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Journal of Clinical Oncology, Vol 26, No 25 (September 1), 2008: pp. 4226-4227 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.4390
Inhibition of Imatinib Transport by Uremic Toxins During Renal FailureDepartment of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN To the Editor: Recently in Journal of Clinical Oncology, two important reports were published that evaluated the role of organ failure (renal and hepatic) on the pharmacokinetics of the tyrosine kinase inhibitor, imatinib mesylate. Ramanathan et al1 found that there was no correlation between the severity of hepatic failure and the pharmacokinetics of imatinib. Conversely, the study on renal failure by Gibbons et al2 saw that progressively worse renal function was associated with decreased clearance, increased maximum concentration, and increased area under the curve (AUC) of imatinib. As mentioned by Judson3 in the accompanying editorial, these findings are surprising because imatinib is predominantly eliminated by hepatic metabolism and subsequent biliary excretion.4 Gibbons et al2 hypothesize that the increased systemic exposure to imatinib in patients with renal failure could be due to decreased cytochrome P450 (CYP) activity. This contention was based on previous studies indicating that CYP function is decreased in animal models of end-stage renal disease.5-7 One possible contributing mechanism that was not discussed is that increased circulating concentrations of uremic toxins associated with renal failure could potentially directly impact the extent of hepatocellular uptake of imatinib. Patients with end-stage renal disease have increased levels of uremic toxins, which are derived from dietary protein and are normally eliminated in the urine.8 Several of these uremic toxins are organic anions that accumulate in the body because of impaired tubular secretion. One such uremic toxin is 3-caboxy-4-methyl-5-propyl-2-furan propionic acid (CMPF), the circulating concentrations of which can approach 400 µmol/L in patients with renal failure.9,10 Previous studies with a rodent model have demonstrated that uremic toxins, such as CMPF, can inhibit the uptake of p-aminohippurate in isolated renal tissues and erythromycin in isolated hepatic tissues.11,12 We have recently found that imatinib is a substrate of the organic anion transporting polypeptide OATP1B3,13 a transporter that is highly expressed on the basolateral membrane of human hepatocytes and as such is likely involved in the uptake of imatinib into the liver. Using Xenopus laevis oocytes injected with OATP1B3 transporter cRNA, we found that OATP1B3-mediated uptake of imatinib was completely blocked by CMPF (P = .0101; Fig 1A) at a clinically relevant concentration. This supports the possibility that, in addition to known effects on protein expression, uremic toxins can directly inhibit the hepatic uptake of imatinib by the OATP1B3 transporter. We also hypothesized that this inhibitory effect would be seen with other substrates for OATP1B3 that are predominantly metabolized by the liver, such as paclitaxel.14 Indeed, as shown in Figure 1B, CMPF is a very effective inhibitor of OATP1B3-mediated uptake of paclitaxel (P = .0152). This finding is consistent with a previous study indicating that the clearance of paclitaxel was impaired in a patient with end-stage renal failure,15 similar to the findings with imatinib,2 but not in an anephric patient on dialysis.16
The findings reported by Gibbons et al2 support a growing body of evidence that renal failure can dramatically impact the pharmacokinetics of agents for which elimination is critically dependent on metabolism in the liver. Future studies should further evaluate the hypothesis that increased systemic concentrations of uremic toxins can directly inhibit the hepatic uptake of several anticancer agents, and that consideration of this type of interaction can guide the design and interpretation of dose-finding studies in patients with renal dysfunction. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Supported by the American Lebanese Syrian Associated Charities. REFERENCES
1. Ramanathan RK, Egorin MJ, Takimoto CH, et al: Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: A study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 26:563-569, 2008 2. Gibbons J, Egorin MJ, Ramanathan RK, et al: Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: A study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 26:570-576, 2008 3. Judson IR: Imatinib for patients with liver or kidney dysfunction: No need to modify the dose. J Clin Oncol 26:521-522, 2008 4. Peng B, Lloyd P, Schran H: Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44:879-894, 2005[CrossRef][Medline] 5. Nolin TD, Naud J, Leblond FA, et al: Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin Pharmacol Ther 83:898-903, 2008[CrossRef][Medline] 6. Leblond FA, Petrucci M, Dube P, et al: Downregulation of intestinal cytochrome p450 in chronic renal failure. J Am Soc Nephrol 13:1579-1585, 2002 7. Leblond F, Guevin C, Demers C, et al: Downregulation of hepatic cytochrome P450 in chronic renal failure. J Am Soc Nephrol 12:326-332, 2001 8. Niwa T, Ise M: Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med 124:96-104, 1994[Medline] 9. Niwa T, Aiuchi T, Nakaya K, et al: Inhibition of mitochondrial respiration by furancarboxylic acid accumulated in uremic serum in its albumin-bound and non-dialyzable form. Clin Nephrol 39:92-96, 1993[Medline] 10. Lim CF, Bernard BF, de Jong M, et al: A furan fatty acid and indoxyl sulfate are the putative inhibitors of thyroxine hepatocyte transport in uremia. J Clin Endocrinol Metab 76:318-324, 1993[Abstract] 11. Henderson SJ, Lindup WE: Renal organic acid transport: Uptake by rat kidney slices of a furan dicarboxylic acid which inhibits plasma protein binding of acidic ligands in uremia. J Pharmacol Exp Ther 263:54-60, 1992 12. Sun H, Huang Y, Frassetto L, et al: Effects of uremic toxins on hepatic uptake and metabolism of erythromycin. Drug Metab Dispos 32:1239-1246, 2004 13. Hu S, Franke RM, Filipski KK, et al: Interaction of imatinib with human organic ion carriers. Clin Cancer Res 14:3141-3148, 2008 14. Smith NF, Acharya MR, Desai N, et al: Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biol Ther 4:815-818, 2005[Medline] 15. Gelderblom H, Verweij J, Brouwer E, et al: Disposition of [G-(3)H]paclitaxel and cremophor EL in a patient with severely impaired renal function. Drug Metab Dispos 27:1300-1305, 1999 16. Woo MH, Gregornik D, Shearer PD, et al: Pharmacokinetics of paclitaxel in an anephric patient. Cancer Chemother Pharmacol 43:92-96, 1999[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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