This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ratain, M. J. Search for Related Content PubMed PubMed Citation Articles by Ratain, M. J.

Insights into the Pharmacokinetics and Pharmacodynamics of Irinotecan

Department of Medicine, Committee on Clinical Pharmacology and Cancer Research Center, University of Chicago, Chicago, Illinois 60637-1470

ABSTRACT

Irinotecan is a relatively new anticancer agent of interest for both its clinical activity and its complex clinical pharmacology. It is a prodrug, requiring activation by carboxylesterases to SN-38, an inhibitor of topoisomerase I. Recent studies suggest that human carboxylesterase-2 is the primary carboxylesterase involved in the hydrolysis at pharmacological concentrations (1) . Irinotecan is also oxidized by CYP3A4³ to the inactive metabolite 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin as well as to 7-ethyl-10-[4-(piperidino)-1-amino]carbonyloxycamptothecin, which can undergo hydrolysis to SN-38 (2, 3, 4) . SN-38 undergoes glucuronidation by UGT1A1 (5) and is possibly oxidized by CYP3A4 as well (6) . Mass balance studies have demonstrated that 64% of the total dose is excreted in the feces, confirming the important role of biliary excretion (7) . Studies suggest that canalicular multispecific organic anion transporter is the major transporter of irinotecan and its metabolites, although P-glycoprotein probably also participates in irinotecan excretion (8 , 9) .

The pharmacodynamics of irinotecan are less well understood. The major toxicities of irinotecan are diarrhea and myelosuppression, which are clearly dose dependent. In addition, schedule may also affect the relationship between dose and diarrhea, because the intermittent (every 3 weeks) dosing schedule appears to have a lower incidence of diarrhea. Prior studies at the University of Chicago have demonstrated that the biliary index, a surrogate measure of biliary excretion, correlates with the risk of diarrhea on the weekly schedule, suggesting that diarrhea is a function of the intraluminal exposure to SN-38 (10) . This finding has not been confirmed using the intermittent dosing schedule. Myelosuppression has been correlated with the area under the concentration-time curve of both irinotecan and SN-38 (11) .

Determinants of response are less clear. Response has been related to intracellular carboxylesterase activity in preclinical studies (12 , 13) . Thus, irinotecan, in contrast to the other camptothecins, may be a selective prodrug. This may explain the higher response rate to irinotecan in most solid tumors, in comparison to other camptothecins such as topotecan and 9-aminocamptothecin.

The current study by Kehrer and his colleagues from Rotterdam provides further insights into the pharmacokinetics and pharmacodynamics of irinotecan. Using a highly sensitive high-performance liquid chromatography assay and prolonged sampling (3 weeks), they demonstrate that the terminal half-life of SN-38 is 2 days, longer than can be demonstrated with conventional sampling approaches. This finding is not surprising for any drug that is highly protein bound, and it is unclear whether the prolonged exposure to subnanomolar concentrations of SN-38 is clinically relevant. The finding of a decreased ratio of SN-38 glucuronide to SN-38 over time would not necessarily have been predicted. The pharmacokinetic findings, in concert with the elegant transport studies in Caco-2 monolayers, are evidence to support an enterohepatic circulation for SN-38.

Of particular interest is the authors’ finding that individual fecal levels of ß-glucuronidase did not correlate with any SN-38 kinetic parameters, suggesting that the activity of this enzyme is not of particular importance. Although the authors’ sample size did not permit correlation of fecal ß-glucuronidase with diarrhea, our own studies demonstrating an inverse relationship between SN-38 glucuronidation and diarrhea are in concordance with this observation (10) . If fecal ß-glucuronidase activity were a major determinant of diarrhea, then SN-38 glucuronidation would not be protective from diarrhea, because SN-38 would be able to be reformed from SN-38 glucuronide.

Kehrer and colleagues raise one last issue that requires comment. They include in their study a case report of a patient who developed obstructive jaundice, increased SN-38 concentrations, and fatal toxicity. The authors hypothesize that the pharmacokinetic findings are secondary to competitive inhibition by bilirubin of SN-38 glucuronidation. SN-38 glucuronidation is determined primarily by genetic factors, because there is a common polymorphism in the UGT1A1 promoter (14) . Prior studies have demonstrated that there is a correlation between genotype and glucuronidation in vitro (15) , and preliminary results of an ongoing clinical study at the University of Chicago demonstrate similar results in vivo (16) . In addition, there is a common polymorphism in the coding region of UGT1A1 in Asian populations that has been associated with neonatal jaundice (17) . Review of Fig. 3 of Kehrer’s paper suggests that there is an abrupt decrease in SN-38 clearance (at 6 h) with ongoing formation of SN-38 glucuronide. This pattern is more consistent with inhibition of biliary excretion than glucuronidation. Hyperbilirubinemia may also lead to decreased plasma protein binding and increased free SN-38, which would further increase the toxicity in this patient with markedly impaired SN-38 clearance.

