Chronopharmacokinetics of theophylline after sustained release and intravenous administration to adults

Summary

The influence of time of drug administration on pharmacokinetics of theophylline was studied both after ingestion of a sustained-release tablet, containing choline theophyllinate (Zy 15061-S. R.; Teovent^®; Sabidal^®; ZYMA S.A.) and after intravenous infusion of aminophylline to eight healthy volunteers. Both drugs were administered in the morning (10 a.m.) and on a separate occasion in the evening (10 p.m.) after a 12 h period of fasting.

After oral administration of a dose of 540 mg theophylline, the drug was steadily absorbed, both during day-time and during night-time. In some subjects absorption was slower in the evening. Maximum theophylline plasma concentrations were reached after 3.3±0.4 h (mean±SD) and 3.9±1.4 h respectively (not significantly differentp>0.05).

The maximum plasma concentrations were almost identical after administration in the morning and in the evening (12.6±3.3 mg·l⁻¹ and 13.1±1.4 mg·l⁻¹ respectively).

There was also no significant difference (p>0.05) between the areas under the plasma concentration-time curves after oral and intravenous administration, both at day-time and at night-time. This finding indicates complete bioavailability of the sustained release tablets on both occasions.

After administration of the tablets in the morning the plasma concentration 12 h post dosing was significantly lower than after administration in the evening: c ¹₁₂ accounted for 6.0±2.0 mg·l⁻¹ after intake at 10 a.m. and for 7.9±2.1 mg·l⁻¹ after ingestion at 10 p.m. (p<0.01).

A similar observation was done after intravenous administration of the drug: c₁₂ was 6.6±1.6 mg·l⁻¹ after starting the infusion in the morning and 8.0±1.8 mg·l⁻¹ after infusing the drug in the evening (p<0.01). This phenomenon could be explained by the finding of a significantly prolonged half-life of theophylline during night-time, provided that the plasma concentrations were in the range of 5 to 15 mg·l⁻¹ (which coincides approximately with the therapeutic range of the drug). For day-time elimination the half-life of theophylline was found to be 6.2±0.9 h and for night-time elimination 8.0±2.0 h (p<0.01), which means an increase of 29.6±20.9% during the night. The prolonged half-life of theophylline at night-time might be of therapeutic benefit in preventing bronchus obstruction in the morning.