Neuropharmacokinetics of two investigational compounds in rats: divergent temporal profiles in the brain and cerebrospinal fluid.

Two investigational compounds (FRM-1, (R)-7-fluoro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and FRM-2, (R)-7-cyano-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide) resided in rat brain longer than in systemic circulation. In Caco-2 directional transport studies, they both showed good intrinsic passive permeability but differed significantly in efflux susceptibility (efflux ratio of <2 and ∼7, respectively), largely attributed to P-glycoprotein (P-gp). Capitalizing on these interesting properties, we investigated how cerebrospinal fluid (CSF) concentration (CCSF) would be shaped by unbound plasma concentration (Cu,p) and unbound brain concentration (Cu,b) in disequilibrium conditions and at steady state. Following subcutaneous administration, FRM-1CCSF largely followed Cu,p initially and leveled between Cu,p and Cu,b. However, it gradually approached Cu,b and became lower than, but parallel to Cu,b at the terminal phase. In contrast, FRM-2CCSF temporal profile mostly paralleled the Cu,p but was at a much lower level. Upon intravenous infusion to steady state, FRM-1CCSF and Cu,b were similar, accounting for 61% and 69% of the Cu,p, indicating a case of largely passive diffusion-governed brain penetration where CCSF served as a good surrogate for Cu,b. On the contrary, FRM-2CCSF and Cu,b were remarkably lower than Cu,p (17% and 8% of Cu,p, respectively), suggesting that FRM-2 brain penetration was severely impaired by P-gp-mediated efflux and CCSF underestimated this impact. A semi-physiologically based pharmacokinetic (PBPK) model was constructed that adequately described the temporal profiles of the compounds in the plasma, brain and CSF. Our work provided some insight into the relative importance of blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) in modulating CCSF.

The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex) in a nonhuman primate model.

PURPOSE: Raltitrexed (Tomudex), ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model. METHODS: Animals received 3 mg/m(2) (n = 1), 6 mg/m(2) (n = 3), or 10 mg/m(2) (n = 3) i.v. over 15 min, and frequent plasma samples were obtained over 48 h. CSF samples were drawn from an indwelling 4th ventricular Ommaya reservoir over 48 h. Plasma and CSF raltitrexed concentrations were measured with a novel, sensitive enzyme inhibition assay with a lower limit of quantification of 0.005 microM. A three-compartment pharmacokinetic model was fitted to the raltitrexed plasma concentration-time data. RESULTS: The plasma concentration-time profile of raltitrexed was triexponential with a rapid initial decline and a prolonged terminal elimination phase (t(1/2) > 24 h), which was related to retention of raltitrexed in a deep tissue compartment. At the peak approximately 30% of the administered dose was in the deep tissue compartment, and 24 h after the dosing >20% of the administered dose remained in the body with >99% in the deep tissue compartment. The mean peak (end of infusion) plasma concentrations after the 3, 6, and 10 mg/m(2) doses were 1.5, 2.4 and 4.8 microM, respectively. The clearance of raltitrexed ranged from 110 to 165 ml/min per m(2), and the steady-state volume of distribution exceeded 200 l/m(2). The CSF penetration of raltitrexed was limited (0.6 to 2.0%) and drug could only be detected in the CSF following a 10 mg/m(2 )dose. CONCLUSIONS: The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans.