Pharmacokinetics of theophylline: a dose‐range study.

Abstract

1 Pharmacokinetics of theophylline were investigated in a group of healthy adult volunteers (non smokers and on xanthine-free diet) following single oral administration of 125, 250, 375 and 500 mg doses as tablets (Theodel(®). 2 Absorption of theophylline was rapid and followed first-order kinetics. Plasma curves were fitted according to a one compartment open model.3 There was a linear relationship (P < 0M.0)) between plasma Cmax or AUC, values and the administered dose. The analysis of variance showed that the pharmacokinetic parameters of theophylline (t,, abs, tmai, t. 3,, CL, CLR, Vd and F) were not modified at any dose.4 Absorption of the drug was complete since the recovery in urine of theophylline (13.7 to 16.8% of the dose) and its major metabolites, 1,3-dimethyluric acid (35 to 42%), 1-methyluric acid (21.3 to 26.7%) and 3-methylxanthine (11.5 to 13.7%), accounted for the administered dose. Some impairment of demethylation to 3-methylxanthine was observed in two subjects, however the percentage of theophylline and its major metabolites excreted in urine was constant for all the four doses. 5 On the basis of these results, after single oral administration, elimination of theophylline followed first-order kinetics in the range of doses investigated (1.62 to 10.42 mg/kg).

Preparation of Extended-Release Theophylline for Gastric Tube Administration Significantly Impairs Gradual Resorption

“…The occurrence of the side effects in our study corresponds with the findings in a study evaluating dosage forms of theophylline with immediate release, where side effects occurred at doses >300 mg [6]. In the case of intact dosage forms, no side effects were noticed during the whole study.…”

“…Tmax of both crushed drugs is approximately 1 hour, which is comparable with immediate release theophylline T max of 0.5-3 h [6]. The modified release properties of both theophylline dosage forms were lost by crushing; therefore, the mechanism of formulation of modified-release drugs has likely no influence on the preservation of extended-release properties.…”

Polymorphism of theophylline metabolism in man.

“…In addition to providing blood, three subjects collected saliva samples, which were stimulated by chewing parafilm, at 4,8,12,16,20,24,28,32, and 36 h after drug administration. These three subjects did not take theophylline again.…”

“…At 0800, after an 8-h fast, all subjects received an oral dose (5 mg/kg) of theophylline (Elixicon, by Berlex Laboratories). Saliva samples, stimulated by chewing parafilm, were collected at 2, 4, 6, 10, 16,20,24, and 28 h after theophylline.…”

“…A 10-,d aliquot of internal standard, 2 ml of acetonitrile, and 0.5 ml of saliva which had been centrifuged for 20 min at 2,000 g were vortexed 15 s and centrifuged for 15 Pharmacokinetic analysis. Theophylline, when administered at a sub-therapeutic dose (5 mg/kg), and its three main metabolites, conform to an open one-compartment model with parallel, simultaneously occurring, first-order reactions in which excretion is faster than metabolite formation (23)(24)(25)(26)(27). Kinetic data on theophylline elimination were analyzed by two different methods, the Rate method and the SigmaMinus method described in detail elsewhere (16,26,27).…”