When barriers ignore the “rule-of-five”

• Published in: Advanced drug delivery reviews 2016-06, Vol.101, p.62-74
• Main Authors: Krämer, Stefanie D., Aschmann, Hélène E., Hatibovic, Maja, Hermann, Katharina F., Neuhaus, Claudia S., Brunner, Cyrill, Belli, Sara
• Format: Article
• Language: English
• Subjects: Absorption; Animals; Beyond the rule of five; Charge; Drug; Humans; Hydrogen Bonding; Intestinal Absorption; Intestinal Mucosa - metabolism; Intramolecular H-bonds; Labetalol - metabolism; Lipid bilayer; Lipid Bilayers - metabolism; Liposomes; Metoprolol - metabolism; Molecular Dynamics Simulation; Permeation; Pharmaceutical Preparations - metabolism; Rifampin - metabolism; Tetracycline - metabolism
• ISSN: 0169-409X; 1872-8294
• DOI: 10.1016/j.addr.2016.02.001

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. [Display omitted]