the aminophylline and aminophylline plus phenobarbital groups, respectively). The mean slope, an indicator of the average change in theophylline clearance, was 2.19 for the aminophylline group and 3.27 for the aminophylline plus phenobarbital group (p greater than 0.2), indicating that the theophylline clearance for neonates receiving phenobarbital was not significantly different from that for neonates receiving aminophylline alone. Based on this information, aminophylline does not need to be adjusted solely based on concomitant phenobarbital administration; however, theophylline concentrations should be monitored since theophylline clearance can change rapidly and unpredictably in neonates.

Evaluation of the effect of norfloxacin on the pharmacokinetics of theophylline.

To investigate a possible interaction between norfloxacin and theophylline, eight healthy nonsmoking volunteers (mean age 27 +/- 5.3 years) were administered aminophylline, 5 mg/kg, before and after a 6-day course of norfloxacin, 400 mg every 12 hours, and changes in pharmacokinetic parameters were measured and compared. Norfloxacin induced significant decreases in theophylline clearance (14.9%; p less than 0.01) and the terminal phase slope (13.3%; p less than 0.02) and increased the AUC (16.6%; p less than 0.01). The apparent volume of distribution at steady state was unchanged. The greatest norfloxacin-induced individual change in theophylline clearance was a reduction of 28.6%. Given these findings, we advise that, for patients who are treated with theophylline and are subsequently treated with norfloxacin, adjustment of the theophylline dosage may be necessary in some patients to minimize the risk of theophylline toxicity.

The theophylline-erythromycin interaction.

Since its publication in 1976, the original report of an interaction between erythromycin and theophylline by Cummin, Kozak, and Gillman has generated considerable interest and controversy. Many studies with considerably different designs have been performed to address this question. Those studies that most closely simulate the clinical setting suggest that a 7- to 10-day course of concurrent theophylline and erythromycin therapy will result in variable changes in theophylline clearance. It may be that as many as 25% of patients, especially when maintained with serum theophylline concentrations at the upper portion of the therapeutic range, display elevations in serum theophylline concentrations that might lead to clinical symptoms of theophylline toxicity. There has been a suggestion, based on the mean changes in several studies, that the interaction may lead to a 25% increase in serum theophylline concentrations; however, it is clear that there may be a much larger increase in some patients. This toxicity can be anticipated and avoided if careful attention is paid to monitoring the serum theophylline concentrations of such high-risk patients when erythromycin therapy is contemplated as an addition to theophylline therapy. Other macrolide antibiotics may display interactions with theophylline, which may be due in part to the ability of the various antibiotics to form complexes with isoenzymes of the cytochromes P-450. The growing impression of the importance of mycoplasma in asthmatics and the introduction of new macrolides onto the market make the appreciation of this possible interaction of extreme importance to primary care and chest physicians.

Intraindividual changes in theophylline clearance during constant aminophylline infusion in children with acute asthma

Intraindividual changes in theophylline clearance were examined in 13 children with acute exacerbation of asthma receiving a 72-hour constant intravenous infusion of aminophylline. The mean (+/- SD) first, second, and third clearances measured at 24, 48, and 72 hours after the infusion increased from 58.1 +/- 13.8 to 69.7 +/- 28.0 to 84.1 +/- 36.3 ml/hr/kg, respectively (P less than 0.02 from the first and P less than 0.05 from the second). Our results suggest that substantial intraindividual changes in theophylline clearance can occur over a rather short time during intravenously administered aminophylline therapy for acute asthma in children. We recommend that plasma theophylline concentrations be monitored frequently and that aminophylline infusion rate be adjusted on the basis of the measured theophylline concentration data during an acute episode of asthma in the pediatric patient.

Theophylline Toxicity and Viral Infections

We were most interested in the article by Kraemer et al1 concerning altered theophylline clearance in asthmatic patients during an influenza B outbreak. We have studied two compliant asthmatic patients who had sudden changes in theophylline clearance at the time of symptomatic viral infections. The first patient was a steroid-dependent asthmatic child who was maintained on 10.54 mg/kg/dose of Theo-Dur for six months with theophylline levels in the therapeutic range of 10 to 20 µg/ ml.

Effect of intravenous isoproterenol on theophylline kinetics

Aminophylline and isoproterenol were simultaneously administered by continuous intravenous infusion to six patients with status asthmaticus and acute respiratory failure. During the isoproterenol administration, an increased theophylline clearance was seen in each patient, with a decrease in clearance after the cessation of the isoproterenol infusion. Arterial pH determinations during this study did not correlate with the changes in theophylline clearance. Two patients treated with mechanical ventilation for acute respiratory failure secondary to status asthmaticus did not demonstrate the changes in theophylline clearance seen in the patients treated with intravenous isoproterenol. Parallel studies done in four mongrel dogs indicated similar results to those noted in patients. In the dogs, urinary theophylline clearances were also measured during the administration of isoproterenol without any detectable change. These observations suggest a significant, previously unreported drug interaction between theophylline and isoproterenol during their simultaneous intravenous administration. Questions regarding the mechanism of the drug interaction and the therapeutic implications of these findings are also raised.

Effects of allopurinol on theophylline metabolism and clearance.

The effects of allopurinol on the plasma clearance and metabolism of theophylline in man were investigated under single-dose and multiple-dosing conditions. No change in theophylline clearance was found with the concomitant use of allopurinol but 1-methylxanthine (1MX), a theophylline metabolite not previously described in man, was detected in urine during control and allopurinol treatment phases under both single- and multiple-dosing conditions. 1MX excretion increased at the expense of 1-methyluric acid (1MU) during the allopurinol treatment phase. It is proposed that the secondary biotransformation of 1MX to 1MU is mediated by xanthine oxidase.

Changes in Theophylline Clearance During Acute Illness

Three patients demonstrated twofold to threefold changes in total-body theophylline clearance during the course of a single hospitalization for an acute illness. These changes paralleled the changes in the patients' clinical status. Theophylline clearance decreased in one patient with worsening airway obstruction, whereas clearance increased in one patient with resolving pneumonia and in one patient with improving congestive heart failure. Total-body theophylline clearance may be unstable in acute, severe illness. Close monitoring of plasma theophylline concentration in such situations will allow appropriate dose adjustments to be made and is, therefore, indicated.

Changes in theophylline clearance during acute illness

Changes in theophylline clearance during acute illness