Drug distribution blood-cerebrospinal fluid barrier

The steady-state volume of distribution following IV administration of a 1.5 mg dose averaged 0.534 L/kg. Cerebrospinal fluid obtained from 9 patients at 2 to 3.5 hours following 0.06 or 0.09 mg/kg IV infusion showed measurable concentrations of zalcitabine. The CSFiplasma concentration ratio ranged from 9% to 37% (mean, 20%), demonstrating drug penetration through the blood-brain barrier. 

Further studies have validated this hypothesis, in part,4 and ultimately this inventive premise was borne out in clinical practice. As a result, 5-FU (5) was eventually approved for treatment of solid tumors, such as breast, colorectal, and gastric cancers. Marketed as Adrucil when administered intravenously, 5-FU can be used either as monotherapy or combination therapy with various cytotoxic drugs and biochemical modulators, such as leucovorin and methotrexate.5 Because 5-fluorouracil is not orally bioavailable, it must be administered by continuous infusion to optimize its efficacy due to its short half-life in plasma. In addition, 5-FU has poor selectivity toward tumors in vivo, and its distribution into tissues such as bone marrow, the gastrointestinal tract, the liver and skin causes high incidences of toxicity. In addition, in spite of its limited lipid solubility, 5-fluorouracil diffuses readily across the blood-brain barrier into cerebrospinal fluid and brain tissue.1,5... 

Injection directly into the cerebrospinal fluid (CFS) ensures complete CNS bioavailability for drugs that cannot cross the blood-brain barrier. This dosage route is used to treat serious CNS infections such as meningitis and ventriculitis, and with such agents as mepivacaine and prilocaine for spinal anesthesia. Drugs injected intrathecally initially distribute into approximately 140 ml of CSF, thus producing high concentrations in the CNS with low risk of systemic toxicity. 

Kaddoumi, A., Choi, S.U., Kinman, L., Whittington, E., Tsai, C.C., Ho, R.J., Anderson, B.D., and Unadkat, J.D. (2007) Inhibition of P-glycoprotein activity at the primate blood-brain barrier increases the distribution of nelflnavir into the brain but not into the cerebrospinal fluid. Drug Metabolism and Disposition, 35, 1459-1462. 

After an IV dose, streptozocin and its metabolites distribute mainly into the liver, kidneys, intestines, and pancreas. The drug has not been shown to cross the blood-brain barrier however, its metabolites achieve concentrations in the cerebrospinal fluid equivalent to the concentration in the plasma. 

The unbound drug in the systemic circulation is available to distribute extravascularly. The extent of distribution is mainly determined by lipid solubility and, for weak organic acids and bases, is influenced by the pK3/pH-dependent degree of ionization because only the more lipid-soluble non-ionized form can passively diffuse through cell membranes and penetrate cellular barriers such as those which separate blood from transcellular fluids (cerebrospinal and synovial fluids and aqueous humour). The milk-to-plasma equilibrium concentration ratio of an antimicrobial agent provides a reasonably... 

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