Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure

Pharmaceutical Research
Ken-ichi FujitaYukio Kato

Abstract

Delayed plasma concentration profiles of the active irinotecan metabolite SN-38 were observed in cancer patients with severe renal failure (SRF), even though SN-38 is eliminated mainly via the liver. Here, we examined the plasma concentrations of unbound SN-38 in such patients. Plasma unbound concentrations were examined by ultrafiltration. Physiologically-based pharmacokinetic (PBPK) models of irinotecan and SN-38 were established to quantitatively assess the principal mechanism for delayed SN-38 elimination. The area under the plasma unbound concentration-time curve (AUC(u)) of SN-38 in SRF patients was 4.38-fold higher than that in normal kidney patients. The unbound fraction of SN-38 was also 2.6-fold higher in such patients, partly because SN-38 protein binding was displaced by the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). This result was supported by correlation of the unbound fraction of SN-38 with the plasma CMPF concentration, which negatively correlated with renal function. PBPK modeling indicated substantially reduced influx of SN-38 into hepatocytes and approximately one-third irinotecan dose for SRF patients to produce an unbound concentration profile of SN-38 similar to normal kidney patie...Continue Reading

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Citations

Mar 28, 2017·British Journal of Clinical Pharmacology·Dirk KropeitHelga Rübsamen-Schaeff
Sep 15, 2017·Expert Review of Clinical Pharmacology·Alexander J Prokopienko, Thomas D Nolin
May 29, 2020·Pharmacotherapy·Stephanie A FlowersJames C Lee
May 26, 2017·Expert Opinion on Drug Metabolism & Toxicology·Nicolas Janus, Vincent Launay-Vacher
Sep 1, 2017·Clinical and Experimental Nephrology·Shigeo HorieSatoru Muto
Nov 7, 2017·NPJ Biofilms and Microbiomes·Leah GuthrieLibusha Kelly
Jun 5, 2021·Materials Science & Engineering. C, Materials for Biological Applications·Nidhi RavalRakesh K Tekade

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