A mechanistic study on altered pharmacokinetics of irinotecan by St. John's Wort

Ze Ping Hu, Xiao Xia Yang, Xiao Chen, Jie Cao, Eli Chan, Wei Duan, Min Huang, Xue Qing Yu, Jing Yuan Wen, Shu Feng Zhou

Research output: Contribution to journalArticle

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Abstract

Irinotecan (CPT-11) is an important anticancer drug in management of advanced colon cancer. A marked protective effect on CPT-11-induced blood and gastrointestinal toxicity is obtained by combination of St. John's wort (SJW) in recent clinical and rat studies. However, the mechanism is unclear. This study aimed to explore the effects of SJW on the pharmacokinetics of CPT-11 and its major metabolites (SN-38 and SN-38 glucuronide) in rats and the underlying mechanisms using several in vitro models. Short-term (3 days) and long-term (14 days) pretreatment with SJW were conducted in rats to examine the effects of co-administered SJW on the plasma pharmacokinetics of CPT-11, SN-38 and SN-38 glucuronide. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were utilized to study the effects of aqueous and ethanolic extracts (AE and EE) and major active components (hyperforin, hypericin and quercetin) of SJW on CPT-11 and SN-38 metabolism and intracellular accumulation. Co-administered SJW for consecutive 14 days significantly decreased the initial plasma concentration (C0) of CPT-11, the area under the concentration-time curve (AUC0-10hr) and maximum plasma concentration (Cmax) of SN-38. The ethanolic extracts (EE) of SJW at 5 μg/ml significantly decreased SN-38 glucuronidation by 45% (P < 0.05) in rat hepatic microsomes. Pre-incubation of aqueous SJW extracts (AE) at 10 μg/ml, SJW EE at 5 μg/ml, and quercetin at 10 μM significantly increased the glucuronidation of SN-38 in H4-II-E cells. A 2-hr pre-incubation of quercetin (100 μM) significantly increased the intracellular accumulation of CPT-11 (P < 0.05). However, pre-incubation of hypericin (20 nM and 200 nM) and hyperforin (1μM) significantly decreased the intracellular accumulation of CPT-11. In addition, pre-incubation of hypericin, SJW EE and quercetin significantly increased the intracellular accumulation of SN-38. Aqueous and ethanolic SJW extracts and its major active components did not alter the plasma protein binding of CPT-11 and SN-38. These results indicated that the aqueous and ethanolic extracts of SJW and its major active components could markedly alter glucuronidation of SN-38 and intracellular accumulation of CPT-11 and SN-38, which probably provides partial explanation for the altered plasma pharmacokinetics of CPT-11 and SN-38 and the antagonizing effects on the toxicities of CPT-11. Further studies are needed to explore the role of both pharmacokinetic and pharmacodynamic components in the protective effect of SJW against the toxicities of CPT-11.

Original languageEnglish (US)
Pages (from-to)157-171
Number of pages15
JournalCurrent Drug Metabolism
Volume8
Issue number2
DOIs
StatePublished - Feb 2007

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irinotecan
Hypericum
Pharmacokinetics
Rats
Quercetin

Keywords

  • Hyperforin
  • Hypericin
  • Irinotecan (CPT-11)
  • Metabolism
  • Pharmacokinetics
  • SN-38
  • St. John's Wort
  • Transport

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

A mechanistic study on altered pharmacokinetics of irinotecan by St. John's Wort. / Hu, Ze Ping; Yang, Xiao Xia; Chen, Xiao; Cao, Jie; Chan, Eli; Duan, Wei; Huang, Min; Yu, Xue Qing; Wen, Jing Yuan; Zhou, Shu Feng.

In: Current Drug Metabolism, Vol. 8, No. 2, 02.2007, p. 157-171.

Research output: Contribution to journalArticle

Hu, ZP, Yang, XX, Chen, X, Cao, J, Chan, E, Duan, W, Huang, M, Yu, XQ, Wen, JY & Zhou, SF 2007, 'A mechanistic study on altered pharmacokinetics of irinotecan by St. John's Wort', Current Drug Metabolism, vol. 8, no. 2, pp. 157-171. https://doi.org/10.2174/138920007779815995
Hu, Ze Ping ; Yang, Xiao Xia ; Chen, Xiao ; Cao, Jie ; Chan, Eli ; Duan, Wei ; Huang, Min ; Yu, Xue Qing ; Wen, Jing Yuan ; Zhou, Shu Feng. / A mechanistic study on altered pharmacokinetics of irinotecan by St. John's Wort. In: Current Drug Metabolism. 2007 ; Vol. 8, No. 2. pp. 157-171.
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T1 - A mechanistic study on altered pharmacokinetics of irinotecan by St. John's Wort

