Abstract
In the clinical setting, drug concentrations in cerebrospinal fluid (CSF) are sometimes used as a surrogate for drug concentrations at the target site within the brain. However, the brain consists of multiple compartments and many factors are involved in the transport of drugs from plasma into the brain and the distribution within the brain. In particular, active transport processes at the level of the blood-brain barrier and blood-CSF barrier, such as those mediated by P-glycoprotein, may lead to complex relationships between concentrations in plasma, ventricular and lumbar CSF, and other brain compartments. Therefore, CSF concentrations may be difficult to interpret and may have limited value. Pharmacokinetic data obtained by intracerebral microdialysis monitoring may be used instead, providing more valuable information. As non-invasive alternative techniques, positron emission tomography or magnetic resonance spectroscopy may be of added value.
Similar content being viewed by others
References
Collins JM, Dedrick LD. Distributed model for drag delivery to CSF and brain tissue. Am J Physiol 1983; 14: R303–10
Kandel E, Schwartz J. Principles of neural sciences. 2nd ed. New York: McGraw Hill, 1985: 840
Abott NJ, Revest PA. Control of brain endothelial permeability. Cerebrovasc Brain Metab Rev 1991; 3: 39–72
Bodor N, Brewster ME. Problems of drug delivery of drugs to the brain. Pharmacol Ther 1983; 19: 337–86
Comford EM. The blood-brain barrier, a dynamic regulatory interface. Mol Physiol 1985; 7: 219–60
Pardridge WM. Recent advances in blood-brain barrier transport. Annu Rev Pharmacol Toxicol 1988; 28: 25–39
Rubin LL, Staddon JM. The cell biology of the blood-brain barrier. Annu Rev Neurosci 1999; 22: 11–28
Vorbrodt AW. Ultrastructural cytochemistry of blood-brain barrier endothelia. Prog Histochem Cytochem 1988; 18: 1–99
Cserr HF. Physiology of the choroid plexus. Physiol Rev 1971; 51: 273–311
Davson H, Segal MB. Physiology of the CSF and blood-brain barriers. Boca Raton (FL): CRC Press, 1996
Meller K. Ultrastructural aspects of the choroid plexus epithelium as revealed by rapid-freezing and deep etching techniques. Cell Tissue Res 1985; 239: 189–201
Mihorat TH. Structure and function of the choroid plexus and other sites of cerebrospinal fluid formation. Int Rev Cytol 1976; 47: 225–89
Spector R, Johanson CE. The mammalian choroid plexus. Sci Am 1989; 261: 68–74
Gross PM, Sposito NM, Pettersen SE, et al. Differences in function and structure of the capillary endothelium in gray matter, white matter, and a circumventricular organ of rat brain. Blood Vessels 1886; 23: 261–70
Levin VA. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 1980; 23: 682–4
Oldendorf WH. Lipid solubility and drug penetration of the blood-brain barrier. Proc Exp Biol Med 1974; 14: 813–6
Oldendorf WH. Measurement of brain uptake of radiolabelled substances using a tritiated water internal standard. Brain Res 1970; 24: 372–6
Fenstermacher JD, Wei L, Acuff V, et al. The dependency of influx across the blood-brain barrier on blood flow and the apparent flow-independence of glucose influx during stress. In: Greenwood J, Begley DJ, Segal MB, et al., editors. New concepts of a blood-brain barrier. New York: Plenum Press, 1995: 89–101
Rowley M, Kulagowski JJ, Watt AP, et al. Effect of plasma protein binding on in vivo activity and brain penetration of glycine/NMDA receptor antagonists. J Med Chem 1997; 40: 4053–68
Robinson PJ, Rapoport SI. Kinetics of protein binding determine rates of uptake of drugs by brain. Am J Physiol 1986; 251: R1212–20
Cox EH, Kerbusch T, van der Graaf PH, et al. Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of synthetic opioids in the rat. Correlation with binding at the μ-opioid receptor. J Pharmacol Exp Ther 1998; 284: 1095–103
