Theophylline kinetics and metabolism following single intravenous infusion of theophylline dose (6mg/kg) were examined in 8 young non-smoking adults.- Study design stressed stringent control of several external factors known to influence theophylline. metabolism. The concentrations of theophylline were analyzed over a 24-hr period´ in plasma. Theophylline and its major metabolites weremeasured over a 96-h period in urine after the given dose. A 2-compartment model was required to describe the theophylline plasma concentration time course in all 8 subjects.
The results are as follows.
1. Theophylline is quickly transferred from plasma to tissue with high rates of intercompartmental clearance (mean S.D; 1.04--+ 0.53 L/min). Steady-state volume of distribution of theophylline `showed little intersubject variability with average of 0.42 0.02 L/kg,.
2. The elimination half´-life of theophylline varied greatly among subjects and ranged from 4.56 to 11.11 hours, Similarly, the non-renal clearance also showed wide intersubject variation (coef fient of variation; 3.517o).
3. The unbound fraction of theophylline was 62.6 4.117o at the plasma concentration around 10 mg/ml.
4. About 82% of theophylline administered was recovered until 96-hr after dose as unchanged form or major metabolites. A 17.55% of theophylline was excreted in urine as unchanged form. Molar . fraction of theophylline metabolites 1.3-dimethyl uric acid, 3-methylxanthine and 1-methyl uric acid excreted in urine were 35.147o, 11.62% and 17.6417o, respectively.
From the above results, It is suggested that great variation of theophylline elimination half-life seems to be mainly due to wide intersubject variation of non-renal clearance of theophylline. Importance of including an assessment of plasma protein binding in studies of theophylline disposition would-be emphasized, because theophylline metabolism showed a restrictive pattern. Incomplete recovery of theophylline from the administered dose imply the possbility of exsistence of additional minor pathways in theophylline disposition, which could not be identified in the study.
|