Abstract
Groups of male CF-1 mice received 3 and 10 µmol/kg diazepam, lorazepam, and oxazepam intravenously. Between 1 min and 24 h after injection, benzodiazepine concentrations were determined by gas chromatography (GLC) in plasma and in one brain hemisphere; in the other hemisphere, ex vivo benzodiazepine receptor occupancy was measured using3H-flunitrazepam displacement. Based on GLC data, diazepam entered brain rapidly, and was also cleared rapidly, yielding desmethyldiazepam and oxazepam as metabolites in plasma and brain. However, lorazepam and oxazepam entered brain slowly, with brain:plasma equilibrium achieved at 30–60 min; thereafter, the drugs were eliminated from plasma and brain in parallel. The time course and extent of ex vivo occupancy were highly consistent with GLC data (for diazepam, GLC levels were expressed as the sum of diazepam, desmethyldiazepam, and oxazepam, with metabolite concentrations, normalized for molecular weight and for in vitro benzodiazepine receptor affinity.) Between-method correlations were 0.95 or higher. Thus benzodiazepine receptor occupancy is highly dependent on benzodiazepine concentrations in brain. Differences in the time-course of onset and duration of pharmacologic activity between the highly lipophilic benzodiazepine diazepam and the less lipophilic hydroxylated derivatives lorazepam and oxazepam are largely explained by differences in systemic kinetics and in the rate of uptake into brain.
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Ameer B, Greenblatt DJ (1981) Lorazepam. Drugs 21:161–200
Arendt RM, Greenblatt DJ, deJong 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 227:95–106
Arendt RM, Greenblatt DJ, Liebisch DC, Luu MD, Paul SM (1987) Determinants of benzodiazepine brain uptake: lipophilicity versus binding affinity. Psychopharmacology 93:72–76
Conner JT, Katz RL, Bellville JW, Graham C, Pagano R, Dorey F (1978) Diazepam and lorazepam for intravenous surgical premedication. J Clin Pharmacol 18:285–292
Ellinwood EH, Nikaido AM, Heatherly DG, Bjornsson TD (1987) Benzodiazepine pharmacodynamics: evidence for biophase rate limiting mechanisms. Psychopharmacology 91:168–174
Friedman H, Abernethy DR, Greenblatt DJ, Shader RI (1986) The pharmacokinetics of diazepam and desmethyldiazepam in rat brain and plasma. Psychopharmacology 88:267–270
George KA, Dundee JW (1977) Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man. Br J Clin Pharmacol 4:45–50
Greenblatt DJ (1981) Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet 6:89–105
Greenblatt DJ, Koch-Weser J (1975) Clinical pharmacokinetics. N Engl J Med 293:702–705, 964–970
Greenblatt DJ, Shader RI (1987) Pharmacokinetics of antianxiety agents. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, 1377–1386
Greenblatt DJ, Ehrenberg BL, Gunderman J, Scavone JM, Tai NT, Harmatz JS, Shader RI (1989a) Kinetic and dynamic study of intravenous lorazepam: comparison with intravenous diazepam. J Pharmacol Exp Ther 250:134–140
Greenblatt DJ, Ehrenberg BL, Gunderman J, Locniskar A, Scavone JM, Harmatz JS, Shader RI (1989b) Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo. Clin Pharmacol Ther 45:356–365
Greenblatt DJ, Franke K, Shader RI (1978) Analysis of lorazepam and its glucuronide metabolite by electron-capture gas-liquid chromatography: use in pharmacokinetic studies of lorazepam. J Chromatogr 146:311–320
Greenblatt DJ, Ochs HR, Lloyd BL (1980) Entry of diazepam and its major metabolite into cerebrospinal fluid. Psychopharmacology 70:89–93
Haefely W, Kyburz E, Gerecke M, Möhler H (1985) Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure-activity relationships of their agonists and antagonists. Adv Drug Res 14:165–322
Harmatz JS, Greenblatt DJ (1987) A SIMPLEX procedure for fitting nonlinear pharmacokinetic models. Comp Biol Med. 17:199–208
Igari Y, Sugiyama Y, Sawada Y, Iga T, Hanano M (1982) Tissue distribution of14C-diazepam and its metabolites in rats. Drug Metab Dispos 10:676–679
Klockowski PM, Levy G (1988) Kinetics of drug action in disease states. XXIV. Pharmacodynamics of diazepam and its active metabolites in rats. J Pharmacol Exp Ther 244:912–918
Jack ML, Colburn WA, Spirt NM, Bautz G, Zanko M, Horst WD, O'Brien RA (1983) A pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of pharmacological activity of the benzodiazepines. Prog Neuropsychopharmacol Biol Psychiatry 7:629–635
Jones DR, Hall SD, Jackson EK, Branch RA, Wilkinson GR (1988) Brain uptake of benzodiazepines: effects of lipophilicity and plasma protein binding. J Pharmacol Exp Ther 245:816–822
Keller F, Waser PG (1984) Brain pharmacokinetics of centrally acting drugs, a quantitative autoradiographic study. Arch Int Pharmacodyn Ther 267:200–212
Löscher W, Frey H-H (1984) Kinetics of penetration of common antiepileptic drugs into cerebrospinal fluid. Epilepsia 25:346–352
Miller LG, Greenblatt DJ, Paul SM, Shader RI (1987) Benzodiazepine receptor occupancy in vivo: correlation with brain concentrations and pharmacodynamic actions. J Pharmacol Exp Ther 240:516–522
Ochs HR, Pabst J, Greenblatt DJ, Hartlapp J (1982) Digitoxin accumulation. Br J Clin Pharmacol 14:225–229
Paulson OB, Györy A, Hertz MM (1982) Blood-brain barrier transfer and cerebral uptake of antiepileptic drugs. Clin Pharmacol Ther 32:466–477
Ramsay RE, Hammond EJ, Perchalski RJ, Wilder BJ (1979) Brain uptake of phenytoin, phenobarbital, and diazepam. Arch Neurol 36:535–539
Scavone JM, Friedman H, Greenblatt DJ, Shader RI (1987) Effect of age, body composition, and lipid solubility on benzodiazepine tissue distribution in rats. Arzneimittelforschung 37:2–6
Sethy VH, Harris DW (1982) Benzodiazepine receptor number after acute administration of alprazolam and diazepam. Res Commun Chem Pathol Pharmacol 35:229–235
Sethy VH, Daenzer CL, Russell RR (1983a) Interaction of N-alkylamainobenzophenones with benzodiazepine receptors. J Pharm Pharmacol 35:194–195
Sethy VH, Francis JW, Elfring G (1987) Onset and duration of action of benzodiazepines as determined by inhibition of (3H)-flunitrazepam binding. Drug Dev Res 10:117–121
Sethy VH, Russell RR, Daenzer CL (1983b) Interaction of triazolobenzodiazepines with benzodiazepine receptors. J Pharm Pharmacol 35:524–526
Tedeschi G, Smith AT, Dhillon S, Richens A (1983) Rate of entrance of benzodiazepines into the brain determined by eye movement recording. Br J Clin Pharmacol 15:103–107
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Supported in part by grants MH-34223, DA-05258, and AG-00106 from the United States Public Health Service
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Greenblatt, D.J., Sethy, V.H. Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam, lorazepam, and oxazepam. Psychopharmacology 102, 373–378 (1990). https://doi.org/10.1007/BF02244106
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DOI: https://doi.org/10.1007/BF02244106