On Quantitative Relationships Between Drug-Like Compound Lipophilicity and Plasma Free Fraction in Monkey and Human

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 (fP) and lipophilicity for low molecular weight nonacidic drug-like compounds. We measured the n-octanol-buffer distribution coefficients at pH 7.4 (mlogD) of 18 diverse radiotracers (<470 Da) used for brain imaging with positron emission tomography in vivo. Lipophilicities were also computed as clogD with two software packages. The fP values for monkeys and humans were determined by ultrafiltration and transformed into mlogDpr/pl values representing the log10 of the within phase partition of the radiotracers between plasma proteins and remaining plasma. mlogDpr/pl correlated strongly with mlogD for human (mlogDpr/pl = 0.733mlogD−0.780, r2 = 0.74) and monkey (mlogDpr/pl = 0.780mlogD−1.15, r2 = 0.83), but less strongly with clogD. These relationships were significantly different between species (P = 0.006). Removal of eight fluorinated compounds from the datasets raised r2 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 mlogD accounts for over 74% of compound mlogDpr/pl and is a strong determinant of fP.

Synthesis, F-18 radiolabeling, and microPET evaluation of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor

“…The octanol/aqueous buffer partition coefficients (log P 7.4 ) of [ 18 F] 26 - [ 18 F] 29 (Table 2) were measured by the shake-flask method as previously reported by Wilson and Houle, 104, 105 and were found to be between log P 7.4 = ~2.2 – 2.8 which is in the appropriate range for brain entry. 90, 91, 93 …”

“…Compounds [ 18 F] 1 and [ 123 I] 2 had limited aqueous solubility (20% EtOH in saline was required to dissolve the compounds), 80 and biological evaluation in rats showed very low brain uptake indicating that the compounds did not diffuse through the blood-brain barrier (BBB). 90-93 In vivo biodistribution studies with [ 76 Br] 3 in rats demonstrated brain penetrance, and in vitro autoradiography studies demonstrated specific binding. 82 Compounds [ 11 C] 6 , [ 11 C] 7 , and [ 11 C] 8 all penetrated the BBB of a baboon but did not display specific binding and were rapidly metabolized.…”

[ carbonyl - 11 C]4-Fluoro- N -methyl- N -(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([ 11 C]FIMX) is an effective radioligand for PET imaging of metabotropic glutamate receptor 1 (mGluR1) in monkey brain

“…The f P value increased to 0.042 ± 0.003 ( n = 3) under the pre-blocked condition. These f P values are in the range expected for a radioligand with a measured logD value of 3.27 [41]. …”

“…Knowledge of logD, as an index of lipophilicity, is useful, for example, for benchmarking the lipophilicities of radiometabolites. The logD of [ 11 C]FIMX was determined essentially by a previously described technique [41] based on distribution of the radioligand between 1-octanol and sodium phosphate buffer (0.15 M; pH 7.4), but with a correction for radioligand instability because it was found that [ 11 C]FIMX degraded in the buffer to 79.1 ± 3.3% ( n = 4) of its original radiochemical purity over 57 min at room temperature (Fig. 1).…”

“…The value for the distribution coefficient (logD) of [ 11 C]FIMX between 1-octanol and sodium phosphate buffer (0.15 M, pH 7.4) was determined essentially with a technique described previously [41], but with correction for radioligand instability in the buffer phase. For the purpose of measuring the degree of instability, formulated [ 11 C]FIMX solution was placed in sodium phosphate buffer (0.15 M; pH 7.4) for the duration of a logD determination, and reanalyzed by radio-HPLC on an X-Terra C18 column (10 μm; 7.8 × 300 mm; Waters Corp.) eluted with MeOH: H 2 O: Et 3 N (65: 35: 0.1 by vol.)…”