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Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man

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Summary

Various parameters which may be useful in quantification of drug transit from blood into CSF and vice versa after a short duration infusion are compared here by recalculating previously published data from our group.

Due to the slower entry into and elimination from the CSF compartment as compared to the central compartment, the ratio of drug concentrations in CSF and serum sampled at the same time increase with time after an infusion. Therefore, concentration quotients of simultaneously drawn blood and CSF are inadequate to characterise CSF penetration.

The ratio of the areas under the concentration-time curves in a body fluid and serum (AUCbody fluid/AUCS) is an established measure to quantify overall penetration from the central into a peripheral compartment. AUCCSF/AUCS is closely correlated with the quotient of the maximum CSF and serum concentrations (CmaxCSF/ CmaxS) (rS=0.87, n=42, P<0.001) and with the rate constant of distribution in CSF (CLin/VCSF) (rS=0.80, n=42, P<0.001).

Since CmaxCSF/CmaxS depends on the mode of drug administration, it is suggested that AUCCSF/AUCS be used to quantify overall drug transit into CSF. CLin/VCSF is of use when CSF can only be sampled once, or when the velocity of the transit of a drug into CSF is to be described.

The CSF exit rate constant (CLout/VCSF) characterises elimination from CSF independent of the elimination from serum and may be applied to estimate the formation rate of CSF; in the present study it averaged 20 ml/h.

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References

  • Ames A, Higashi K, Nesbett FB (1965) Effects of pCO2, acetazolamide and ouabain on volume and composition of choroid plexus fluid. J Physiol 181: 516–524

    Google Scholar 

  • Benet LZ, Mitchell JR, Sheiner LB (1990) Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: Gilman AG, Rall TW, Nies AS, Taylor P (eds) Goodman and Gilman's The pharmacological basis of therapeutics, 8th edn. Pergamon Press, New York, pp 3–32

    Google Scholar 

  • Bergan T, Engeset A, Olszewski W, Oestby N, Solberg R (1986) Pharmacokinetics of ciprofloxacin in peripheral lymph and skin blisters. Eur J Clin Microbiol 4: 458–461

    Google Scholar 

  • Beyssac E, Cardot JM, Colnet G, Sirot J, Aiache JM (1987) Pharmacokinetics of cefotaxime and its desacetyl metabolite in plasma and in cerebrospinal fluid. Eur J Drug Metab Pharmacokinet 12: 91–102

    Google Scholar 

  • Bitar N, Claes R, van der Auwera P (1989) Concentrations of ofloxacin in serum and cerebrospinal fluid of patients without meningitis receiving the drug intravenously and orally. Antimicrob Agents Chemother 33: 1686–1690

    Google Scholar 

  • Brock M, Dietz H (1982) Produktion und Resorption des Liquors. Pathophysiologie des intrakraniellen Drucks. In: Dietz H, Umbach W, Wüllenweber R (eds) Klinische Neurochirurgie, vol 1. Thieme, Stuttgart, pp 77–87

    Google Scholar 

  • Crone C (1971) The blood-brain barrier — facts and questions. In: Siesjö BK, Sörensen SC (eds) Ion homeostasis of the brain. Munksgaard, Kopenhagen, pp 52–62

    Google Scholar 

  • Cserr HF, Cooper DN, Suri PK, Patlak CS (1981) Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol 240: F319–328

    Google Scholar 

  • Davies BI, Maesen FPV, Teengs JP, Baur C (1986) The quinolones in chronic bronchitis. Pharmaceutisch Weekblad 8: 53–59

    Google Scholar 

  • Davson H, Spaziani E (1959) The blood-brain barrier. J Physiol 149: 135–143

    Google Scholar 

  • Davson H, Welch K, Segal MB (1987) Physiology and pathophysiology of the cerebrospinal fluid. Churchill Livingstone, Edinburgh London

    Google Scholar 

  • Dixon RL, Owens ES, Rall DP (1969) Evidence of active transport of benzyl-14C-penicillin from cerebrospinal fluid to blood. J Pharm Sci 58: 1106–1109

    Google Scholar 

  • Dow J, Chazal J, Frydman AM, Janny P, Woehrle R, Djebbar F, Gaillot J (1986) Transfer kinetics of pefloxacin into cerebro-spinal fluid after one hour iv infusion of 400 mg in man. J Antimicrob Chemother 17 [Suppl B]: 81–87