Kim KS, Wass CA, Cross AS. Blood-brain barrier permeability during the development of experimental bacterial meningitis in the rat. Exp Neurol 1997; 145: 253–7
Mandema JW, Danhof M. EEG effect measures and relationships between pharmacokinetics and pharmacodynamics of psychotropic drugs [thesis]. The Netherlands: Leiden, Division of Pharmacology, Center for Biopharmaceutical Sciences, 1991
Cornford EM, Young D, Paxton JW, et al. Blood-brain barrier penetration of felbamate. Epilepsia 1992; 33: 944–54
Jolliet P, Simon N, Bree F, et al. Blood-to-brain transfer of various oxicams: effects of plasma binding on their brain delivery. Pharm Res 1997; 14: 650–6
Lin TH, Sawada Y, Sugiyama Y, et al. Effects of albumin and alpha 1-acid glycoprotein on the transport of imipramine and desipramine through the blood-brain barrier in rats. Chem Pharm Bull (Tokyo) 1987; 35: 294–301
Lolin YI, Ratnaraj N, Hjelm M, et al. Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid. Epilepsy Res 1994; 19: 99–110
Tanaka H, Mizojiri K. Drug-protein binding and blood-brain barrier permeability. J Pharmacol Exp Ther 1999; 288: 912–8
Urien S, Pinquier JL, Paquette B, et al. Effect of the binding of isradipine and darodipine to different plasma proteins on their transfer through the blood-brain barrier. J Pharmacol Exp Ther 1987; 242: 349–53
Pardridge WM, Sakiyama R, Fierer G. Transport of propanolol and lidocaine through the rat blood-brain barrier. Primary role of globulin-bound drug. J Clin Invest 1983; 71: 900–8
Cserr HF. Convection of brain interstitial fluid. In: Shapiro K, Marmarou A, editor. Hydrocephalus. New York: Raven Press, 1984: 59–68
Segal MB. The blood-CSF barrier and the choroid plexus. In: Pardridge WM, editor. Introduction to the blood-brain barrier: methodology, biology and pathology. Cambridge: Cambridge University Press, 1998: 251–8
Atack JR, Rapoport SI, Shapiro MB. Cerebrospinal fluid production is normal in Down Syndrome. Neurobiol Aging 1998; 19: 307–9
Williams SA, Davson H, Segal MB. Transport of the nucleoside thymidine, in the central nervous system: the blood-cerebrospinal fluid and blood-brain barriers. In: Greenwood J, Begley DJ, Segal MB, editors. New concepts of a blood-brain barrier. New York: Plenum Press, 1995: 175–87
Bruni JE. Ependymal development, proliferation, and functions: a review. Microsc Res Tech 1998; 41: 2–13
Del Bigio MR. The ependyma: a protective barrier between brain and cerebrospinal fluid. Glia 1995; 14: 1–13
Fenstermacher JD, Patlak CS, Blasberg RG. Transport of material between brain extracellular fluid, brain cells and blood. Fed Proc 1974; 33: 2070–4
Fenstermacher JD, Rall DP, Patlak CS, et al. Ventricular perfusion as a technique for analysis of brain capillary permeability and extracellular transport. In: Crone C, Lassen N, editors. Capillary permeability. Copenhagen: Munksgaard, 1970: 483–90
Malhotra BK, Lemaire M, Sawchuk RJ. Investigation of the distribution of EAB 515 to cortical ECF and CSF in freely moving rats utilizing microdialysis. Pharm Res 1994; 11: 1223–31
Aird RB. A study of intrathecal, cerebrospinal fluid-to-brain exchange. Exp Neurol 1984; 86: 342–58
Blasberg RG, Patlak CS, Fenstermacher JD, et al. Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther 1975; 195: 73–83
De Lange ECM, Danhof M, De Boer AG, et al. Critical factors of intracerebral microdialysis as a technique to determine the pharmacokinetics of drugs in rat brain. Brain Res 1994; 666: 1–8
Patlak CS, Fenstermacher JD. Measurements of dog blood-brain transfer constants by ventriculocisternal perfusion. Am J Physiol 1975; 229: 877–84
De Lange ECM, Bouw MR, Danhof M, et al. Application of intracerebral microdialysis to study regional distribution kinetics of drugs in rat brain. Br J Pharmacol 1995; 116: 538–2544
Baker SD, Heideman RL, Crom WR, et al. Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 1996; 37: 195–202
