Quantitative Prediction of P-Glycoprotein-Mediated Intestinal Absorption for Molecules Beyond the Rule of Five Using Model Animals

概要

Since it was first formulated in 1997, Lipinski's rule of five (Ro5)(7) has been widely
proposed as a qualitative predictive model for characterizing oral absorption trends. The
Ro5 outlined that 90% of oral drugs in use at that time obeyed three out of four of the
following guidelines: molecular weight (MW) ≤ 500 Da, cLogP ≤ 5, H-bond donors
(HBD) ≤ 5, and H-bond acceptors (HBA) ≤ 10 (7, 8). By contrast, in drug discovery
today, difficult targets with large and flat binding sites are often better suited to
molecules beyond the rule of 5 (bRo5) (8). Consequently, the trend of drug discovery in
chemistry has shifted from Ro5 molecules to bRo5 molecules such as cyclic peptides.
However, increased MW is known to be correlated with decreased solubility, decreased
permeability, and increased transporter-mediated efflux (8). Thus, bRo5 molecules tend
to have poor pharmacokinetics, such as low bioavailability.
ATP-binding cassette (ABC) transporters are membrane-embedded proteins that
mediate the uptake or export of an enormous variety of substrates via an active
energy-dependent mechanism. Drug efflux transporters of the ABC family limit the
intracellular concentration of substrate agents by pumping them out of cells.
P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) are important drug
efflux transporters located in the apical domain of the enterocyte of the lower
gastro-intestinal tract, thereby limiting the absorption of drug substrates from the
gastro-intestinal tract (9).
Transporter gene knockout models can provide useful information for understanding
transporter-limited or transporter-mediated drug absorption, distribution, and excretion
(10). Pharmacokinetic data obtained from studies using transporter knockout models are
helpful for determining the impact of transporters in both pre-clinical compound
selection and clinical compound-selection. Thus far, there have been many studies on
transporter-mediated disposition using transporter gene knockout mice and rats (11).
Transporter gene knockout rats, in particular, are a useful tool for pharmacokinetic
studies for several reasons: first, rats have sufficient blood volume and other relevant
bodily fluids for ease of surgical operation. Secondly, rats can be used to predict oral
drug absorption in the human small intestine because of their similar drug intestinal
absorption profiles and transporter expression patterns (12). Thirdly, there have been
several reports on SAGE Mdr1a and Bcrp knockout rats that demonstrate modest
compensatory changes in gene expression and overall pathology (13) as well as the
absorption, distribution, metabolism, and excretion (ADME) of various transporter
substrates (14-17). While P-gp knockout mice may be more widely used to evaluate
pharmacokinetics, their compensatory changes in gene expression and pathology have
not been reported.
To the best of our knowledge, many bRo5 molecules (MW > 700 Da) launched on the
market to date are substrates for efflux transporters. The purpose of this study was to
evaluate in vivo the impact of efflux transporters on the oral absorption and systemic
clearance of bRo5 molecules using rats which lack P-gp and/or Bcrp expression. ...

この論文で使われている画像