Elevation of serum theophylline levels by ipriflavone in a patient with chronic obstructive pulmonary disease

Takahashi, Jun; Kawakatsu, Kazuo; Wakayama, Teruhiko; Sawaoka, Hitoshi

doi:10.1007/bf01740674

Cited by 8 publications

(7 citation statements)

References 8 publications

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“…In accordance with the in vivo observation of Takahashi et al (2), N-demethylation of theophylline that results in the formation of 3-methylxanthine and 1-methylxanthine (or further I-methyluric acid) is inhibited by ipriflavone and its main metabolites. Thus, these compounds are responsible for reduction of theophylline metabolism and decrease the elimination of theophylline.…”

supporting

confidence: 56%

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The effect of ipriflavone and its main metabolites on theophylline biotransformation

Monostory

Vereczkey

1996

European Journal of Drug Metabolism and Pharmacokinetics

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The effect of ipriflavone and its major metabolites, 7-hydroxy-isoflavone and 7-(1-carboxy-ethoxy)-isoflavone on theophylline metabolism was examined in vitro in human liver microsomes. The compounds inhibited the N-demethylation to 1- or 3-methylxanthine, the major pathway of theophylline metabolism. The effect showed concentration dependence. The oxidation of theophylline to 1,3-dimethyluric acid was slightly affected by ipriflavone and its metabolites and the effect was non-specific. Results indicate that the reduction of theophylline clearance by concomitant ipriflavone administration observed by Takahashi et al. [Takahashi J., Kawakatsu K., Wakayama T., Sawaoka H. (1992): Elevation of serum theophylline levels by ipriflavone in a patient with chronic obstructive pulmonary disease. Eur. J. Clin. Pharmacol., 43, 207-208] is primarily due to an interaction of the inhibitory ipriflavone and/or its metabolites with cytochrome P450 enzyme(s) that mediate N-demethylation of theophylline.

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confidence: 56%

“…A 65-year-old patient with chronic obstructive pulmonary disease who showed an increase in the serum theophylline level following the initiation of ipriflavone treatment has been reported (2). After withdrawing ipriflavone, the serum theophylline level decreased to an extent similar to that found before administration of ipriflavone.…”

Section: Introductionmentioning

confidence: 82%

The effect of ipriflavone and its main metabolites on theophylline biotransformation

Monostory

Vereczkey

1996

European Journal of Drug Metabolism and Pharmacokinetics

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“…Furthermore, case studies indicated that minocycline, [249.250] ipriflavone [251] and pyrantel [252] have an inhibitory effect on the metabolism of theophy lline.…”

Section: Enzyme Inhibitionmentioning

confidence: 99%

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

Tröger

Meyer

1995

Clinical Pharmacokinetics

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Theophylline has been widely used as a bronchodilatory drug for the treatment of neonatal apnoea in premature newborns and patients with obstructive airways disease. The development of analytical equipment and procedures to determine the systemic concentration of theophylline renders it possible to improve the effectiveness of theophylline therapy and reduce the incidence of toxic and adverse effects. Since the beginning of the 1970s, endogenous and exogenous factors (e.g. age, blood pH, concomitant diseases and drug therapy, meal preparation procedure, nutritional habits, pregnancy, gender, smoking and, to a lesser extent, biorhythms), influencing nearly all parameters of theophylline pharmacokinetics have been described. Drug absorption depends on galenic formulation, drug delivery, nutritional habits and the chemical derivatives used. The mean plasma protein binding rates depend on the method of plasma protein determination: acidic blood pH values and advanced age may result in reduced plasma proteins. The volume of distribution depends primarily on age; it is 2-fold greater in newborns than in adults. Furthermore, changes in blood pH values, the plasma protein content and the administration of concomitant drugs may vary this parameter. Biotransformation is the most clinically important pharmacokinetic parameter. Hepatic metabolism accounts for 90% of the metabolism of theophylline. Essentially, 2 microsomal isoenzymes of the cytochrome P450 system appear to be responsible for the N-methylation and 8-hydroxylation of the drug. Age and concomitant disease are the major endogenous effectors influencing biotransformation of theophylline, whereas biorhythms, gender and pregnancy are of lesser importance. Exogenous factors, such as concomitantly administered drugs, smoking and nutritional factors, affect biotransformation by inducing or inhibiting the metabolising enzymes. Because of intra- and interindividual variability in the pharmacokinetics of theophylline, which may be increased by the presence of endogenous and/or exogenous effectors, it is necessary to supervise theophylline therapy by therapeutic drug monitoring if target concentrations are to be achieved.

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“…Ipriflavone, a synthetic flavonoid developed for treatment of osteoporosis, may inhibit bone resorption and enhance the stimulating effect of oestrogen on calcitonin secretion (Yamazaki & Kinoshita, 1986). A 65‐year‐old patient with chronic obstructive pulmonary disease who showed an increase in serum theophylline level following the initiation of ipriflavone treatment has been studied (Takahashi et al , 1992). After withdrawal of ipriflavone, serum theophylline level decreased to a level similar to that found before administration of ipriflavone.…”

Section: Introductionmentioning

confidence: 99%

Ipriflavone as an inhibitor of human cytochrome P450 enzymes

Monostory

Vereczkey

Lévai

et al. 1998

British J Pharmacology

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1 Reduction of theophylline metabolism and elimination were observed in a theophylline-treated patient during ipri¯avone administration. After withdrawal of ipri¯avone, the serum theophylline level decreased to an extent similar to that found before administration of ipri¯avone. The e ects of ipri¯avone and its major metabolites 7-hydroxy-iso¯avone and 7-(1-carboxy-ethoxy)-iso¯avone on cytochrome P450 activities were studied in vitro in human liver microsomes from three donors. 2 Ipri¯avone and 7-hydroxy-iso¯avone competitively inhibited phenacetin O-deethylase and tolbutamide hydroxylase activity. The parent compound and its dealkylated metabolite were strong inhibitors exhibiting K i values around 10 ± 20 mM, while 7-(1-carboxy-ethoxy)-iso¯avone had no e ect on the cytochrome P450 activities investigated. 7-Hydroxy-iso¯avone is the only one that in¯uenced nifedipine oxidase activity. It competitively inhibited this activity with a K i value of 129.5 mM. 3 The steady state concentrations of ipri¯avone and 7-hydroxy-iso¯avone in plasma of patients receiving 36200 mg daily doses of ipri¯avone for 48 weeks were found to be 0.33+0.32 mM and 1.44+0.77 mM, respectively. 4 The results indicate that the decrease in theophylline metabolism observed in a patient treated with ipri¯avone may be due to a competitive interaction of ipri¯avone or its metabolite, 7-hydroxy-iso¯avone with CYP1A2. On the other hand, our in vitro ®ndings predict some more interaction with CYP2C9.

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Elevation of serum theophylline levels by ipriflavone in a patient with chronic obstructive pulmonary disease

Cited by 8 publications

References 8 publications

The effect of ipriflavone and its main metabolites on theophylline biotransformation

The effect of ipriflavone and its main metabolites on theophylline biotransformation

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

Ipriflavone as an inhibitor of human cytochrome P450 enzymes

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