Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues

Version 1 : Received: 12 May 2021 / Approved: 20 May 2021 / Online: 20 May 2021 (10:52:33 CEST)

A peer-reviewed article of this Preprint also exists.

Almeida, A.; Fernandes, E.; Sarmento, B.; Lúcio, M. A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues. Pharmaceutics 2021, 13, 869. Almeida, A.; Fernandes, E.; Sarmento, B.; Lúcio, M. A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues. Pharmaceutics 2021, 13, 869.

Journal reference: Pharmaceutics 2021, 13, 869
DOI: 10.3390/pharmaceutics13060869

Abstract

Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood-brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS=5.75 ± 0.932 L·Kg-1) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.

Subject Areas

camptothecin; drug distribution; drug-membrane interaction; biophysical profiling; biomimetic models; partition coefficient; ADMET/PK prediction; small and wide-angle X-ray diffraction; fluorescence spectroscopy; human serum albumin (HSA)

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