AU - Hu, Ze Ping

AU - Yang, Xiao Xia

AU - Chen, Xiao

AU - Cao, Jie

AU - Chan, Eli

AU - Duan, Wei

AU - Huang, Min

AU - Yu, Xue Qing

AU - Wen, Jing Yuan

AU - Zhou, Shu Feng

PY - 2007/2

Y1 - 2007/2

N2 - Irinotecan (CPT-11) is an important anticancer drug in management of advanced colon cancer. A marked protective effect on CPT-11-induced blood and gastrointestinal toxicity is obtained by combination of St. John's wort (SJW) in recent clinical and rat studies. However, the mechanism is unclear. This study aimed to explore the effects of SJW on the pharmacokinetics of CPT-11 and its major metabolites (SN-38 and SN-38 glucuronide) in rats and the underlying mechanisms using several in vitro models. Short-term (3 days) and long-term (14 days) pretreatment with SJW were conducted in rats to examine the effects of co-administered SJW on the plasma pharmacokinetics of CPT-11, SN-38 and SN-38 glucuronide. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were utilized to study the effects of aqueous and ethanolic extracts (AE and EE) and major active components (hyperforin, hypericin and quercetin) of SJW on CPT-11 and SN-38 metabolism and intracellular accumulation. Co-administered SJW for consecutive 14 days significantly decreased the initial plasma concentration (C0) of CPT-11, the area under the concentration-time curve (AUC0-10hr) and maximum plasma concentration (Cmax) of SN-38. The ethanolic extracts (EE) of SJW at 5 μg/ml significantly decreased SN-38 glucuronidation by 45% (P < 0.05) in rat hepatic microsomes. Pre-incubation of aqueous SJW extracts (AE) at 10 μg/ml, SJW EE at 5 μg/ml, and quercetin at 10 μM significantly increased the glucuronidation of SN-38 in H4-II-E cells. A 2-hr pre-incubation of quercetin (100 μM) significantly increased the intracellular accumulation of CPT-11 (P < 0.05). However, pre-incubation of hypericin (20 nM and 200 nM) and hyperforin (1μM) significantly decreased the intracellular accumulation of CPT-11. In addition, pre-incubation of hypericin, SJW EE and quercetin significantly increased the intracellular accumulation of SN-38. Aqueous and ethanolic SJW extracts and its major active components did not alter the plasma protein binding of CPT-11 and SN-38. These results indicated that the aqueous and ethanolic extracts of SJW and its major active components could markedly alter glucuronidation of SN-38 and intracellular accumulation of CPT-11 and SN-38, which probably provides partial explanation for the altered plasma pharmacokinetics of CPT-11 and SN-38 and the antagonizing effects on the toxicities of CPT-11. Further studies are needed to explore the role of both pharmacokinetic and pharmacodynamic components in the protective effect of SJW against the toxicities of CPT-11.

AB - Irinotecan (CPT-11) is an important anticancer drug in management of advanced colon cancer. A marked protective effect on CPT-11-induced blood and gastrointestinal toxicity is obtained by combination of St. John's wort (SJW) in recent clinical and rat studies. However, the mechanism is unclear. This study aimed to explore the effects of SJW on the pharmacokinetics of CPT-11 and its major metabolites (SN-38 and SN-38 glucuronide) in rats and the underlying mechanisms using several in vitro models. Short-term (3 days) and long-term (14 days) pretreatment with SJW were conducted in rats to examine the effects of co-administered SJW on the plasma pharmacokinetics of CPT-11, SN-38 and SN-38 glucuronide. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were utilized to study the effects of aqueous and ethanolic extracts (AE and EE) and major active components (hyperforin, hypericin and quercetin) of SJW on CPT-11 and SN-38 metabolism and intracellular accumulation. Co-administered SJW for consecutive 14 days significantly decreased the initial plasma concentration (C0) of CPT-11, the area under the concentration-time curve (AUC0-10hr) and maximum plasma concentration (Cmax) of SN-38. The ethanolic extracts (EE) of SJW at 5 μg/ml significantly decreased SN-38 glucuronidation by 45% (P < 0.05) in rat hepatic microsomes. Pre-incubation of aqueous SJW extracts (AE) at 10 μg/ml, SJW EE at 5 μg/ml, and quercetin at 10 μM significantly increased the glucuronidation of SN-38 in H4-II-E cells. A 2-hr pre-incubation of quercetin (100 μM) significantly increased the intracellular accumulation of CPT-11 (P < 0.05). However, pre-incubation of hypericin (20 nM and 200 nM) and hyperforin (1μM) significantly decreased the intracellular accumulation of CPT-11. In addition, pre-incubation of hypericin, SJW EE and quercetin significantly increased the intracellular accumulation of SN-38. Aqueous and ethanolic SJW extracts and its major active components did not alter the plasma protein binding of CPT-11 and SN-38. These results indicated that the aqueous and ethanolic extracts of SJW and its major active components could markedly alter glucuronidation of SN-38 and intracellular accumulation of CPT-11 and SN-38, which probably provides partial explanation for the altered plasma pharmacokinetics of CPT-11 and SN-38 and the antagonizing effects on the toxicities of CPT-11. Further studies are needed to explore the role of both pharmacokinetic and pharmacodynamic components in the protective effect of SJW against the toxicities of CPT-11.

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KW - Hypericin

KW - Irinotecan (CPT-11)

KW - Metabolism

KW - Pharmacokinetics

KW - SN-38

KW - St. John's Wort

KW - Transport

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