Renal Clearance Of Theophylline 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.

Effect of low-dose macrolide antibiotics on theophylline disposition in pediatric patients

Low-dose macrolide antibiotics are administered for the treatment of certain chronic inflammatory sinopulmonary diseases (e.g., sinusitis and panbronchiolitis). Because 14-membered ring macrolide antibiotics administered at antimicrobial doses have been suggested to elicit a significant inhibitory effect on the hepatic metabolism of theophylline, we studied whether low-dose macrolide antibiotic therapy also evokes a clinically relevant alteration in the disposition of theophylline. The steady-state serum theophylline concentration and the urinary concentrations of theophylline and its metabolites [i.e., 1-methyluric acid (1MU), 3-methylxanthine (3MX), 1, 3-dimethyluric acid (DMU), and caffeine] were examined in nine stable asthmatic children who received both theophylline and lowdose erythromycin or clarithromycin (12.3±4.5mg/kg body weight/day) and in ten children who received theophylline alone.An immunoassay and high-performance liquid chromatography with ultraviolet detection (HPLC-UV) were used for serum and urinary drug assay, respectively. Results demonstrated no significant differences in serum theophylline concentration, the metabolic clearance of theophylline to its metabolites, and the renal clearance of theophylline between the two groups. In conclusion, the administration of low-dose macrolide antibiotics for the treatment of sinopulmonary diseases would not stipulate a dosage reduction of concomitantly administered theophylline in pediatric patients

Effect of a newly developed ketolide antibiotic, telithromycin, on metabolism of theophylline and expression of cytochrome P450 in rats

The effects of a newly-developed ketolide antibiotic, telithromycin, on the metabolism of theophylline and the expression of hepatic cytochrome P450 (CYP) 1A2 and CYP3A2 were investigated in rats. Telithromycin at a high dose (100 mg/kg of body weight) was injected intraperitoneally once a day for 3 days. Twenty-four hours (day 4) after the final administration of telithromycin, theophylline (10 mg/kg) was administered intravenously. The presence of telithromycin significantly delayed the disappearance of theophylline from plasma. Parameters related to the pharmacokinetic interaction between theophylline and telithromycin were examined by noncompartmental methods. A significant decrease in the systemic clearance of theophylline was observed in the presence of telithromycin. Pretreatment with telithromycin significantly decreased the metabolic clearance of the major metabolites, 1-methyluric acid and 1,3-dimethyluric acid, with no change in the renal clearance of theophylline, suggesting that the decreased systemic clearance of theophylline by telithromycin is due to reduction of their metabolic clearance. Pretreatment with telithromycin significantly decreased the activity of 7-ethoxyresorufin O-deethylation and testosterone 6β-hydroxylation, suggesting that telithromycin decreases the activity of hepatic CYP1A2 and CYP3A2. Western blot analysis revealed that telithromycin significantly decreased the protein levels of CYP1A2 and CYP3A2 in the liver, which could explain the observed decreases in the systemic clearance of theophylline and metabolic clearance of 1-methyluric acid and 1,3-dimethyluric acid. The present study suggests that telithromycin at the dose used in this study alters the pharmacokinetics and metabolism of theophylline, due to reductions in the activity and expression of hepatic CYP1A2 and CYP3A2.

Tegaserod Coadministration Does Not Alter the Pharmacokinetics of Theophylline in Healthy Subjects