Balis FM, Blaney SM, McCully CL, et al. Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration. Cancer Chemother Pharmacol 2000; 45: 259–64
Blaney SM, Daniel MJ, Harker AJ, et al. Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates. Antimicrob Agents Chemother 1995; 39: 2779–82
Freund M, Adwan M, Kooijman H, et al. Quantitative analysis of spinal CSF dynamics using magnetic resonance imaging: experimental and clinical studies. Rofo Fortschritte Geb Rontgenstr Bild Verfahren 2001; 173: 306–14
Kawakami J, Yamamoto K, Sawada Y, et al. Prediction of brain delivery of ofloxacin, a new quinolone, in the human from animal data. J Pharmacokinet Biopharm 1994; 22: 207–27
Marsala M, Malmberg AB, Yaksh TL. The spinal loop dialysis catheter: characterization of use in the unanesthetized rat. J Neurosci Methods 1995; 62: 43–53
Morikawa N, Mori T, Kawashima H, et al. Pharmacokinetics of anticancer drugs in cerebrospinal fluid. Ann Pharmacother 1998; 32: 1008–12
Falkenstein E, Tillmann HC, Christ M, et al. Multiple actions of steroid hormones: a focus on rapid, nongenomic effects. Pharmacol Rev 2000; 52: 513–55
Gottesman MM. Report of a meeting: molecular basis of cancer therapy. J Natl Cancer Inst 1994; 86: 1277–85
Fletcher CV. Pharmacologic considerations for therapeutic success with antiretroviral agents. Ann Pharmacother 1999; 33: 989–95
Peter K, Gambertoglio JG. Intracellular phosphorylation of zidovudine (ZDV) and other nucleoside reverse transcriptase inhibitors (RTI) used for human immunodeficiency virus (HIV) infection. Pharm Res 1998; 15: 819–25
De Lange ECM, Danhof M, De Boer AG, et al. Methodological considerations of intracerebral microdialysis in pharmacokinetic studies on blood-brain barrier transport of drugs. Brain Res Brain Res Rev 1997; 25: 27–49
Muller M. Microdialysis in clinical drug delivery studies. Adv Drug Deliv Rev 2000; 45: 255–69
De Lange EC, de Bock G, Schinkel AH, et al. BBB transport and P-glycoprotein functionality using MDR1A (-/-) and wild-type mice. Total brain versus microdialysis concentration profiles of rhodamine-123. Pharm Res 1998; 15: 1657–65
Hammarlund-Udenaes M, Paalzow LN, De Lange ECM. Drug equilibration across the blood-brain barrier-pharmacokinetic considerations based on the microdialysis method. Pharm Res 1997; 14: 128–34
Hammarlund-Udenaes M. The use of microdialysis in CNS drug delivery studies. Pharmacokinetic perspectives and results with analgesics and antiepileptics. Adv Drug Deliv Rev 2000; 45: 283–94
Sawchuk RJ, Elmquist WF. Microdialysis in the study of drug transporters in the CNS. Adv Drug Deliv Rev 2000; 45: 295–306
Wang YF, Welty DF. The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm Res 1996; 13: 398–403
Xie R, Hammarlund-Udenaes M, de Boer AG, et al. The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice. Br J Pharmacol 1999; 128: 563–8
Kerr IG, Zimm S, Collins JM, et al. Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey. Cancer Res 1984; 44: 4929–32
Ghersi-Egea JF, Minn A, Siest G. A new aspect of the protective functions of the blood-brain barrier; activities of four drug metabolizing enzymes in isolated brain microvessels. Life Sci 1998; 42: 2515–23
Ghersi-Egea JF, Leininger-Muller B, Suleman G, et al. Localization of drug-metabolizing enzyme activities to blood-brain interfaces and circumventricular organs. J Neurochem 1994; 62: 1089–96
Ghersi-Egea JF, Strazielle N. Brain drug delivery, drug metabolism, and multidrug resistance at the choroid plexus. Microsc Res Tech 2001; 52: 83–8
Johnson JA, Barbary A, Kornguth SE, et al. Glutathion S-transferase isoenzymes in rat brain neurons and glia. J Neurosci 1993; 13: 2013–23
Tayarani I, Cloez I, Clement M, et al. Antioxidant enzymes and related trace elements in aging brain capillaries and choroid plexus. J Neurochem 1989; 53: 817–24
