Chronopharmacokinetics of theophylline after sustained release and intravenous administration to adults

Abstract

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 different p greater than 0.05). The maximum plasma concentrations were almost identical after administration in the morning and in the evening (12.6 +/- 3.3 mg X l-1 and 13.1 +/- 1.4 mg X l-1 respectively). There was also no significant difference (p greater than 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: c1 12 accounted for 6.0 +/- 2.0 mg X l-1 after intake at 10 a.m. and for 7.9 +/- 2.1 mg X l-1 after ingestion at 10 p.m. (p less than 0.01). A similar observation was done after intravenous administration of the drug: c12 was 6.6 +/- 1.6 mg X l-1 after starting the infusion in the morning and 8.0 +/- 1.8 mg X l-1 after infusing the drug in the evening (p less than 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 X l-1 (which coincides approximately with the therapeutic range of the drug).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of dosing time on the pharmacokinetics and pharmacodynamics of a ‘once‐a‐day’ sustained release theophylline preparation.

“…Several investigators have studied the circadian variation in pharmacokinetics of theophylline administered in different dosage forms (Lemmer, 1984). In healthy volunteers Jonkman et al (1984) observed an increased half-life of theophylline during the night after intravenous administration. Similarly St.…”

“…Drug concentrations were measured by high pressure liquid chromatography (h.p.l.c.) (Jonkman et al, 1984) to check that steady-state had been established by day 5.…”

Chronopharmacokinetics of theophylline in the cat

“…Still other publications have reported temporal variation in theophylline elimination as well (Giacona et al, 1983;Straughn, 1984). Jonkman (1984) reported temporal rhythms in both theophylline absorption and elimination. However, the changes in elimination (following intravenous and oral theophylline administration) were only apparent at theophylline concentrations above 5 pg/rnl.…”

Acute and chronic pharmacokinetics of asymmetrical doses of slow release choline theophyllinate in asthma.

“…Several studies have previously shown that with a conventional twicedaily equal dose regime of a slow release theophylline preparation, the concentrations of theophylline in the morning are consistently higher than those in the evening and at night. This observation may be explained either by an alteration in nocturnal elimination of theophylline (Jonkman et al, 1984) or by delayed nocturnal absorption of the drug (Kyle et al, 1980;Decourt et al, 1982;Nakano et al, 1982). In the present study the time between dosing and peak plasma concentrations after regular treatment with this slow-release preparation was three times as long after the evening than after the morning dose, a difference which was not apparent during the first day of the study ( Figure 2a).…”

“…A slow-release preparation of this drug is now available in the form of Sabidal SR270 which contains 424 mg choline theophyllinate (equivalent to 270 mg anhydrous theophylline) in a non-toxic, plastic membrane containing microholes to allow slow diffusion of the active drug into the gastrointestinal tract along a concentration gradient (Dahlqvist & Billing, 1983;Jonkman et al, 1984;Berg et al, 1985). The present study investigates the day and night pharmacokinetics of choline theophyllinate with asymmetrical doses of 424 mg in the morning and 848 mg at night in a group of patients with severe chronic reversible airflow obstruction.…”