    Google Scholar 

  • Fenstermacher JD (1989) Pharmacology of the blood-brain barrier. In: Neuwelt EA (ed) Implications of the blood-brain barrier and its manipulation, vol 1. Plenum, New York

    Google Scholar 

  • Fenstermacher JD, Blasberg RG, Patlak CS (1981) Methods for quantifying the transport of drugs across brain barrier systems. Pharmacol Ther 14: 217–248

    Google Scholar 

  • Fishman RA (1966) Blood-brain and CSF barriers to penicillin and related organic acids. Arch Neurol 15: 113–124

    Google Scholar 

  • Grygiel JJ, Balis FM, Collins JM, Lester CM, Poplack DG (1985) Pharmacokinetics of tiazofurin in the plasma and cerebrospinal fluid of rhesus monkeys. Cancer Res 45: 2037–2039

    Google Scholar 

  • Heideman RL, Kelley JA, Packer RJ, Reaman GH, Roth JS, Balis F, Ettinger LJ, Doherty KM, Jeffries SL, Poplack DG (1988) A pediatric phase I and pharmacokinetic study of spirohydantoin mustard. Cancer Res 48: 2292–2295

    Google Scholar 

  • Johnson RN, Maffeo CJ, Dacey RG, Butler AB, Bass NH (1979) Mechanism for intracranial hypertension during experimental subarachnoid hemorrhage: acute malfunction of arachnoid villi by components of plasma. Trans Amer Neurol Assoc 103: 138–142

    Google Scholar 

  • LeBel M, Vallee F, Bergeron MG (1986) Tissue penetration of ciprofloxacin after single and multiple doses. Antimicrob Agents Chemother 29: 501–505

    Google Scholar 

  • Lode H, Höffken G, Olschewski P, Sievers B, Kirch A, Borner K, Koeppe P (1988) Comparative pharmacokinetics of intravenous ofloxacin and ciprofloxacin. J Antimicrob Chemother 22 [Suppl C]: 73–79

    Google Scholar 

  • Martins AN, Ramirez A, Solomon LS, Wiese GM (1974) The effect of dexamethasone on the rate of formation of cerebrospinal fluid in the monkey. J Neurosurg 41: 550–554

    Google Scholar 

  • McComb JG (1983) Recent research into the nature of cerebrospinal fluid formation and absorption. J Neurosurg 59: 369–393

    Google Scholar 

  • Nabeshima S, Reese TS, Landis DMD, Brightman MW (1975) Junctions in the meninges and marginal glia. J Comp Neurol 164: 127–170

    Google Scholar 

  • Nau R, Prange HW, Martell J, Sharifi S, Kolenda H, Bircher J (1990) Penetration of ciprofloxacin into the cerebrospinal fluid of patients with uninflamed meninges. J Antimicrob Chemother 25: 965–973

    Google Scholar 

  • Nau R, Dreyhaupt T, Kolenda H, Prange HW (1992a) Low blood to cerebrospinal fluid passage of sorbitol after intravenous infusion. Stroke 23: 1276–1279

    Google Scholar 

  • Nau R, Prange HW, Menck S, Kolenda H, Visser K, Seydel JK (1992b) Passage of rifampicin into the cerebrospinal fluid of adults with uninflamed meninges. J Antimicrob Chemother 29: 719–724

    Google Scholar 

  • Nau R, Prins FJ, Kolenda H, Prange HW (1992c) Temporary reversal of serum to cerebrospinal fluid glycerol concentration gradient after intravenous infusion of glycerol. Eur J Clin Pharmacol 42: 181–185

    Google Scholar 

  • Nau R, Emrich D, Prange HW (1993a) Inverse correlation between disappearance of intrathecally injected 111In-DTPA from CSF with CSF protein content and CSF-to-serum albumin ratio. J Neurol Sci 115: 102–104

    Google Scholar 

  • Nau R, Prange HW, Muth P, Mahr G, Menck S, Kolenda H, Sörgel F (1993b) Passage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges. Antimicrob Agents Chemother 37: 1518–1524

    Google Scholar 

  • Nau R, Scholz P, Sharifi S, Rohde S, Kolenda H, Prange HW (1993) Netilmicin cerebrospinal fluid concentrations after an intravenous infusion of 400 mg in patients without meningeal inflammation. J Antimicrob Chemother (in press)

  • Nix DE, Wilton JH, Velasquez N, Budny JL, Lassman HB, Mitchell P, Divan K, Schentag JJ (1992) Cerebrospinal fluid penetration of cefpirome in patients with non-inflamed meninges. J Antimicrob Chemother 29 [Suppl A]: 51–57