There are many future challenges to improve the therapeutic index of this fascinating and active drug. One approach ongoing at the University of Chicago is pharmacokinetic modulation with inhibitors of biliary excretion (e.g., canalicular multispecific organic anion transporter and P-glycoprotein) and inducers of UGT1A1 (18 , 19) . A clinical study of irinotecan, cyclosporine A, and phenobarbital is in progress (20) . Responses have been observed without significant diarrhea, despite a very low SN-38 area under the concentration-time curve. This finding is supportive of the hypothesis that intratumoral hydrolysis may be more important than plasma SN-38 concentrations. Thus, studies using gene therapy to increase intratumoral activation are of high interest and may result in a major advance in the use of camptothecins (21 , 22) .

Studies are also ongoing to try to use UGT1A1 genotyping to individualize dosing. Future studies will also search for relationships between toxicity (and possibly response) and polymorphisms in the other enzymes and transporters involved in the pharmacokinetics and pharmacodynamics of irinotecan.

FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637-1470. Phone: (773) 702-4400; Fax: (773) 702-3969.

² Dr. Ratain is the principal inventor of an issued patent (held by ARCH Development Corporation, wholly owned by the University of Chicago): US Patent 5,786,344 (7/28/98) entitled, "Camptothecin Drug Combinations and Methods with Reduced Side Effects" (inventors Mark J. Ratain and Elora Gupta).

³ The abbreviations used are: CYP3A4, cytochrome P450 3A4; SN-38, 7-ethyl-10-hydroxycamptothecin.

Received 5/23/00; REFERENCES

1. Humerickhouse R., Lohrbach K., Li L., Bosron W. F., Dolan M. E. Characterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2. Cancer Res., 60: 1189-1192, 2000.[Abstract/Free Full Text]
2. Rivory L. P., Riou J-F., Haaz M-C., Sable S., Vuilhorgne M., Commercon A., Pond S. M., Robert J. Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. Cancer Res., 56: 3689-3694, 1996.[Abstract/Free Full Text]
3. Haaz M. C., Riche C., Rivory L. P., Robert J. Biosynthesis of an aminopiperidino metabolite of irinotecan [7-ethyl-10- [4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] by human hepatic microsomes. Drug Metab. Dispos., 26: 769-774, 1998.[Abstract/Free Full Text]
4. Haaz M-C., Rivory L., Riché C., Vernillet L., Robert J. Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. Cancer Res., 58: 468-472, 1998.[Abstract/Free Full Text]
5. Iyer L., King C. D., Whitington P. F., Green M. D., Roy S. K., Tephly T. R., Coffman B. L., Ratain M. J. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J. Clin. Investig., 101: 847-854, 1998.[Medline]
6. Shepard D. R., Ramirez J., Iyer L., Ratain M. J. Metabolism of SN-38 by CYP3A4 and microsomes from human liver. Proc. Am. Soc. Clin. Oncol., 18: 176a 1999.
7. Slatter J. G., Schaaf L. J., Sams J. P., Feenstra K. L., Johnson M. G., Bombardt P. A., Cathcart K. S., Verburg M. T., Pearson L. K., Compton L. D., Miller L. L., Baker D. S., Pesheck C. V., Lord R. S., III. Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following I. V. infusion of [¹⁴C]CPT-11 in cancer patients. Drug Metab. Dispos., 28: 423-433, 2000.[Abstract/Free Full Text]
8. Chu X-Y., Kato Y., Sugiyama Y. Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats. Cancer Res., 57: 1934-1938, 1997.[Abstract/Free Full Text]
9. Chu X. Y., Kato Y., Sugiyama Y. Possible involvement of P-glycoprotein in biliary excretion of CPT-11 in rats. Drug Metab. Dispos., 27: 440-441, 1999.[Abstract/Free Full Text]
10. Gupta E., Mick R., Ramirez J., Wang X., Lestingi T. M., Vokes E. E., Ratain M. J. Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J. Clin. Oncol., 15: 1439-1443, 1997.[Abstract]
11. Sasaki Y., Hakusui H., Mizuno S., Morita M., Miya T., Eguchi K., Shinkai T., Tamura T., Ohe Y., Saijo N. A pharmacokinetic and pharmacodynamic analysis of CPT-11 and its active metabolite SN-38. Jpn. J. Cancer Res., 86: 101-110, 1995.[CrossRef][Medline]
12. van Ark-Otte J., Kedde M. A., van der Vijgh W. J., Dingemans A. M., Jansen W. J., Pinedo H. M., Boven E., Giaccone G. Determinants of CPT-11 and SN-38 activities in human lung cancer cells. Br. J. Cancer, 77: 2171-2176, 1998.[Medline]
13. Guichard S., Terret C., Hennebelle I., Lochon I., Chevreau P., Fretigny E., Selves J., Chatelut E., Bugat R., Canal P. CPT-11 converting carboxylesterase and topoisomerase activities in tumour and normal colon and liver tissues. Br. J. Cancer, 80: 364-370, 1999.[CrossRef][Medline]
14. Monaghan G., Ryan M., Seddon R., Hume R., Burchell B. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet, 347: 578-581, 1996.[CrossRef][Medline]
15. Iyer L., Hall D., Das S., Mortell M. A., Ramirez J., Kim S., Di Rienzo A., Ratain M. J. Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin. Pharmacol. Ther., 65: 576-582, 1999.[CrossRef][Medline]
16. Iyer L., Janisch L., Das S., Ramirez J., Hurley-Buterman C. E., DeMario M. D., Vokes E. E., Kindler H. L., Ratain M. J. UGT1A1 promoter genotype correlates with pharmacokinetics of irinotecan (CPT-11). Proc. Am. Soc. Clin. Oncol., 19: 178a 2000.
17. Akaba K., Kimura T., Sasaki A., Tanabe S., Ikegami T., Hashimoto M., Umeda H., Yoshida H., Umetsu K., Chiba H., Yuasa I., Hayasaka K. Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese. Biochem. Mol. Biol. Int., 46: 21-26, 1998.[Medline]
18. Gupta E., Safa A. R., Wang X., Ratain M. J. Pharmacokinetic modulation of irinotecan and metabolites by cyclosporine A. Cancer Res., 56: 1309-1314, 1996.[Abstract/Free Full Text]
19. Gupta E., Wang X., Ramirez J., Ratain M. J. Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital. Cancer Chemother. Pharmacol., 39: 440-444, 1997.[CrossRef][Medline]
20. Ratain M. J., Goh B. C., Iyer L., Fagbemi S., Mani S., Vogelzang N. J., Schilsky R. L., Kunkel K. A Phase I study of irinotecan with pharmacokinetic modulation by cyclosporine A and phenobarbital. Proc. Am. Soc. Clin. Oncol., 18: 202a 1999.
21. Kojima A., Hackett N. R., Ohwada A., Crystal R. G. In vivo human carboxylesterase cDNA gene transfer to activate the prodrug CPT-11 for local treatment of solid tumors. J. Clin. Investig., 101: 1789-1796, 1998.[Medline]
22. Danks M. K., Morton C. L., Krull E. J., Cheshire P. J., Richmond L. B., Naeve C. W., Pawlik C. A., Houghton P. J., Potter P. M. Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy. Clin. Cancer Res., 5: 917-924, 1999.[Abstract/Free Full Text]

