Temporal variation in the disposition of theophylline and its metabolites

Abstract

The temporal aspects of theophylline disposition are of interest, as there are predictable time-dependent fluctuations in the pulmonary function of patients with asthma and theophylline serum concentrations may vary throughout a 24-hour period. We studied the extent to which there are significant temporal changes in theophylline kinetics and the relative contribution of distribution, metabolism, and excretion to this phenomenon. Eight healthy men received an intravenous dose (6 mg/kg) of theophylline at 8 AM and 8 PM at 1-week intervals. Serum and urine were analyzed for theophylline and its three major metabolites by HPLC. Distribution volumes and total body and nonrenal clearances showed no differences between morning and evening dosing. The elimination rate was 12% greater after morning dosing. Renal clearance was 24% greater after morning dosing and was accompanied by an increased excretion fraction of unchanged theophylline. Based on total urinary metabolite excretion and the metabolite serum AUCs, there was no evidence of time-dependent variation in theophylline biotransformation. Although theophylline renal clearance is greater after morning dosing, it is only a small fraction of the overall drug elimination and does not change the total body clearance after morning or evening dosing.

Bayesian derived predictions for twice daily theophylline under outpatient conditions and an assessment of optimal sampling times.

“…There was no significant difference in the area under the curve between day and night time administration suggesting that bioavailability and clearance were unchanged, a finding previously reported (Birkett etal., 1983;Taylor et al, 1983;Taylor et al, 1984;Isles et al, 1984;Watanabe et al, 1984), but in contrast to a decrease in theophylline elimination at night found by others (Jonkman, 1983;St Pierre et al, 1985). In accordance with a recently published study (Chrystyn et al, 1988a) it was found that the technique of Bayesian analysis using slow release theophylline 400 mg tablets is accurate for twice daily dosing, and for use in the outpatient clinic over a period of 3 months.…”

A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

“…Reported f e ranges 13-18% (n = 22) in nonpregnant, nonsmoking healthy volunteers (Tang-Liu et al, 1982;St-Pierre et al, 1985) and 16.0% 6 3.3% (n = 5) in postpartum women (Frederiksen et al, 1986) following i.v. dosing.…”

“…Jornil et al (2010) showed that, in addition to CYPs 2D6, 3A and 1A2 are involved in the metabolism of PAR. The authors then used prior in vitro and in vivo information on the metabolism of PAR to predict the exposure in EM and PM individuals receiving single and multiple dosing regimens using (Hendeles et al, 1985;St-Pierre et al, 1985), and the mean value was used.…”

Pharmacokinetics of temafloxacin in humans after multiple oral doses

“…There is substantial evidence that the rate of absorption of drugs and nutrients is generally lower in the evening (10,17,24). For the present study with temafloxacin, absorption was delayed after the evening dose, and part of the circadian effect with Cmin was partially attributable to this effect.…”

“…Urine was collected before dosing and 0 to 6, 6 to 12, and 12 to 24 h after the morning dose of study days 1, 4, and 7. In addition, on days 7 to 9, urine was collected 24 10 ,ug/ml, with regression correlation coefficients averaging over 0.998.…”