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Originally published as JCO Early Release 10.1200/JCO.2006.07.2355 on August 8 2006 © 2006 American Society of Clinical Oncology.
Role for Drug Transporters Beyond Tumor Resistance: Hepatic Functional Imaging and Genotyping of Multidrug Resistance Transporters for the Prediction of Irinotecan Toxicity
Department of Biopharmaceutical Sciences and Institute for Human Genetics, University of California San Francisco, San Francisco, CA The multigenic nature of drug response is increasingly recognized and underscores our current difficulties with adequately predicting interindividual variability in both the response to and toxicity of many chemotherapeutic agents. The clinical pharmacology of irinotecan nicely illustrates the complexity of drug response pathways and highlights the pressing need to develop easily measured markers that are predictive of drug disposition, toxicity, and efficacy. Until recently, the main focus has been on understanding the variation in irinotecan metabolism, since it was considered the primary factor controlling systemic exposure to this drug.1-3 Irinotecan is a prodrug that must be metabolized to the active compound SN-38, a potent inhibitor of topoisomerase I.1 Metabolism of irinotecan to SN-38 is catalyzed largely by carboxylesterase-2 (CES2), and CYP3A4/CYP3A5 catalyzes the formation of inactive metabolites. A significant fraction of SN-38 is converted to the glucuronide conjugate (SN-38G)—a conversion catalyzed largely by UGT1A1. More than 10 years of research have nicely illustrated the critical role of UGT1A1 activity in determining the pharmacologic response to irinotecan, as well as in the development of its rate-limiting toxicities of neutropenia and late-onset diarrhea.4-9 In vivo and genetic markers have been established for many drug metabolizing enzymes, and in the case of UGT1A1, genotyping alone is highly predictive of function.10 However, metabolism is only one factor controlling the systemic and cellular exposure to irinotecan and its metabolites. Drug transporters have also been implicated in the disposition of irinotecan, SN-38 and SN-38G, with evidence for transport by P-glycoprotein (Pgp; encoded by ABCB1), multidrug resistance-associated protein 1 (MRP1; ABCC1), MRP2 (ABCC2), and mitoxantrone resistance protein (MXR; ABCG2).11-14 More recently, an organic anion transporting polypeptide (OATP1B1; SLCO1B1) was shown to transport SN-38 but not irinotecan or SN-38G.15 An accurate prediction of those patients most likely to develop life-threatening toxicities during irinotecan therapy needs to consider variation in not only the metabolism of this important drug but also its transport into and out of both tumor cells and those cells associated with its disposition and toxicity. The article in this issue by Michael et al is an important contribution to the development of more comprehensive biomarkers of irinotecan disposition.16 Hepatic imaging was performed in advanced colorectal cancer patients using well-characterized substrates of the multidrug resistance transporters Pgp, MRP1 and MRP2, and hepatic functional imaging parameters were correlated with irinotecan pharmacokinetics. The area under the curve (AUC) of SN-38 was positively correlated with the hepatic retention of the imaging agents, a significant finding since SN-38 exposure is linked to the neutropenia and late-onset diarrhea associated with irinotecan therapy.4,9 Indeed, there was a trend toward an association between hepatic imaging parameters and toxicity. A preliminary analysis of ABCB1 genotypes was also performed and is consistent with the important role of Pgp in the disposition of the imaging agents. Hepatobiliary imaging was developed for the evaluation of hepatic dysfunction and to monitor the response to drugs and other interventions.17 The two classes of 99mTc-labeled agents that were used in these studies are rapidly taken up into the hepatocyte and eliminated into the bile by distinct active transport mechanisms. The iminodiacetic acid (IDA) analogs (99mTc-DIDA and 99mTc-DISIDA) are organic anions and likely require uptake transporters for entry into the hepatocyte.17 Biliary excretion of 99mTc-DIDA and 99mTc-DISIDA is mediated by MRP2 while transport by MRP1 will eliminate drug from the hepatocyte back into the systemic circulation.18 Consistent with the significant role of MRP2 in the elimination of IDA agents, their biliary excretion is decreased in Dubin-Johnson syndrome patients who often carry polymorphisms in ABCC2 that result in a loss of MRP2 function.19-21 99mTc-labeled sestamibi (99mTc-MIBI) is a Pgp substrate and has been used to demonstrate Pgp inhibition by pharmacologic agents and genetic disruption.22,23 These imaging agents have great potential in the evaluation of drug transport function in the liver and fill a current void in this area. The lack of selective substrates that are metabolically stable has made it difficult to assess in vivo transporter function.24 Most substrates of Pgp, MRP1, and MRP2 undergo significant first pass and systemic metabolism and pharmacokinetic parameters for these substrates will therefore reflect both metabolism and transporter function. Inhibitors of multidrug resistance transporters also lack specificity, limiting their use for the measurement of transporter-specific contributions to pharmacokinetic parameters.24 The use of stable hepatic imaging agents that are rapidly effluxed by the multidrug resistance transporters avoids these problems and provides the most direct measure available for in vivo transporter function. In addition, imaging studies will provide information about the general function of the liver that can also be considered in the selection of appropriate chemotherapy treatment. The utility of hepatic functional imaging in irinotecan dose optimization is dependent on the degree to which hepatic transport function predicts toxicity. Neutropenia has been positively correlated with SN-38 plasma concentrations,9 suggesting that reduced biliary secretion of SN-38 would be associated with higher rates of neutropenia. An association between increased hepatic retention of the imaging agents with SN-38 AUC is consistent with this parameter reflecting biliary transporter function. There was also a suggestion