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Transport Characteristics of L-Carnosine and the Anticancer Derivative 4-Toluenesulfonylureido-Carnosine in a Human Epithelial Cell Line

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Abstract

Purpose. The aim of the present study was to evaluate whether the transepithelial transport of the anticancer compound 4-toluenesulfonylureido-carnosine (Ts-carnosine) and the dipeptide moiety L-carnosine was due to a hPepT1 carrier-mediated flux.

Methods. Transport experiments were conducted using Caco-2 cell monolayers and either reversed-phase HPLC-UV or liquid scintillation counting methods for quantification. pKa, LogD, and LogP were determined using the Sirius GlpKa meter.

Results. L-carnosine was transported across the apical membrane with a Km,app of 2.48 ± 1.16 mM and a Vmax of 2.08 ± 0.34 nmol · cm−2 · min−1 and across the basolateral membrane with a Km,app of 7.21 ± 3.17 mM and a Vmax of 0.54 ± 0.10 nmol · cm−2 · min−1, and transepithelially with a Papp of 4.46 · 10−2 ± 6.4 · 10−6 cm · min−10. Ts-carnosine had an affinity (Ki) for hPepT1 of 2.33 ± 0.54 mM; however, the transepithelial transport was low as compared to that of L-carnosine.

Conclusions. L-carnosine was transported across both the apical and basolateral membrane of Caco-2 cell monolayers in a carrier-mediated manner however, the transepithelial transport followed apparent simple non-saturable kinetics. Ts-carnosine had an affinity for hPepT1 but a relatively low transepithelial transport. This indicates that the transepithelial transport of L-carnosine and Ts-carnosine is not hPepT1 carrier-mediated and that L-carnosine is not a suitable dipeptide moiety for hPepT1-mediated absorption of sulfonamide-type anticancer compounds.

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Authors and Affiliations

  1. Department of Pharmaceutics, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Carsten Uhd Nielsen, Sven Frokjaer, Bente Steffansen & Birger Brodin

  2. Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Università degli Studi, Via della Lastruccia, 3, Polo Scientifico, 50019, Sesto Fiorentino, Florence, Italy

    Claudiu T. Supuran & Andrea Scozzafava

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Nielsen, C.U., Supuran, C.T., Scozzafava, A. et al. Transport Characteristics of L-Carnosine and the Anticancer Derivative 4-Toluenesulfonylureido-Carnosine in a Human Epithelial Cell Line. Pharm Res 19, 1337–1344 (2002). https://doi.org/10.1023/A:1020306926419

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