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 language | English |
|---|---|
| Pages (from-to) | 616-620 |
| Number of pages | 5 |
| Journal | American Review of Respiratory Disease |
| Volume | 146 |
| Issue number | 3 |
| Publication status | Published - 1992 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
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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 journal › Article
}
TY - JOUR
T1 - Effect of leukotriene C4 on theophylline disposition in guinea pigs
AU - Tanigawara, Yusuke
AU - Yano, I.
AU - Yasuhara, M.
AU - Hori, R.
PY - 1992
Y1 - 1992
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=0026612724&partnerID=8YFLogxK
M3 - Article
C2 - 1519837
AN - SCOPUS:0026612724
VL - 146
SP - 616
EP - 620
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 3
ER -