Volk B, Hettmansperger U, Papp TH, et al. Mapping of phenytoin-inducible cytochrome P450 immunoreactivity in the mouse central nervous system. Neuroscience 1991; 42: 215–35
Kurata N, Inagaki M, Iwase M, et al. Pharmacokinetic study of trimethadione and its metabolite in blood, liver and brain by microdialysis in conscious, unrestrained rats. Res Commun Mol Pathol Pharmacol 1995; 89: 45–56
Banks WA. Physiology and pathology of the blood-brain barrier: implications for microbial pathogenesis, drug delivery and neurodegenerative disorders. J Neurovirol 1999; 5: 538–55
De Vries HE, Kuiper J, de Boer AG, et al. The role of the blood-brain barrier in neuro-inflammatory diseases. Pharmacol Rev 1997; 49: 143–56
Kramer K, Kushner B, Heller G, et al. Neuroblastoma metastatic to the central nervous system: The Memorial Sloan-Kettering Cancer Center experience and a literature review. Cancer 2001; 91: 1510–9
Brosman CF, Claudio L. Brain microvasculature in multiple sclerosis. In: Pardridge WM, editor. Introduction to the blood-brain barrier; methodology, biology and pathology. Cambridge: Cambridge University Press, 1998: 386–400
Filippi M, Rovaris M. Magnetisation transfer imaging in multiple sclerosis. J Neurovirol 2000; 6: S115–20
Johansson BB. Hypertension. In: Pardridge WM, editor. Introduction to the blood-brain barrier; methodology, biology and pathology. Cambridge: Cambridge University Press, 1998: 427–33
Nottet HSLM. Interactions between macrophages and brain microvascular endothelial cells: role in pathogenesis of HIV-1 infection and blood-brain barrier function. J Neurovirol 1999; 5: 659–69
Petito CK. HIV infection and the blood-brain barrier. In: Pardridge WM, editor. Introduction to the blood-brain barrier: methodology, biology and pathology. Cambridge: Cambridge University Press, 1998: 419–26
Povlishock JT. The pathophysiology of blood-brain barrier dysfunction due to traumatic brain injury. In: Pardridge WM, editor. Introduction to the blood-brain barrier; methodology, biology and pathology. Cambridge: Cambridge University Press, 1998: 441–53
De Lange ECM, De Vries JD, Zurcher C, et al. The use of intracerebral microdialysis for the determination of pharmacokinetic profiles of anticancer drugs in tumor-bearing rat brain. Pharm Res 1995; 12: 1924–31
Shapiro WR, Shapiro JR. Principles of brain tumor chemotherapy. Semin Oncol 1986; 13: 56–69
Suzuki H, Terasaki T, Sugiyama Y. Role of efflux transport across the blood-brain barrier and blood-cerebrospinal fluid barrier on the disposition of xenobiotics in the central nervous system. Adv Drug Deliv Rev 1997; 25: 257–85
Vajkoczy P, Menger MD. Vascular microenvironment in gliomas. J Neuro-Oncol 2000; 50: 99–108
Steward PA, Mikulis D. The blood-brain barrier in brain tumours. In: Pardridge WM, editor. Introduction to the blood-brain barrier; methodology, biology and pathology. Cambridge: Cambridge University Press, 1998: 434–40
Turner G. Cerebral malaria and brain microvasculature. In: Pardridge WM, editor. Introduction to the blood-brain barrier; methodology, biology and pathology. Cambridge: Cambridge University Press, 1998: 454–61
Bolwig TG, Hertz MM, Paulson OB, et al. The permeability of the blood-brain barrier during electrically induced seizures in man. Eur J Clin Invest 1977; 7: 87–93
Nitsch C, Klatzo I. Regional patterns of blood-brain barrier breakdown during epileptiform seizures induced by various convulsive agents. J Neurol Sci 1983; 59: 305–22
Petito CK, Schaefer JA, Plum F. Ultrastructural characteristics of the brain and blood-brain barrier in experimental seizures. Brain Res 1977; 127: 251–67
Mayhan WG. Regulation of blood-brain barrier permeability. Microcirculation 2001; 8: 89–104
Modai J. Diffusion of 3-quaternary ammonium cephem antibiotics into cerebrospinal fluid of patients with bacterial meningitis. J Chemother 1996; 8: 83–90
Spellerberg B, Tuomanen EI. The pathophysiology of pneumococcal meningitis. Ann Med 1994; 26: 411–8
