Determinants of benzodiazepine brain uptake: lipophilicity versus binding affinity
Factors influencing brain uptake of benzodiazepine derivatives were evaluated in adult Sprague Dawley rats (n=8–10 per drug). Animals received single intraperitoneal doses of alprazolam, triazolam, lorazepam, flunitrazepam, diazepam, midazolam, desmethyldiazepam, or clobazam. Concentrations of each drug (and metabolites) in whole brain and serum 1 h after dosage were determined by gas chromatography. Serum free fraction was measured by equilibrium dialysis. In vitro binding affinity (apparentK i) of each compound was estimated based on displacement of tritiated flunitrazepam in washed membrane preparations from rat cerebral cortex. Lipid solubility of each benzodiazepine was estimated using the reverse-phase liquid chromatographic (HPLC) retention index at physiologic pH. There was no significant relation between brain:total serum concentration ratio and either HPLC retention (r=0.18) or bindingK i (r=−0.34). Correction of uptake ratios for free as opposed to total serum concentration yielded a highly significant correlation with HPLC retention (r=0.78,P<0.005). However, even the corrected ratio was not correlated with bindingK i (r=−0.22). Thus a benzodiazepine's capacity to diffuse from systemic blood into brain tissue is much more closely associated with the physico-chemical property of lipid solubility than with specific affinity. Unbound rather than total serum or plasma concentration most accurately reflects the quantity of drug available for diffusion.
Key wordsBenzodiazepines Binding affinity Lipid solubility Brain uptake Metabolites Pharmacokinetics
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- Arendt RM, Greenblatt DJ, Jong RH, Bonin JD, Abernethy DR, Ehrenberg BL, Giles HG, Sellers EM, Shader RI (1983) In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action, and peripheral distribution. J Pharmacol Exp Ther 227:95–106Google Scholar
- Greenblatt DJ, Shader RI (1985) Clinical pharmacokinetics of the benzodiazepines. In: Smith DE, Wesson DR (eds) The benzodiazepines: current standards for medical practice. M.T.P. Press, Lancaster, UK, pp 43–58Google Scholar
- Greenblatt DJ, Shader RI, Abernethy DR, Ochs HR, Divoll M, Sellers EM (1982a) Benzodiazepines and the challenge of pharmacokinetic taxonomy. In: Usdin E, Skolnick P, Tallman JF, Greenblatt D, Paul SM (eds) Pharmacology of benzodiazepines. MacMillan, London, pp 257–269Google Scholar
- Guentert TW (1984) Pharmacokinetics of benzodiazepines and of their metabolites. Prog Drug Metab 8:241–386Google Scholar
- Klotz U, Kangas L, Kanto J (1980) Clinical pharmacokinetics of benzodiazepines. Prog Pharmacol 3 (No. 3):1–72Google Scholar
- Sellers EM, Naranjo CA, Khouw V, Greenblatt DJ (1982) Binding of benzodiazepines to plasma proteins. In: Usdin E, Skolnick P, Tallman JF, Greenblatt D, Paul SM (eds) Pharmacology of benzodiazepines. MacMillan, London, pp 271–284Google Scholar