    Google Scholar 

  • O'Brien MM, Schofield PJ, Edwards MR (1983) Polyol-pathway enzymes of human brain. Partial purification and properties of sorbitol dehydrogenase. Biochem J 211: 81–90

    Google Scholar 

  • Ochs HR, Greenblatt DJ, Burstein ES, Eichelkraut W, Hahn N (1988) Pharmacokinetics and CSF entry of flunitrazepam in dogs. Pharmacology 36: 166–171

    Google Scholar 

  • Pardridge WM (1983) Neuropeptides and the blood-brain barrier. Ann Rev Physiol 45: 73–82

    Google Scholar 

  • Pioget JC, Wolff M, Singlas E, Laisne MJ, Clair B, Regnier B, Vachon F (1989) Diffusion of ofloxacin into cerebrospinal fluid of patients with purulent meningitis or ventriculitis. Antimicrob Agents Chemother 33: 933–936

    Google Scholar 

  • Reiber H, Felgenhauer K (1987) Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system. Clin Chim Acta 163: 319–328

    Google Scholar 

  • Rosenberg GA, Kyner WT, Estrada E (1980) Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Physiol 238: H42–48

    Google Scholar 

  • Sawchuk RJ, Hedaya MA (1990) Modeling the enhanced uptake of zidovudine (AZT) into cerebrospinal fluid. 1. Effect of probenecid. Pharm Res 7: 332–338

    Google Scholar 

  • Scheld WM, Dacey RG, Winn HR, Welsh JE, Jane JA, Sande MA (1980) Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. J Clin Invest 66: 243–253

    Google Scholar 

  • Shapiro WR, Young DF, Mehta PM (1975) Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. New Engl J Med 293: 161–166

    Google Scholar 

  • Sloviter HA, Shimkin P, Suhara K (1966) Glycerol as a substrate for brain metabolism. Nature 210: 1334–1336

    Google Scholar 

  • Sörgel F, Jaehde U, Naber K, Stephan U (1989) Pharmacokinetic disposition of quinolones in human body fluids and tissues. Clin Pharmacokin 16 [Suppl 1]: 5–24

    Google Scholar 

  • Spector R (1986) Ceftriaxone pharmacokinetics in the central nervous system. J Pharmacol Exp Ther 236: 380–383

    Google Scholar 

  • Spector R (1987) Ceftriaxone transport through the blood-brain barrier. J Infect Dis 156: 209–211

    Google Scholar 

  • Thea D, Barza M (1989) Use of antibacterial agents in infections of the central nervous system. Infect Dis Clin N Amer 3: 553–570

    Google Scholar 

  • van Deurs B (1980) Structural aspects of brain barriers, with special reference to the permeability of the cerebral endothelium and choroidal epithelium. Int Rev Cytol 65: 117–191

    Google Scholar 

  • Wiesinger H, Hamprecht B (1989) Purification and characterization of sorbitol dehydrogenase from bovine brain. J Neurochem 52: 342–348

    Google Scholar 

  • Wolff M, Boutron L, Singlas E, Clair B, Decazes JM, Regnier B (1987) Penetration of ciprofloxacin into cerebrospinal fluid of patients with bacterial meningitis. Antimicrob Agents Chemother 31: 899–902

    Google Scholar 

  • Wolff M, Chavanet P, Kazmierczak, Pechinot A, Dematons C, Portier H, Lenfant B (1992) Diffusion of cefpirome into the cerebrospinal fluid of patients with purulent meningitis. J Antimicrob Chemother 29 [Suppl A]: 59–62

    Google Scholar 

  • Zimm S, Collins JM, Curt GA, O'Neill D, Poplack DG (1984) Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzoquinone. Cancer Res 44: 1698–1701

    Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, University of Göttingen, Germany

    R. Nau, G. Zysk & H. W. Prange

  2. Department of Psychiatriy, University of Göttingen, Germany

    A. Thiel

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  1. R. Nau
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  2. G. Zysk
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  3. A. Thiel
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  4. H. W. Prange
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This work is dedicated to Prof. Dr. K. Felgenhauer, Head of the Department of Neurology, University of Göttingen, on the occasion of his 60th birthday

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Nau, R., Zysk, G., Thiel, A. et al. Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man. Eur J Clin Pharmacol 45, 469–475 (1993). https://doi.org/10.1007/BF00315520

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