Tegaserod (HTF 919), a selective 5‐HT4 receptor partial agonist, is in development for the treatment of functional gastrointestinal motility disorders. Tegaserod has been found to inhibit cytochrome P‐450 (CYP) 1A2, for which theophylline is a prototype substrate. This study was designed to assess the effect of tegaserod on the single‐dose pharmacokinetic and safety profile of theophylline. Eighteen subjects were enrolled in a randomized, open‐label, two‐period crossover study. After an overnight fast, subjects were randomized to receive one of two treatments: (1) a single dose of controlled‐release formulation of theophylline (Theo‐Dur®, 600 mg) on day 1 or (2) a single dose of tegaserod (6 mg) on day 1, concomitant administration of tegaserod (6 mg) and theophylline (600 mg) on the morning of day 2, followed by an additional dose of tegaserod (6 mg) 12 hours later. Four to 10 days later, the subjects received the alternative treatment regimen. The pharmacokinetic parameters of theophylline, including AUC, Cmax' and t1/2Λz' were similar for both treatment regimens, although the tmax of theophylline was statistically different between the treatments. Except for a decrease in partial metabolic formation clearance from theophylline to 1‐methyluric acid, which is unlikely to be clinically relevant, there were no statistically significant differences in renal clearance of theophylline and partial metabolic formation clearances following the combined treatment compared with theophylline alone. The results of the current study indicate that no dose adjustment is required when drugs metabolized via CYP1A2 are coadministered with tegaserod.

Circadian Rhythms in Theophylline Disposition: Simulations and Observations in the Dog

A constant-rate iv infusion of aminophylline approaching steady state in four dogs was used to investigate a circadian rhythm in theophylline disposition. A significant circadian rhythm (p < 0.05, group cosinor analysis) was observed for serum theophylline concentrations and for the urinary excretion rates of theophylline and 3-methylxanthine. The phase relationship of the observed circadian rhythms in urinary pH to circadian changes in serum theophylline concentrations were supportive of a circadian rhythm in renal clearance of theophylline. Computer simulations indicated that circadian changes in serum theophylline concentration and urinary excretion of theophylline and its metabolites could be accounted for by a circadian rhythm in theophylline renal clearance and metabolism to 3-methylxanthine. A circadian rhythm in theophylline volume of distribution could not be totally dismissed as potentially having some effect on disposition. The timing of food intake is hypothesized to play a role in synchronizing the observed rhythm in serum theophylline concentrations.

Effects of enoxacin on renal and metabolic clearance of theophylline in rats

The effects of enoxacin and its metabolite 4-oxoenoxacin on the disposition of theophylline were investigated in rats. Systemic clearance of theophylline was significantly decreased by approximately 40, 46, and 50% after oral coadministration of 25, 100, and 200 mg of enoxacin per kg, respectively. No significant changes in the volume of distribution of theophylline were observed. 4-Oxoenoxacin had no direct effect on theophylline disposition. Significant changes in urinary excretion of theophylline and its metabolites were observed. (i) Urinary excretion of unchanged theophylline was significantly increased in proportion to increases in enoxacin dosage. (ii) Decreases in renal clearance of theophylline and metabolic clearance of 1-methyluric acid and 1,3-dimethyluric acid were observed. (iii) The percent decreases in the metabolic clearance of 1-methyluric acid were dependent on enoxacin dosage. It is likely that enoxacin inhibits the elimination process, which depends on cytochrome P-450-mediated isozymes for N demethylation and oxidation, and that the capacity of the inhibitory effect of enoxacin is greater in the N-demethylation pathway than it is in oxidation.

Renal clearance of theophylline and its major metabolites: age and urine flow dependency in paediatric patients.

The renal clearance of theophylline (TH) and its metabolites 1,3-dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX), and 1-methyluric acid (1-MU) has been studied in 10 children aged 8 months to 14 years. Individual renal clearances were calculated from serum levels and amounts excreted in urine after i.v. administration of the parent drug. The clearance of 1,3-DMU was found to depend both upon urine flow rate and age, which are interrelated. An effect of urinary pH was expected, but was not studied. Consistent age-dependent changes in the relative quantities of metabolites excreted were not observed.

The influence of ofloxacin and enoxacin on the metabolic pathways of theophylline in healthy volunteers. A pilot study.