This article has been cited by other articles:

				L. J. Schaaf, L. A. Hammond, S. J. Tipping, R. M. Goldberg, R. Goel, J. G. Kuhn, L. L. Miller, L. D. Compton, L. A. Cisar, G. L. Elfring, et al. Phase 1 and pharmacokinetic study of intravenous irinotecan in refractory solid tumor patients with hepatic dysfunction. Clin. Cancer Res., June 15, 2006; 12(12): 3782 - 3791. [Abstract] [Full Text] [PDF]

				S. P. Sanghani, S. K. Quinney, T. B. Fredenburg, W. I. Davis, D. J. Murry, and W. F. Bosron HYDROLYSIS OF IRINOTECAN AND ITS OXIDATIVE METABOLITES, 7-ETHYL-10-[4-N-(5-AMINOPENTANOIC ACID)-1-PIPERIDINO] CARBONYLOXYCAMPTOTHECIN AND 7-ETHYL-10-[4-(1-PIPERIDINO)-1-AMINO]-CARBONYLOXYCAMPTOTHECIN, BY HUMAN CARBOXYLESTERASES CES1A1, CES2, AND A NEWLY EXPRESSED CARBOXYLESTERASE ISOENZYME, CES3 Drug Metab. Dispos., May 1, 2004; 32(5): 505 - 511. [Abstract] [Full Text] [PDF]

				J. D. Chester, S. P. Joel, S. L. Cheeseman, G. D. Hall, M. S. Braun, J. Perry, T. Davis, C. J. Button, and M. T. Seymour Phase I and Pharmacokinetic Study of Intravenous Irinotecan Plus Oral Ciclosporin in Patients With Fluorouracil-Refractory Metastatic Colon Cancer J. Clin. Oncol., March 15, 2003; 21(6): 1125 - 1132. [Abstract] [Full Text] [PDF]

				R. H. Tukey, C. P. Strassburg, and P. I. Mackenzie Pharmacogenomics of Human UDP-Glucuronosyltransferases and Irinotecan Toxicity Mol. Pharmacol., September 1, 2002; 62(3): 446 - 450. [Full Text] [PDF]

				C. D. Turner, S. Gururangan, J. Eastwood, K. Bottom, M. Watral, R. Beason, R. E. McLendon, A. H. Friedman, S. Tourt-Uhlig, L. L. Miller, et al. Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: The Duke experience Neuro-oncol, April 1, 2002; 4(2): 102 - 108. [Abstract] [PDF]

				L. Bomgaars, S. L. Berg, and S. M. Blaney The Development of Camptothecin Analogs in Childhood Cancers Oncologist, December 1, 2001; 6(6): 506 - 516. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ratain, M. J. Search for Related Content PubMed PubMed Citation Articles by Ratain, M. J.