that higher grade neutropenia was associated with functional imaging parameters indicating lower biliary excretion, though this did not reach statistical significance. Late-onset diarrhea is often rate-limiting for irinotecan treatment and has been attributed to secretion of SN-38 into the intestine.4 In this case, decreased biliary secretion would protect against diarrhea. The current study supports this hypothesis, with increased diarrhea in those patients with hepatic functional imaging parameters consistent with significant biliary transport function. While these data do not allow us to identify the level of individual transporter function within the patient, they indicate that hepatic functional imaging is promising as a general marker of active biliary secretion. Interestingly, there was much more variability associated with the hepatic imaging parameters for 99mTc-MIBI than for 99mTc-DIDI/99mTc-DISIDA, possibly reflecting greater variability in Pgp function than in MRP2-mediated secretion. Consideration of serum bilirubin and the 1-hour retention parameter for 99mTc-MIBI accounted for 44% of the variation in SN-38 AUC. A combination of hepatic imaging and standard laboratory tests may therefore have a high predictive power for the detection of individuals at risk for irinotecan neutropenia and diarrhea. Irinotecan is also one of only a handful of drugs for which genetic variation has been linked with response and toxicity, and it is quickly gaining "poster child" status in the field of pharmacogenetics. A common genetic polymorphism in UGT1A1 results from a dinucleotide (TA) insertion in the TATA box of the UGT1A1 promoter and the occurrence of seven TA repeats instead of the usual six.25 The UGT1A1*28 allele with the additional TA repeat is associated with reduced gene expression and functional activity, as measured by SN-38 and bilirubin glucuronidation.6,10 Individuals homozygous for the UGT1A1*28 genotype have an increased risk of severe neutropenia and diarrhea and require lower doses of irinotecan compared with those with the reference allele.5-9 Despite labeling revisions noting an increased risk of toxicity and a need for reduced dosage in patients homozygous for the UGT1A1*28 genotype, initial dosing of irinotecan is still largely based on body-surface area—a parameter with no known relationship to the disposition of this drug. The current study reported by Michael et al suggests that UGT1A1 genotype alone may not be sufficient to identify patients who would benefit from a lower starting dose of irinotecan.16 They also genotyped for three common coding region variants of ABCB1, two synonymous changes, and a nonsynonymous change resulting in the Ala893Ser variant of Pgp. The functional significance of these variants is still unclear; the 3435C>T polymorphism has been associated with lower hepatic ABCB1 mRNA levels, and most studies suggest that the Ser893 variant of Pgp has relatively normal transport function.26,27 Unfortunately the present study was not sufficiently powered to adequately test whether ABCB1 genotype or haplotype influences irinotecan pharmacokinetics. The half-life of 99mTc-MIBI was longer, and its 1-hour retention was greater in those patients with the 3435TT genotype compared with the 3435CT or 3435CC genotypes. This would be consistent with a decreased function of Pgp-mediated biliary secretion of the imaging agent and presumably of irinotecan and SN-38 in patients homozygous for the 3435T allele. While these results can only be considered preliminary based on the small number of patients that were studied (n = 21), they raise the exciting possibility that a combination of drug response gene polymorphisms and hepatic functional imaging might provide the best predictive power to identify a priori those cancer patients at high risk of toxicity. It is intriguing to hypothesize that a combination of low UGT1A1 metabolizer status and decreased function of Pgp and/or MRP2 would be associated with increased systemic exposure to SN-38 and an increased risk of neutropenia. Likewise, the increased risk of late-onset diarrhea associated with the UGT1A1*28 genotype could be significantly attenuated in those patients with reduced biliary transport function. The potential impact of UGT1A1 genotyping is already significant, but is likely to become even more important in the context of polymorphisms relevant to the complete irinotecan drug response pathway. So how do we move forward from these initial preliminary findings? Correlations between SN-38 exposure, in vivo measures of transporter function, and transporter and enzyme genotypes need to be studied in larger populations. If genotypes of the ABC transporters are highly predictive of in vivo transporter function measured by functional imaging, then genotyping alone may be sufficient to identify patients with low biliary secretion of irinotecan and its metabolites. Clearly, this would be advantageous from a clinical perspective and would be much more easily integrated into practice than functional imaging. Additional genotyping for polymorphisms in ABCG2, ABCC2, and SLCO1B1 are also supported by functional data illustrating interactions with irinotecan.12,14,15 Challenges remain in the successful integration of multiple biomarkers for the prediction of a single drug response or toxicity and will likely require the application of sophisticated modeling techniques. Such approaches, however, will become increasingly common as we exploit the power of the Human Genome and HapMap data for the individualization of cancer chemotherapy. Time will tell whether the inclusion of biomarkers of transporter function will improve the current ability to identify patients at high risk of irinotecan toxicity. In the interim, wider application of UGT1A1 genotyping should be encouraged so that incremental improvements in patient care are realized. Author's Note Disclaimer: Dr Kroetz is listed as an inventor on pending patents related to irinotecan. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. ACKNOWLEDGMENTS This work was supported by National Institutes of Health Grant No. GM61390. NOTES published online ahead of print at www.jco.org on August 7, 2006. REFERENCES
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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