title: When barriers ignore the "rule-of-five".
abstract: Why are a few drugs with properties beyond the rule of 5 (bRo5) absorbed across the intestinal mucosa while most other bRo5 compounds are not? Are such exceptional bRo5 compounds exclusively taken up by carrier-mediated transport or are they able to permeate the lipid bilayer (passive lipoidal diffusion)? Our experimental data with liposomes indicate that tetracycline, which violates one rule of the Ro5, and rifampicin, violating three of the rules, significantly permeate a phospholipid bilayer with kinetics similar to labetalol and metoprolol, respectively. Published data from experimental work and molecular dynamics simulations suggest that the formation of intramolecular H-bonds and the possibility to adopt an elongated shape besides the presence of a significant fraction of net neutral species facilitate lipid bilayer permeation. As an alternative to lipid bilayer permeation, carrier proteins can be targeted to improve absorption, with the potential drawbacks of drug-drug interactions and non-linear pharmacokinetics.
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland. Electronic address: stefanie.kraemer@pharma.ethz.ch.
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Hélène E
authors.initials: HE
authors.lastname: Aschmann
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Hatibovic
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Katharina F
authors.initials: KF
authors.lastname: Hermann
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Neuhaus
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Cyrill
authors.initials: C
authors.lastname: Brunner
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Sara
authors.initials: S
authors.lastname: Belli
mesh_terms: D000818:Animals; D006801:Humans; D006860:Hydrogen Bonding; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007741:Labetalol / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism*; D008081:Liposomes; D008790:Metoprolol / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012293:Rifampin / Q000378:metabolism; D013752:Tetracycline / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D008081:Liposomes; D004364:Pharmaceutical Preparations; D013752:Tetracycline; D008790:Metoprolol; D007741:Labetalol; D012293:Rifampin
keywords: Absorption; Alprenolol (PubChem CID: 2119); Atenolol (PubChem CID: 2249); Beyond the rule of five; Charge; Cyclosporin A (PubChem CID: 5,284,373); Doxorubicin (PubChem CID: 31,703); Drug; Gentamicin (PubChem CID: 3467); Intramolecular H-bonds; Lipid bilayer; Metoprolol (PubChem CID: 4171); Permeation; Pindolol (PubChem CID: 4828); Rifampicin (PubChem CID: 5,381,226); Tetracycline (PubChem CID: 54,675,776); Valproic acid (PubChem CID: 3121)