Effect of leukotriene C4 on theophylline disposition in guinea pigs

Yusuke Tanigawara, I. Yano, M. Yasuhara, R. Hori

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The pharmacokinetics of theophylline in acutely ill patients show wide intraindividual variability associated with the severity of clinical status. To investigate the mechanism of this variability, we studied the effects of leukotriene C4 (LTC4)-induced pathophysiologic changes on the disposition of theophylline. The plasma concentration-time profiles were measured after simultaneous intravenous bolus injection of theophylline and antipyrine in guinea pigs. The animals received 5 μg/kg of LTC4 intravenously 60 min later. The plasma theophylline concentration 30 min after LTC4 treatment was significantly lower (p < 0.05) than that of nontreated control animals, whereas the plasma antipyrine concentration at that time was not affected. In addition, the treated animals showed significantly slower declines in plasma concentrations of both drugs (0.0805 ± 0.0199 and 0.291 ± 0.020 h-1 for theophylline and antipyrine, respectively, mean ± SEM) than did controls (0.197 ± 0.010 and 0.439 ± 0.028 h-1). Leukotriene C4 treatment also induced moderate bronchoconstriction and metabolic acidosis, increased blood hemoglobin concentration and hematocrit, and decreased concentration of serum proteins. In connection with these changes, the plasma unbound fraction of theophylline increased significantly (p < 0.001, 94.4 ± 3.3% in treatment versus 58.2 ± 4.4% in control), but that of antipyrine was unchanged (94.9 ± 3.0% in treatment versus 92.1 ± 0.9% in control). These findings indicated that an increase in the volume of distribution was responsible for the abrupt change in plasma theophylline concentration following LTC4 treatment, and the apparent change in the volume of distribution was estimated as 26.1 ± 5.6%. Results showed that the LTC4 response can influence the disposition kinetics of theophylline and suggested a possible mechanism for the intraindividual variability in acutely ill patients.

Original languageEnglish
Pages (from-to)616-620
Number of pages5
JournalAmerican Review of Respiratory Disease
Volume146
Issue number3
Publication statusPublished - 1992
Externally publishedYes

Fingerprint

Leukotriene C4
Theophylline
Guinea Pigs
Antipyrine
Therapeutics
Bronchoconstriction
Acidosis
Hematocrit
Intravenous Injections
Blood Proteins
Hemoglobins
Pharmacokinetics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Effect of leukotriene C4 on theophylline disposition in guinea pigs. / Tanigawara, Yusuke; Yano, I.; Yasuhara, M.; Hori, R.

In: American Review of Respiratory Disease, Vol. 146, No. 3, 1992, p. 616-620.

Research output: Contribution to journalArticle

Tanigawara, Yusuke ; Yano, I. ; Yasuhara, M. ; Hori, R. / Effect of leukotriene C4 on theophylline disposition in guinea pigs. In: American Review of Respiratory Disease. 1992 ; Vol. 146, No. 3. pp. 616-620.
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abstract = "The pharmacokinetics of theophylline in acutely ill patients show wide intraindividual variability associated with the severity of clinical status. To investigate the mechanism of this variability, we studied the effects of leukotriene C4 (LTC4)-induced pathophysiologic changes on the disposition of theophylline. The plasma concentration-time profiles were measured after simultaneous intravenous bolus injection of theophylline and antipyrine in guinea pigs. The animals received 5 μg/kg of LTC4 intravenously 60 min later. The plasma theophylline concentration 30 min after LTC4 treatment was significantly lower (p < 0.05) than that of nontreated control animals, whereas the plasma antipyrine concentration at that time was not affected. In addition, the treated animals showed significantly slower declines in plasma concentrations of both drugs (0.0805 ± 0.0199 and 0.291 ± 0.020 h-1 for theophylline and antipyrine, respectively, mean ± SEM) than did controls (0.197 ± 0.010 and 0.439 ± 0.028 h-1). Leukotriene C4 treatment also induced moderate bronchoconstriction and metabolic acidosis, increased blood hemoglobin concentration and hematocrit, and decreased concentration of serum proteins. In connection with these changes, the plasma unbound fraction of theophylline increased significantly (p < 0.001, 94.4 ± 3.3{\%} in treatment versus 58.2 ± 4.4{\%} in control), but that of antipyrine was unchanged (94.9 ± 3.0{\%} in treatment versus 92.1 ± 0.9{\%} in control). These findings indicated that an increase in the volume of distribution was responsible for the abrupt change in plasma theophylline concentration following LTC4 treatment, and the apparent change in the volume of distribution was estimated as 26.1 ± 5.6{\%}. Results showed that the LTC4 response can influence the disposition kinetics of theophylline and suggested a possible mechanism for the intraindividual variability in acutely ill patients.",
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