Intestinal Permeability of β-Lapachone and Its Cyclodextrin Complexes and Physical Mixtures

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 41; no. 6; pp. 795 - 806
• Main Authors: Mangas-Sanjuan, Victor, Gutiérrez-Nieto, Jorge, Echezarreta-López, Magdalena, González-Álvarez, Isabel, González-Álvarez, Marta, Casabó, Vicente-Germán, Bermejo, Marival, Landin, Mariana
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2016
• Subjects: Animals; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - metabolism; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family B - metabolism; beta-Cyclodextrins - chemistry; Biomedical and Life Sciences; Biomedicine; Cell Membrane Permeability; Dogs; Drug Compounding; Drug Liberation; Electric Impedance; Excipients - chemistry; Human Physiology; Intestinal Absorption; Intestinal Mucosa - metabolism; Intestine, Small - metabolism; Madin Darby Canine Kidney Cells; Medical Biochemistry; Methylation; Naphthoquinones - chemistry; Naphthoquinones - metabolism; Original Research Article; Perfusion; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Rats, Wistar; Recombinant Proteins - metabolism; Solubility; Cyclodextrin; Physical Mixture; Intestinal Permeability; Dissolution Rate; Inclusion Complex
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-015-0310-5

Background and objectives β-Lapachone (βLAP) is a promising, poorly soluble, antitumoral drug. βLAP combination with cyclodextrins (CDs) improves its solubility and dissolution but there is not enough information about the impact of cyclodextrins on βLAP intestinal permeability. The objectives of this work were to characterize βLAP intestinal permeability and to elucidate cyclodextrins effect on the dissolution properties and on the intestinal permeability. The final goal was to evaluate CDs influence on the oral absorption of βLAP. Methods Binary systems (physical mixtures and inclusion complexes) including βLAP and CDs (β-cyclodextrin: βCD, random-methyl-β-cyclodextrin: RMβCD and sulfobutylether-β-cyclodextrin: SBEβCD) have been prepared and analysed by differential scanning calorimetry. βLAP (and its combinations with CDs) absorption rate coefficients and effective permeability values have been determined in vitro in MDCK or MDCK-Mdr1 monolayers and in situ in rat by a closed loop perfusion technique. Results DSC results confirmed the formation of the inclusion complexes. βLAP–CDs inclusion complexes improve drug solubility and dissolution rate in comparison with physical mixtures. βLAP presented a high permeability value which can provide complete oral absorption. Its oral absorption is limited by its low solubility and dissolution rate. Cyclodextrin (both as physical mixtures and inclusion complexes) showed a positive effect on the intestinal permeability of βLAP. Complexation with CDs does not reduce βLAP intestinal permeability in spite of the potential negative effect of the reduction in free fraction of the drug. Conclusions The use of RMβCD or SBEβCD inclusion complexes could benefit βLAP oral absorption by enhancing its solubility, dissolution rate and permeability.