LIPOPHILICITY AT PH 7.4 AND MOLECULAR-SIZE GOVERN THE ENTRY OF THE FREE SERUM FRACTION OF DRUGS INTO THE CEREBROSPINAL-FLUID IN HUMANS WITH UNINFLAMED MENINGES

Physicochemical properties of drugs were related to their ability to enter the cerebrospinal fluid (CSF) in humans by reevaluation of previously reported studies. Either the quotients of the drug concentrations in CSF and serum at steady state (C(CSF)ss/C(S)ss) or, since in most cases CSF passage was studied after a short-term infusion, the ratios of the areas under the concentration-time curves in CSP and serum (AUC(CSF)/AUC(S)) were taken as measures of CSF passage. AUC(S) and C(S)ss were corrected for binding to serum proteins (AUC(S)f, C(S)ssf). Of the drugs studied the quotient of the octanol/water partition coefficient at pH 7.4 (PC) as a measure of lipophilicity and the square root of the molecular weight (MW(1/2)) correlated with AUC(CSF)/AUC(S) (Spearman's rank correlation coefficient r(S) = 0.78, P < 0.01) and with AUC(CSF)/AUC(S)f (r(S) = 0.90, P < 0.01). PC.MW(-1/2) was related to AUC(CSF)/AUC(S)f (or C(CSF)ss/C(S)ssf, respectively) by the equation: AUC(CSF)/AUC(S)f = 0.96 + 0.091 In(PC MW(-1/2)). For 0.0001 less than or equal to PC MW(-1/2) less than or equal to 1.0 this function may be of value for the prediction of CSF penetration in humans when the physicochemical properties of a drug are known and when active transport or metabolism are negligible.