Clinical Drug Investigation

, Volume 9, Issue 3, pp 131–140 | Cite as

Early Pharmacokinetics of Midazolam

Sampling Site and Schedule Considerations
  • V. Mastey
  • F. Donati
  • F. Varin
Original Research Clinical Pharmacokinetics


The influence of sampling site and sampling schedule on the early pharmacokinetics of a lipophilic drug, midazolam, was studied in 6 anaesthetised patients following an intravenous bolus injection of 0.05 mg/kg. Arterial and venous blood samples were drawn simultaneously over a period of 180 minutes. An extensive sampling procedure was used during the initial distribution phase; specifically, 12 arterial and 4 venous samples within the first 2 minutes. Midazolam concentrations were measured by high-performance liquid chromatography. Compared with peak venous concentrations, peak arterial concentrations were 2-fold greater and were reached 1 minute earlier. Although arterial concentrations exceeded corresponding venous concentrations for up to 90 minutes, a significant arteriovenous difference was observed during the first 2 minutes only. Consequently, noncompartmental pharmacokinetic parameters (mean residence time, volume of distribution at steady-state, total body clearance) obtained from arterial and venous values did not differ significantly. In addition, similar results were obtained for pharmacokinetic parameters using either the complete (continuous sampling over 2 minutes) or limited (assuming 1- and 2-minute samples only) arterial data set. It is concluded that both the sampling site and the sampling schedule altered the initial plasma concentration-time profile of midazolam. Although neither of these factors had a strong influence on the overall pharmacokinetic parameters of midazolam, their potential effect on the pharmacokinetic/pharmacodynamic relationship of midazolam during the onset phase should be considered.


