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)

1 The pharmacokinetic interaction of terbutaline and theophylline and chronopharmacokinetics of both drugs were studied in a three-way crossover study with repeated administration of terbutaline (Bricanyl Depot®) 7.5 mg twice daily, theophylline (TheoDurg) 300 mg twice daily alone or the combination of both for 7 days to 12 healthy volunteers (six male and six female). 2 After the morning dose on day 7, blood and urine were sampled for 12 h, and after the evening dose on day 7, blood and urine were sampled for 48 h. Theophylline concentrations in plasma and concentrations of unchanged drug and metabolites in urine were determined by two selective high performance liquid chromatography methods. Terbutaline concentrations in plasma and urine were measured with a gas chromatography-mass spectrometry method. Area under the plasma concentration-time curve, fluctuations in plasma concentration, mean residence time, elimination half-life, renal clearance as well as maximal, minimal and average plasma concentration at steady state were evaluated. 3 The addition of terbutaline to the repeated administration of theophylline lowered the relative bioavailability of theophylline by approximately 11% during the night interval, The rate of elimination of theophylline and mean residence time were influenced accordingly. No significant changes in excretion of the theophylline metabolites were observed, but the excretion of 3-methylxanthine was slightly reduced by the concomitant terbutaline administration. None of the observed changes should be of any clinical importance.4 The addition of theophylline did not influence any of the calculated pharmacokinetic parameters of terbutaline. 5 It can be concluded that no dosage adjustment is necessary when terbutaline and theophylline are given together. 6 Significant differences between the rates of absorption at day-time and at night-time were observed, both for theophylline and for terbutaline. The extent of absorption, however, was not different.

The effect of food on the rate and extent of absorption of theophylline was studied in healthy adults given a single dose of theophylline (aqueous solution of choline theophyllinate containing 270 mg of theophylline) in the evening either on an empty stomach or together with supper. Food appeared to decrease the absorption rate of theophylline significantly, tmax being prolonged from 1.34 h (mean) to 4.40 h and cmax decreased from 7.82 mg . l-1 to 5.47 mg . l-1. The area under the plasma concentration-time curve (AUC) after drug intake with supper was slightly but not significantly smaller, indicating that theophylline (as a solution of choline theophyllinate) can be taken together with food without substantial loss of the quantity of drug absorbed. The elimination rate was not influenced by concomitant intake of supper.

The influence of amoxycillin and theophylline on their mutual steady-state pharmacokinetics was studied in healthy adults by comparing the pharmacokinetic parameters as obtained during a 10-day course of each drug alone and after giving the drugs in combination. Amoxycillin and theophylline plasma concentrations were measured by means of HPLC methods. On the 9th day of each of the two periods of drug administration, a concentration-time curve was evaluated. These showed no influence of theophylline on absorption, elimination or volume of distribution of amoxycillin, demonstrating that the mean steady-state plasma concentrations were not significantly different during the two treatments. Amoxycillin also has no significant effect on theophylline steady-state pharmacokinetics. It is concluded that both drugs can be given concomitantly without any dosage adjustment.

A new rapid, selective and sensitive high pressure liquid chromatographic (HPLC) assay for indomethacin in plasma is described. The method involves precipitation of proteins with perchloric acid, followed by dichloromethane extraction using flurbiprofen as an internal standard. The organic solvent was evaporated and the residue dissolved in a water-methanol (2 + 3) phosphate buffer mixture with an apparent pH of 6.8. Aliquots of 100 microliters were injected automatically into the chromatograph. The separation of indomethacin was achieved on a reversed phase (C18, 10 micron) column with a mobile phase consisting of 65% (vol/vol) methanol in water solution of apparent pH 6.8 containing tetrabutylammonium hydrogensulfate as an ion pairing agent. Quantitation of indomethacin was performed by UV detection at 235 nm. At a 2.0 mg X l-1 concentration of indomethacin in plasma the analytical recovery was 82.9 +/- 3.4% (n = 7), the intra-day variability (CV) was 3.6% (n = 7) and the inter-day variability (CV) was 11.0% (n = 7). The calibration curve was linear (typical r-values greater than 0.990) in the range of plasma concentrations as usually found during indomethacin therapy (up to 6 mg X l-1). The limit of sensitivity is 0.025 mg X l-1. The metabolites O-desmethylindomethacin and O-desmethyldeschlorobenzoylindomethacin did not interfere with the method. The capacity of an analyst using this method with automated injection and peak integration is about forty samples in duplicate per day. The applicability of the method for pharmacokinetic studies is demonstrated.