P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice.

Michael Tagen, Yanli Zhuang, Fan Zhang, K. Elaine Harstead, Jun Shen, Paula Schaiquevich, Charles H. Fraga, John C. Panetta, Christopher Waters, Clinton F. Stewart

Research output: Contribution to journalArticle

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Abstract

The ATP-binding cassette transporters P-glycoprotein (ABCB1, MDR1) and multidrug resistance protein 4 (MRP4) efflux irinotecan and its active metabolite SN-38 in vitro, and thus may contribute to system clearance of these compounds. Mdr1a/b(-/-), Mrp4(-/-), and wild-type mice were administered 20 or 40 mg/kg irinotecan, and plasma samples were collected for 6 hours. Irinotecan and SN-38 lactone and carboxylate were quantitated and data were analyzed with nonlinear mixed-effects modeling. Mdr1a/b genotype was a significant covariate for the clearance of both irinotecan lactone and SN-38 lactone. Exposures to irinotecan lactone and SN-38 lactone after a 40 mg/kg dose were 1.6-fold higher in Mdr1a/b(-/-) mice compared to wild-type mice. Plasma concentrations of irinotecan lactone, irinotecan carboxylate, and SN-38 lactone in Mrp4(-/-) mice were similar to the wild-type controls. These results suggest that P-gp plays a role in irinotecan and SN-38 elimination, but Mrp4 does not affect irinotecan or SN-38 plasma pharmacokinetics.

Original languageEnglish (US)
Pages (from-to)195-201
Number of pages7
JournalDrug metabolism letters
Volume4
Issue number4
DOIs
StatePublished - Jan 1 2010

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irinotecan
P-Glycoproteins
P-Glycoprotein
Lactones
Plasmas

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science
  • Clinical Biochemistry
  • Biochemistry, medical
  • Pharmacology (medical)

Cite this

P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice. / Tagen, Michael; Zhuang, Yanli; Zhang, Fan; Harstead, K. Elaine; Shen, Jun; Schaiquevich, Paula; Fraga, Charles H.; Panetta, John C.; Waters, Christopher; Stewart, Clinton F.

In: Drug metabolism letters, Vol. 4, No. 4, 01.01.2010, p. 195-201.

Research output: Contribution to journalArticle

Tagen, M, Zhuang, Y, Zhang, F, Harstead, KE, Shen, J, Schaiquevich, P, Fraga, CH, Panetta, JC, Waters, C & Stewart, CF 2010, 'P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice.', Drug metabolism letters, vol. 4, no. 4, pp. 195-201. https://doi.org/10.2174/187231210792928251
Tagen, Michael ; Zhuang, Yanli ; Zhang, Fan ; Harstead, K. Elaine ; Shen, Jun ; Schaiquevich, Paula ; Fraga, Charles H. ; Panetta, John C. ; Waters, Christopher ; Stewart, Clinton F. / P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice. In: Drug metabolism letters. 2010 ; Vol. 4, No. 4. pp. 195-201.
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