Effects of allopurinol on theophylline metabolism and clearance

1 Theophylline kinetics following a single oral dose were characterized and compared in non‐institutionalized ambulatory elderly and young gender‐matched control subjects. Study design stressed stringent, yet realistic, control of several external factors known to influence theophylline metabolism. 2 Plasma levels of total drug were significantly higher in the elderly only at early sampling times (0.5 and 1 h) and at 36 h, while unbound theophylline levels were significantly higher (P less than 0.05) at all sampling times resulting in a 45% greater AUC for unbound drug. 3 While no significant differences in volume of distribution (Vd) or overall plasma clearance were observed when calculations were based on total plasma theophylline, a 37% reduction in Vd (P less than 0.005) and a 30% reduction in overall plasma clearance (P less than 0.02) in the elderly became apparent when plasma protein binding was taken into account. 4 When urinary excretion patterns were compared, the elderly were found to have excreted a significantly higher fraction of the recovered dose as 1‐methyluric acid (P less than 0.01) and a lower fraction as unchanged theophylline (P less than 0.02). A 47% reduction in the renal clearance of unbound theophylline (P less than 0.005) was also observed in the elderly. 5 Results were consistent with less viable metabolism and renal excretion pathways for theophylline elimination in the elderly and serve to reemphasize the importance of including an assessment of plasma protein binding in studies of drug disposition in the elderly.

Section: Discussionmentioning

confidence: 97%

Theophylline pharmacokinetics in advanced age.

Antal¹,

Kramer²,

Mercik³

et al. 1981

“…Theophylline (1,3-dimethylxanthine) is extens- & Miech, 1976;Grygiel et al, 1979;Jonkman et ively metabolised by hepatic cytochrome P-450 al., 1981;Tang-Liu et al, 1982;Birkett et al, dependent enzymes. Only about 10% of a theo-1985). phylline dose is excreted unchanged in urine.…”

Section: Introductionmentioning

confidence: 99%

Effects of alpha‐interferon on theophylline pharmacokinetics and metabolism.

Jonkman¹,

Nicholson²,

Farrow³

et al. 1989

1 The influence of a-interferon (Roferon-A®) on the pharmacokinetics and metabolism of theophylline was studied in healthy adults. Roferon-A was administered as an intramuscular injection (3 x 106 iu) once-a-day over 3 days. One week prior to and immediately after this course a single 20 min aminophylline infusion (4 mg kg-') was given.2 Blood samples for theophylline analysis were taken over 48 h. Urine was collected up to 72 h and assayed for theophylline and its major metabolites 3-methylxanthine, 1,3-dimethyluric acid and 1-methyluric acid. 3 Pharmacokinetic parameters for theophylline in plasma were calculated. From urinary excretion data the overall metabolic clearance of theophylline and clearances for formation of the metabolites were calculated. 4 After interferon administration, there was a significant increase of approximately 15% in the mean values of the terminal elimination half-life, area under the curve and mean residence time of theophylline in association with a similar decrease in plasma clearance (P < 0.05). Formation clearances of the metabolites tended to be smaller after treatment, but only the change in the overall clearance of theophylline was significantly different (P < 0.05). There was no systematic shift in the metabolic pattern of theophylline.5 Additional investigations of the influence of the duration of CL-interferon treatment are necessary before definite conclusions can be drawn about the mechanism and the clinical relevance of the described interaction.

“…It must be given by the intravenous route as it is poorly absorbed orally, and its approval for human use requires extensive documentation for each batch. To overcome these problems, the present study investigated the use of 1MX derived as an intermediary metabolite of theophylline (Birkett et al, 1983;Grygiel et al, 1979) to assess the degree of xanthine oxidase inhibition during allopurinol therapy. Our previous study (Day et al, 1988a) showed that the relationship between plasma oxipurinol concentration and 1MU/1MX ratio was the same at steady state and during oxipurinol washout.…”

Section: Introductionmentioning

confidence: 99%

1‐Methylxanthine derived from theophylline as an in vivo biochemical probe of allopurinol effect.

Birkett

Miners

Day

1991

The urinary 1-methyluric acid (1MU) to 1-methylxanthine (1MX) ratio has been assessed as a biochemical index of oxipurinol effect in vivo in man. Dosing with theophylline was used to produce 1MX as an intermediate metabolite in six healthy volunteers. A sigmoid Emax model was fitted to the data and gave a mean plasma oxipurinol IC50 of 3.0 ± 1.1 mg '-1, a mean exponent n of 3.4 ± 2.1 and a mean IC90 of 8.5 ± 5.9 mg 1-1. There was marked interindividual variability in the steepness of the plasma oxipurinol concentration response relationship, and in the plasma oxipurinol IC90 values. The study has confirmed the feasibility of using single doses of allopurinol to construct individual plasma oxipurinol concentration-response curves.