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

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2015 Sep 5

PMID 26337772

Citations 17

Authors

Ken-Ichi Fujita

Yusuke Masuo

Hidenori Okumura

Yusuke Watanabe

Hiromichi Suzuki

Yu Sunakawa

Ken Shimada

Kaori Kawara

Yuko Akiyama

Masanori Kitamura

Munetaka Kunishima

Yasutsuna Sasaki

Yukio Kato

Affiliations

Soon will be listed here.

Abstract

Purpose: 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.

Methods: 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.

Results: 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 patients.

Conclusion: The AUC(u) of SN-38 in SRF cancer patients is much greater than that of normal kidney patients primarily because of the reduced hepatic uptake of SN-38.

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