Abstract
This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) ≤20 ml/min] who were undergoing dialysis and received 100 mg/m2 irinotecan as monotherapy were prospectively compared with those in five cancer patients with normal renal function (Ccr ≥60 ml/min). To ensure that the subjects had similar genetic backgrounds of UDP-glucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, *1/*6, or *1/*28 were enrolled. The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was approximately one tenth of that in patients with normal renal function (P = 0.025). Approximately 50% of SN-38 was dialyzed with a 2.1-m2 dialysis membrane, whereas 27% was dialyzed with a 1.5-m2 membrane. Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure compared with patients with normal renal function. We demonstrated that SN-38 was partly dialyzed.
Footnotes
This work was supported in part by the Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan [Grant 21S-8-1]; and a grant-in-aid for “Support Project of Strategic Research Center in Private Universities” from the Ministry of Education, Culture, Sports, Science and Technology (to Saitama Medical University Research Center for Genomic Medicine).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.035451.
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ABBREVIATIONS:
- UGT
- UDP-glucuronosyltransferase
- SN-38
- 7-ethyl-10-hydroxycamptothecin
- SN-38G
- SN-38 glucuronide
- OATP1B1
- organic anion transporter peptide 1B1
- Ccr
- creatinine clearance
- CMPF
- 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid
- IA
- indoleacetic acid
- IS
- indoxyl sulfate
- HA
- hippuric acid
- λz
- terminal elimination rate constant.
- Received July 13, 2010.
- Accepted October 27, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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