The pharmacokinetic parameters of theophylline and its major metabolites were measured in two healthy volunteers, after the administration of theophylline alone and during co-medication with ofloxacin, 200 mg twice daily, or enoxacin, 200 mg twice daily. During enoxacin co-medication, elimination half-lives of theophylline increased from 8.7 h to 17.4 h and from 6.1 to 12.3 h, respectively. As the renal clearance of theophylline did not change, the decreased elimination of theophylline during enoxacin co-medication must result from a reduced metabolic clearance. Enoxacin co-medication caused a clearly decreased formation of the metabolites 1-methyluric acid and 3-methylxanthine, formed by N-demethylation, whereas the C-8 oxidation of theophylline was less influenced compared to the blank. Enoxacin's interference with the theophylline disposition is predominantly based on the inhibition of the microsomal N-demethylation. Ofloxacin co-medication did not induce a change in the plasma parameters or renal excretion of theophylline and its metabolites.

Effects of dietary protein on theophylline pharmacokinetics and caffeine and aminopyrine breath tests.

The effects of low- and high-protein diets on theophylline kinetics and the time course of changes in 13C-labeled caffeine and aminopyrine CO2 breath tests were examined in six young men. With a low-protein diet, mean theophylline clearance fell 21% (P less than 0.04) and the t1/2 rose from 8.0 to 10.6 hours (P less than 0.02). With a high-protein diet, mean theophylline clearance rose 26% (P less than 0.004) and the t1/2 shortened to 7.4 hours (P less than 0.03). Theophylline volume of distribution and protein binding did not change. Renal clearance of theophylline was lowered during the low-protein diet. Theophylline clearance correlated with caffeine breath test values during the low- (r = 0.73) and high- (r = 0.70) protein diets. Theophylline clearance correlated less well with the aminopyrine breath test values during the low- (r = 0.47) and high- (r = 0.55) protein diets. Thus dietary protein significantly influenced theophylline clearance, but the caffeine and aminopyrine breath tests showed a differential response to this important environmental factor.

Urine flow-dependence of theophylline renal clearance in man.

Theophylline renal clearance is highly dependent on urine flow rate and is neither concentration nor dose related. To examine the flow dependency, theophylline was administered in single doses (4.3 mg/kg to 8.6 mg/kg) to 14 volunteers. Seven of these volunteers participated in studies in which theophylline and metabolite concentrations were held constant at six different levels. Due to the diuretic effect of theophylline, its renal clearance contributed up to 70% of the time-averaged total clearance, dose/total area, in the first hour after a single dose. The contribution then dropped to 5% of the time-averaged total clearance when the normal urine flow rate was restored. As a consequence of extensive tubular reabsorption, the urine/plasma concentration ratio of theophylline varied with urine flow rate and approached the value of the unbound fraction in plasma. On assumption that the reabsorption is passive, a mathematical model was used to explain the urine flow dependence of reabsorption and, therefore, the renal clearance of theophylline.

Theophylline Pharmacokinetics-Reply

In Reply .—The slower, initial first-order elimination half-life values are similar in the patient of Kadlec et al 1 and in our much younger patients and seem to indicate saturation of the predominant metabolic pathway. We attributed the slow first-order elimination of methylation, whereas Kadlec et al suggested that first-order renal clearance was apparent. This may not be so, however, since their patient was anuric for ten hours, and there is significant positive correlation between the renal clearance of theophylline and urine flow rate. 2 Kadlec et al suggest that no caffeine was found in their patient because of her age. However, Hartemann et al 3 have found caffeine in the serum of an 18-month-old infant who ingested 204 mg/kg theophylline, achieving a peak serum concentration of 86 μg/mL. We have shown in our laboratory 4 that during analysis of caffeine by high-performance liquid chromatography, excessive heating of samples during

Renal Clearance of Theophylline in Man

The renal clearance of theophylline was determined in 12 experiments with six healthy human adult volunteers and was found to decrease from 8.50+/-2.20 to 276.+/-1.13 ml/min/m2 during 8 hours after oral administration of a single dose of theophylline, 200 mg/m2. There was a strong and highly statistically significant positive correlation between the renal clearance of theophylline and the urine flow rate for each subject, but there was no consistent correlation between renal clearance and plasma concentrations of theophylline.