Pharmacokinetic studies of ciprofloxacin and theophylline and of the interaction between these two drugs in healthy Malaysian volunteers
Loading...
Date
2007
Authors
Saeed Obeid, Abdulla Alfadly
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Theophylline is a bronchodilator frequently used in the treatment of asthma and chronic obstructive pulmonary disease. In human adults, approximately 90% of theophylline is metabolised in the liver by the cytochrome P450 (CYP) enzymes, and only 10% is excreted via the kidneys in unchanged form. The aims of this work were to investigate the pharmacokinetic interaction between a multiple-dose regimen of oral ciprofloxacin and single dose of theophylline and to elucidate the mechanism of such interaction in healthy male volunteers. To achieve these aims, sensitive and selective HPLC methods with ultraviolet detection have been developed and validated for the determination of ciprofloxacin in plasma and theophylline in plasma and urine. The coefficient of variation for ciprofloxacin precision and accuracy was less than 7.8% over the concentration range of 50 to 5500 ng/mL and with limit of detection of 25 ng/mL. The calibration curve for theophylline in plasma was linear (R² = 0.9999) in the concentration range of 62.5 to 20000 ng/mL with a detection limit of 31.2 ng/mL. The coefficient of variation for intra-day and inter-day precision and accuracy was found to be less 7.1%. The overall mean recoveries for theophylline and its three metabolites in urine ranged from 85 to 102%. The detection limit was 0.625 μg/mL for I-MU (1-methyluric acid), 3-MX (3-methylxanthine) and theophylline and 1.25 μg/mL for 1,3-DMU (1,3-dimethyluric acid). The intra-day and inter-day coefficient of variation was less than 8.70%. A total of nine healthy male volunteers participated in the pharmacokinetic interaction study. This study was a randomised, open label, single-dose, fasting and three way crossover design. The volunteers were randomly divided into three groups and received ciprofloxacin alone, theophylline alone and combination of ciprofloxacin and theophylline tablets in the first period of the study. After a one-week washout period the volunteers received the other crossover treatments during the second and third period which were separated also by a one-week washout period. In the combination study, pretreatment with ciprofloxacin 500 mg every 12 hr for six doses was followed by a single dose of 250 mg theophylline. Mean pharmacokinetic parameters were compared by the use of a student paired t-test. The results of the study indicated that pretreatment with ciprofloxacin significantly increased the average AUC0-∞, the peak plasma concentration (Cmax) and the t 1/2 of theophylline by 33.64% (P < 0.001), 15.23% (P < 0.004) and 16.25% (P < 0.034), respectively compared to the treatment by theophylline alone. Ciprofloxacin also markedly reduced the total clearance of theophylline by 27% (P < 0.001). Furthermore, our results showed that the renal clearances of theophylline metabolites formed; 1-MU, 3-MX and 1,3-DMU were significantly decreased (54.13%, 53.18% and 34.98%, respectively). This study revealed that ciprofloxacin significantly raised the AUC0-∞ and the plasma concentration of theophylline by inhibiting its CYP1A2 mediated oxidative metabolism in vivo. Based on the findings of this study, it is strongly recommended that the serum level of theophylline should be closely monitored whenever this drug is used concomitantly with ciprofloxacin in clinical practice. In addition to the interaction study another in-vivo study was performed to evaluate the comparative bioavailability between Enoxin® and Ciprobay® in 24 healthy male volunteers. No significant difference was found based on analysis of variance (ANOVA); the 90% confidence intervals of the mean values for the test/reference ratios were 0.96 to 1.11 for AUC0-t and 0.97 to 1.10 for AUC0-∞ respectively, while that of Cmax was 0.93 to 1.07. It was concluded that both formulations are bioequivalent and thus interchangeable.
Description
Ph.D
Keywords
Pharmaceutical science , Ciprofloxacin , Theophylline