EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS 2001, Vol. 26, No. 1{2, pp.77-83 Dose Dependent Pharmacokinetics of Theophylline: Michaelis-Menten Parameters for Its Major Metabolic Pathways SIMIN DADASHZADEH and HOSNIEH TAJERZADEN Biopharmacy Division, Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences Biopharmacy Division, Faculty of Pharmacy, Tehran Universityh of Medical Sciences, Tehran-IRAN Received for publication: December 22, 1999 Keywords: Theophylline; pharmacokinetics; dose dependent elimination; metabolites. SUMMARY Dose Dependency for pharmacokinetics of theophylline and the formation of its major metabolites, 3-methylxanthine (3-MX); 1- methyluric acid (1-MU); 1,3-dimethyluric acid (DMU), were examined by administering three single oral doses (250, 375,500 mg) of theophylline to six healthy adult volunteers. The serum and urine concentrations of theophylline and the metabolites in serum and urine were determined by high-performance liquid chromatography. Total clearance of theophylline decreased and its halfllifeincreased over the range of doses administered (p<O.OI). There was a significant dose related decrease in the fractional recovery of 3-MX and I-MU (p<O.OOI) and a dose related increase in fractional excretion of DMU and unchanged theophylline (p<O.OI and p<O.OOl respectively). No significant dose related changes were observed in the renal clearance of 3-MX, I-MU and DMU, indicating linear urinary excretion kinetics of the metabolites. Theophylline metabolic clearance to 3-MX as well as to 1-MU decreased with increasing dose but clearance to DMU remained unnaffected by the size of dose. The individual Michaelis- Menten parameters and Vmaxwere estimated for six subjects receiving three different single doses. The K m values for theophylline metabolism to 3-MX, 1-MU and DMU were 2.4±O.6,5.1±1.8± and 112.3±36.8mg/L respectively and the Vmaxvalues were 305±O.7, 705±2.6 and 112.3±36.8 mg/hrrespectively. The K m values for the N-demethylation pathways (3MX and I-MU) were lower corresponding to therapeutic serum concentrations of drug. These results suggest that the elimination kinetics of theophylline is nonlinear in the human in the therapeutic range of serum concenntrations and can be explained by saturable formation kinetics of 3-MX and 1-MU. In contrast to previous studies we didn't find obvious indication for nonlinear formation of DMU at therapeutic concentration range. INTRODUCTION Theophylline is a widely prescribed bronchodilator with a narrow therapeutic range. In human about 10% of the drug is eliminated via renal excretion, whilst the remainder is Please sendreprintrequests to: Simin Dabashzadeh. Biopharmacy Division, Facultyof Pharmacy, Shaheed Beheshi Universityh F. Medical Sciences at NoIOS, Shams Alley,Vali-AsrAve, P.O.Box 14155-6153 Tehran, Iran extensively metabolized to 3-methylxanthine (3-MX), 1- methylluric acid (1-MU) and 1,3-dimethyluric acid (0MU) (1-3). These metaboliets arise from the S-oxidation (DMU), l-demethylation (3-MX) and consecutive 3-demethyllation and oxidation (I-MU) oftheophylline (4). In addition 7- N-methylation of theophyllin giving rise to caffeine, occurs in neonates (5,6). Although dosage adjustments for theophylline therapy have. been based on a linear pharmacokinetic model, but some investigators have suggested that the elimination