Bouw R, Ederoth P, Lundberg J, et al. Increased blood-brain barrier permeability of morphine in a patient with severe brain lesions as determined by microdialysis. Acta Anaesthesiol Scand 2001; 45: 390–2
Angeletti RH, Novikoff PM, Juvvadi SR, et al. The choroid plexus epithelium is the site of the organic anion transport protein in the brain. Proc Natl Acad Sci U S A 1997; 94: 283–6
Cordon-Cardo B, O’Brien JP, Casals D, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989; 86: 689–95
Gao B, Meier PJ. Organic anion transport across the choroid plexus. Microsc Res Tech 2001; 52: 60–4
Nishino J. Transepithelial transport of organic anions across the choroid plexus: possible involvement of organic anion transporter and multidrug resistance-associated protein. J Pharmacol Exp Ther 1999; 290: 289–94
Ogawa M, Suzuki H, Sawada Y, et al. Kinetics of active efflux via choroid plexus of beta-lactam antibiotics from the CSF into the circulation. Am J Physiol 1994; 266: R392–9
Ooie T, Suzuki H, Terasaki T, et al. Kinetic evidence for active efflux transport across the blood-brain barrier of quinolone antibiotics. J Pharmacol ExpTher 1997; 283: 293–304
Rao VV, Dahlheimer JL, Bardgett ME, et al. Choroid plexus epithelial expression of MDR1 P glycoprotein and multi-drug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sei U S A 1999; 96: 3900–5
Schinkel AH, Smit JJM, Van Tellingen O, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491–502
Wijnholds J, de Lange ECM, Scheffer GL, et al. Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. Clin Investig 2000; 105: 279–85
Deguchi Y, Nowaza K, Yamada S, et al. Quantitative evaluation of brain distribution and blood-brain barrier efflux transport of probenecid in rats by microdialysis. Possible involvement of the monocarboxylic acid transport system. J Pharmacol Exp Ther 1997; 280: 551–60
Scism JL, Powers KM, Artru AA, et al. Effects of probenecid on brain-cerebrospinal fluid-blood distribution kinetics of E-Delta(2)-valproic acid in rabbits. Drug Metab Dispos 1997; 25: 1337–46
Thomas S, Cass L, Prince W, et al. Brain and CSF entry of the novel non-nucleoside reverse transcriptase inhibitor GW420-867X. Neuropharmacol Neurotoxicol 2000; 11: 3811–5
Van Amsterdam C, Lemaire M. Pharmacokinetic profile of SDZ EAA 494 in blood, brain, and CSF using microdialysis. Eur J Pharm Sci 1997; 5: 109–16
Walker MC, Tong X, Perry H, et al. Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine. Br J Pharmacol 2000; 130: 242–8
Tsuji A, Tamai I. Carrier-mediated or specialized transport of drugs across the blood-brain barrier. Adv Drug Deliv Rev 1999; 36: 277–90
Greig NH, Momma S, Sweeney DJ, et al. Facilitated transport of melphalan at the rat blood-brain barrier by the large neutral amino acid carrier system. Cancer Res 1987; 47: 1571–6
Tatsua T, Naito M, Mikami K, et al. Enhanced expression by the brain matrix of P-glycoprotein in brain capillary endothelial cells. Cell Growth Differ 1994; 5: 1145–52
Seelig A. A general pattern for substrate recognition by P-glycoprotein. Eur J Biochem 1998; 251: 252–61
De Lange ECM, Marchand S, van den Berg DJ, et al. In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin. Eur J Pharm Sci 2000; 12: 85–93
Desrayaud S, de Lange ECM, Lemaire M, et al. Effect of mdr1a P-glycoprotein disruption on the tissue distribution of SDZ PSC 833, a multidrug resistance reversing agent, in mice. J Pharmacol Exp Ther 1998; 285: 438–43
Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV1 protease inhibitors. J Clin Invest 1998; 101: 289–94
Mayer U, Wagenaar E, Dorobek B, et al. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J Clin Invest 1997; 100: 2430–6
Meijer OC, de Lange ECM, Breimer DD, et al. Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdrla P-glycoprotein knockout mice. Endocrinology 1998; 139: 1789–93
