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Updated: May 26, 2026

A New Straightforward Method for Lipophilicity (logP) Measurement using 19F NMR Spectroscopy
Published on: January 30, 2019
On quantitative relationships between drug-like compound lipophilicity and plasma free fraction in monkey and human
Sami S Zoghbi1, Kacey B Anderson, Kimberly J Jenko
1Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. pikev@mail.nih.gov
Abstract:
Drug interactions with plasma proteins influence their pharmacokinetics and pharmacodynamics. We aimed to test whether a strong quantitative relationship exists between plasma free fraction (f(P) ) and lipophilicity for low molecular weight nonacidic drug-like compounds. We measured the n-octanol-buffer distribution coefficients at pH 7.4 ((m) logD) of 18 diverse radiotracers (<470 Da) used for brain imaging with positron emission tomography in vivo. Lipophilicities were also computed as (c) logD with two software packages. The f(P) values for monkeys and humans were determined by ultrafiltration and transformed into m logD(pr/pl) values representing the log(10) of the within phase partition of the radiotracers between plasma proteins and remaining plasma. (m) logD(pr/pl) correlated strongly with (m) logD for human ((m) logD(pr/pl) = 0.733(m) logD-0.780, r(2) = 0.74) and monkey ((m) logD(pr/pl) = 0.780(m) logD-1.15, r(2) = 0.83), but less strongly with (c) logD. These relationships were significantly different between species (P = 0.006). Removal of eight fluorinated compounds from the datasets raised r(2) to 0.81 and 0.91 for humans and monkeys, respectively. For the tested compounds, we conclude that n-octanol-buffer (pH 7.4) distribution strongly models that between plasma proteins and remaining plasma and moreover that (m) logD accounts for over 74% of compound (m) logD(pr/pl) and is a strong determinant of f(P).
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