A mechanistic study on altered pharmacokinetics of irinotecan by St. John's wort.
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 (AUC(0-10hr)) and maximum plasma concentration (Cmax) of SN-38. The ethanolic extracts (EE) of SJW at 5 microg/ml significantly decreased SN-38 glucuronidation by 45% (P < 0.05) in rat hepatic microsomes. Pre-incubation of aqueous SJW extracts (AE) at 10 microg/ml, SJW EE at 5 microg/ml, and quercetin at 10 microM significantly increased the glucuronidation of SN-38 in H4-II-E cells. A 2-hr pre-incubation of quercetin (100 microM) significantly increased the intracellular accumulation of CPT-11 (P < 0.05). However, pre-incubation of hypericin (20 nM and 200 nM) and hyperforin (1 microM) 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.
Hu
Ze-Ping
ZP
Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, 117543, Singapore.
Yang
Xiao-Xia
XX
Chen
Xiao
X
Cao
Jie
J
Chan
Eli
E
Duan
Wei
W
Huang
Min
M
Yu
Xue-Qing
XQ
Wen
Jing-Yuan
JY
Zhou
Shu-Feng
SF
D000818:Animals; D000873:Anthracenes; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020719:Glucuronides / Q000378:metabolism; D020902:Hypericum / Q000737:chemistry*; D000077146:Irinotecan; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013729:Terpenes / Q000494:pharmacology
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000873:Anthracenes; D000972:Antineoplastic Agents, Phytogenic; D001643:Bridged Bicyclo Compounds; D020719:Glucuronides; D010936:Plant Extracts; D013729:Terpenes; D010569:Perylene; D000077146:Irinotecan; C004965:hypericin; D011794:Quercetin; D010696:Phloroglucinol; C001654:hyperforin; D002166:Camptothecin