Schinkel AH, Wagenaar E, Mol CAAM, et al. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 1996; 97: 2517–24
Schinkel AH, Wagenaar E, Van Deemter L, et al. Absence of the mdr1a p-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96: 1698–705
Uhr M, Steckler T, Yassouridis A, et al. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to Mdr1a P-glycoprotein gene disruption. Neuropsychopharmacology 2000; 22: 380–7
Klopman G, Leming MS, Avner R. Quantitative structure-activity relationship of multidrug resistance reversal agents. Mol Pharmacol 1997; 52: 323–34
Groothuis DR, Levy RM. Entry of antiviral and antiretroviral drugs into the central nervous system. J Neurovirol 1997; 3: 387–400
Takasawa K, Terasaki T, Suzuki H, et al. In vivo evidence for carrier-mediated efflux transport of 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transport system. J Pharmacol Exp Ther 1997; 281: 369–75
Wong SL, Van Belle K, Sawchuk RJ. Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid and cerebrospinal fluid blood-barriers in the rabbit: investigation on the inhibitory effect of probenecid utilizing microdialysis. J Pharmacol Exp Ther 1993; 265: R1205–11
Vladic A, Strikic N, Jurcic D, et al. Homeostatic role of the active transport in elimination of [H-3]benzylpenicillin out of the cerebrospinal fluid system. Life Sci 2000; 67: 2375–85
Dacey RG, Sande MA. Effect of probenecid on cerebrospinal fluid concentrations of penicilline and cephalosporin derivatives. Antimicrob Agents Chemother 1974; 6: 437–41
Spector R. Advances in understanding the pharmacology of agents used to treat bacterial meningitis. Pharmacology 1990; 41: 113–8
Spector R. Ceftriaxone pharmacokinetics in the central nervous system. J Pharmacol Exp Ther 1986; 236: 380–3
Hesselink MB, Smolders H, Eilbacher B, et al. The role of probenecid-sensitive organic acid transport in the pharmacokinetics of N-methyl-D-aspartate receptor antagonists acting at the glycine(B)-site: microdialysis and maximum electroshock seizures studies. J Pharmacol Exp Ther 1999; 290: 543–50
Sawchuk RJ, Yang Z. Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system. Adv Drug Deliv Rev 1999; 39: 5–31
Jedlitschky G, Leier I, Buchholz U, et al. Transport of glutathion, and sulfur conjugates by the MRP gene-encoded conjugate export pump. Cancer Res 1996; 56: 988–94
Wang LP, Schmidt JF. Central nervous side effects after lumbar puncture — a review of the possible pathogenesis of the syndrome of postdural puncture headache and associated symptoms. Dan Med Bull 1997; 44: 79–81
Deuschle M, Hartter S, Hiemke C, et al. Doxepin and its metabolites in plasma and cerebrospinal fluid in depressed patients. Psychopharmacology 1997; 131: 19–22
Agon P, Goethals P, van Haver DK, et al. Permeability of BBB for atenolol studies by PET. J Pharm Pharmacol 1991; 43: 597–600
Yu D-W, Gatley SJ, Wolf AP, et al. Synthesis of carbon-11 labeled ionidated cocaine derivatives and their distribution in baboon brain measured using positron emission tomography. J Med Chem 1992; 35: 2178–83
Bartels M, Gunther U, Albert K, et al. 19F nuclear magnetic resonance spectroscopy of neuroleptics: the first in vivo pharmacokinetics of trifluoperazine in the rat brain and the first in vivo spectrum of fluphenazine in the human brain. Biol Psychol 1991; 30: 656–62
Acknowledgements
No sources of funding were used to assist in the preparation of this manuscript. There are no potential conflicts of interest directly relevant to the contents of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
de Lange, E.C., Danhof, M. Considerations in the Use of Cerebrospinal Fluid Pharmacokinetics to Predict Brain Target Concentrations in the Clinical Setting. Clin Pharmacokinet 41, 691–703 (2002). https://doi.org/10.2165/00003088-200241100-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200241100-00001