Molecular properties that influence the oral bioavailability of drug candidates
Abstract
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.
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In drug development, 500 Da is often quoted as the maximum molecular weight parameter, but molecules with higher molecular weights can be absorbed, and the limits of oral bioavailability appear to extend to about MW ≤ 1000 Da.
“In the development of new drugs, 500 Da is often quoted as the maximum molecular weight parameter. However, it has been observed that molecules with higher molecular weights are also capable of being absorbed, and the limits of oral bioavailability appear to extend to about MW ≤ 1000 Da [70,71,72].”
From The EU’s Per- and Polyfluoroalkyl Substances (PFAS) Ban: A Case of Policy over Science (2023) · cites this paper as [70]
The lipophilic nature and low polarity of sesquiterpenes render them bioavailable at specific sites.
“The lipophilic nature and low polarity of sesquiterpenes render them bioavailable at specific sites [105,153].”
From Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer’s Disease Therapy (2021) · cites this paper as [153]
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- Authors
- Veber, D. F., Johnson, S. R., Cheng, H.-Y., Smith, B. R., Ward, K. W., & Kopple, K. D.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Kopple, Kenneth D.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2002-05-11
- Volume
- 45
- Issue
- 12
- Pages
- 2615-2623
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2105649494
- Cited by
- 8,420
- References
- 30
- Citations by year
- 2026: 858 · 2025: 912 · 2024: 891 · 2023: 846 · 2022: 843 · 2021: 716 · 2020: 553 · 2019: 406 · 2018: 356 · 2017: 265 · 2016: 236 · 2015: 181 · 2014: 196 · 2013: 170 · 2012: 150
- FWCI
- 77.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- oral bioavailability, drug candidates, molecular properties, rotatable bonds, polar surface area, molecular weight, molecular weight cut-off, lipophilicity, in vivo clearance, rat pharmacokinetics, structure-activity relationship
- MeSH terms
- Administration, Oral, Animals, Biological Availability, Humans, Hydrogen Bonding, Lipid Bilayers, Male, Microsomes, Liver, Molecular Weight, Permeability, Pharmacokinetics, Structure-Activity Relationship, Molecular Structure, Databases, Factual, Rats, Sprague-Dawley, Cross-Over Studies, Rats, In Vitro Techniques
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