Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration.
This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (C(u,plasma)) to predict brain unbound concentration (C(u,brain)). The concentration-time profiles in CSF, plasma, and brain of seven model compounds were determined after subcutaneous administration in rats. The C(u,brain) was estimated from the product of total brain concentrations and unbound fractions, which were determined using brain tissue slice and brain homogenate methods. For theobromine, theophylline, caffeine, fluoxetine, and propranolol, which represent rapid brain penetration compounds with a simple diffusion mechanism, the ratios of the area under the curve of C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) were 0.27 to 1.5 and 0.29 to 2.1, respectively, using the brain slice method, and were 0.27 to 2.9 and 0.36 to 3.9, respectively, using the brain homogenate method. A P-glycoprotein substrate, CP-141938 (methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.57 and 0.066, using the brain slice method, and 1.1 and 0.13, using the brain homogenate method, respectively. The slow brain-penetrating compound, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl-]sarcosine, had C(u,brain)/C(CSF) and C(u,brain)/C(u,plasma) ratios of 0.94 and 0.12 using the brain slice method and 0.15 and 0.018 using the brain homogenate method, respectively. Therefore, for quick brain penetration with simple diffusion mechanism compounds, C(CSF) and C(u,plasma) represent C(u,brain) equally well; for efflux substrates or slow brain penetration compounds, C(CSF) appears to be equivalent to or more accurate than C(u,plasma) to represent C(u,brain). Thus, we hypothesize that C(CSF) is equivalent to or better than C(u,plasma) to predict C(u,brain). This hypothesis is supported by the literature data.
Liu
Xingrong
X
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, CT, USA. xingrong.liu@roche.com
Smith
Bill J
BJ
Chen
Cuiping
C
Callegari
Ernesto
E
Becker
Stacey L
SL
Chen
Xi
X
Cianfrogna
Julie
J
Doran
Angela C
AC
Doran
Shawn D
SD
Gibbs
John P
JP
Hosea
Natilie
N
Liu
Jianhua
J
Nelson
Frederick R
FR
Szewc
Mark A
MA
Van Deusen
Jeffrey
J
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005473:Fluoxetine / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013805:Theobromine / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D013806:Theophylline / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics
D005473:Fluoxetine; D013806:Theophylline; D013805:Theobromine