Molecular properties that influence the oral bioavailability of drug candidates.
Oral bioavailability measurements in rats for over 1100 drug candidates studied at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) have allowed us to analyze the relative importance of molecular properties considered to influence that drug property. Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of molecular weight. That on average both the number of rotatable bonds and polar surface area or hydrogen bond count tend to increase with molecular weight may in part explain the success of the molecular weight parameter in predicting oral bioavailability. The commonly applied molecular weight cutoff at 500 does not itself significantly separate compounds with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compounds which meet only the two criteria of (1) 10 or fewer rotatable bonds and (2) polar surface area equal to or less than 140 A(2) (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailability in the rat. Data sets for the artificial membrane permeation rate and for clearance in the rat were also examined. Reduced polar surface area correlates better with increased permeation rate than does lipophilicity (C log P), and increased rotatable bond count has a negative effect on the permeation rate. A threshold permeation rate is a prerequisite of oral bioavailability. The rotatable bond count does not correlate with the data examined here for the in vivo clearance rate in the rat.
Veber
Daniel F
DF
Department of Medicinal Chemistry, GlaxoSmithKline, 709 Swedeland Road, P. O. Box 1539, King of Prussia, PA 19406-0939, USA. veberdf@comcast.net
Johnson
Stephen R
SR
Cheng
Hung-Yuan
HY
Smith
Brian R
BR
Ward
Keith W
KW
Kopple
Kenneth D
KD
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018592:Cross-Over Studies; D016208:Databases, Factual; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008051:Lipid Bilayers; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D008970:Molecular Weight; D010539:Permeability; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D008051:Lipid Bilayers