Midazolam Drug Invest Atracurium Mean Residence Time Mivacurium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Chiou WL. The phenomenon and rationale of marked dependence of drug concentration on blood sampling site: implications in pharmacokinetics, pharmacodynamics, toxicology and therapeutics (Parts I and II). Clin Pharmacokinet 1989; 17: 175–99PubMedCrossRefGoogle Scholar
  2. 2.
    Vaughan DP, Hope I. Applications of a recirculatory stochastic pharmacokinetic model: limitations of compartmental models. J Pharmacokinet Biopharm 1979; 7: 207–25PubMedGoogle Scholar
  3. 3.
    Wagner JG. Do you need a pharmacokinetic model and if so which one. J Pharmacokinet Biopharm 1975; 3: 457–78PubMedGoogle Scholar
  4. 4.
    Chiou WL, Lam G. The significance of the arterial-venous plasma concentration difference in clearance studies. Int J Clin Pharmacol Ther Toxicol 1982; 20: 197–203PubMedGoogle Scholar
  5. 5.
    Bøjholm S, Paulson OB, Flachs H. Arterial and venous concentrations of phenobarbital, phenytoin, clonazepam, and diazepam after rapid intravenous injections. Clin Pharmacol Ther 1982; 32: 478–83PubMedCrossRefGoogle Scholar
  6. 6.
    Burch P, Stanski DR. Decreased protein binding and thiopental kinetics. Clin Pharmacol Ther 1982; 32: 212–7PubMedCrossRefGoogle Scholar
  7. 7.
    Christensen JH, Andreasen F, Jansen JA. Pharmacokinetics and pharmacodynamics of thiopentone. Anaesthesia 1982; 37: 398–404PubMedCrossRefGoogle Scholar
  8. 8.
    Donati F, Varin F, Ducharme J, et al. Pharmacokinetics and pharmacodynamics of atracurium obtained with arterial and venous blood samples. Clin Pharmacol Ther 1991; 49: 515–22PubMedCrossRefGoogle Scholar
  9. 9.
    Gillespie FC, Runcie J, Summer DJ, et al. Integral analysis of renal clearance data in the routine measurement of glomerular filtration rate. J Physiol 1976; 258: 92–3Google Scholar
  10. 10.
    Gray HW, Pack A, Basent RG, et al. Arteriovenous differences: a systematic error of early phase thyroidal clearance measurement. J Nucl Med 1973; 14: 43–66Google Scholar
  11. 11.
    Kosaka Y, Takahash T, Mark LC. Intravenous thiopental anesthesia for cesarian section. J Anesthesiol 1969; 31: 489–506CrossRefGoogle Scholar
  12. 12.
    McQuire EAH, Helderman JH, Tobin JD, et al. Effect of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol 1976; 41: 565–73Google Scholar
  13. 13.
    Orskov H, Christensen NJ. Plasma disappearance rate of injected human insulin in juvenile diabetic, maturity-onset diabetic and nondiabetic subjects. Diabetics 1969; 18: 653–9Google Scholar
  14. 14.
    Tucker GT, Boas RA. Pharmacokinetic aspects of intravenous regional anesthesia. Anesthesiology 1971; 34: 538–49PubMedCrossRefGoogle Scholar
  15. 15.
    Chiou WL, Lam G, Chen M-L, et al. Instantaneous input hypothesis in pharmacokinetic studies. J Pharm Sci 1981; 70: 1037–9PubMedCrossRefGoogle Scholar
  16. 16.
    Ducharme J, Varin F, Bevan DR, et al. Importance of early blood sampling on vecuronium pharmacokinetic and pharmacodynamic parameters. Clin Pharmacokinet 1993; 24: 507–18PubMedCrossRefGoogle Scholar
  17. 17.
    Verpoorte R. Potential effect of early blood sampling schedule on calculated pharmacokinetic parameters of drugs after intravenous administration. J Pharm Sci 1980; 69: 867–8CrossRefGoogle Scholar
  18. 18.
    Henthorn TK, Avram MJ, Krejcie TC. Intravascular mixing and drug distribution: the current disposition of thiopental and indocyanine green. Clin Pharmacol Ther 1989; 45: 56–65PubMedCrossRefGoogle Scholar
  19. 19.
    Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther 1981; 30: 653–61PubMedCrossRefGoogle Scholar
  20. 20.
    Behne M, Zobel R, Asskali F, et al. Pharmacokinetics of midazolam during different kinds of anaesthesia. Anaesthesist 1987; 36: 634–9PubMedGoogle Scholar
  21. 21.
    Clausen TG, Wolff J, Hansen PB, et al. Pharmacokinetics of midazolam and α-hydroxy-midazolam following rectal and intravenous administration. Br J Clin Pharmacol 1988; 25: 457–63PubMedCrossRefGoogle Scholar
  22. 22.
    Greenblatt DJ, Darrell AR, Locniskar A, et al. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 1984; 61: 27–35PubMedGoogle Scholar
  23. 23.
    Greenblatt DJ, Ehrenberg BL, Gunderman J, et al. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo. Clin Pharmacol Ther 1989; 45: 356–65PubMedCrossRefGoogle Scholar
  24. 24.
    Harper KW, Collier PS, Dundee JW, et al. Age and nature of operation influence the pharmacokinetics of midazolam. Br J Anaesth 1985; 57: 866–71PubMedCrossRefGoogle Scholar
  25. 25.
    Heizmann P, Eckert M, Ziegler WH. Pharmacokinetics and bioavailability of midazolam in man. Br J Clin Pharmacol 1983; 16: 43S–49SPubMedCrossRefGoogle Scholar
  26. 26.
    Langlois S, Kreeft JH, Chouinard G, et al. Midazolam: kinetics and effects on memory, sensorium, and hemodynamics. Br J Clin Pharmacol 1987; 23: 273–8PubMedCrossRefGoogle Scholar
  27. 27.
    Patel IH, Soni PP, Fukuda EK, et al. The pharmacokinetics of midazolam in patients with congestive heart failure. Br J Clin Pharmacol 1990; 29: 565–9PubMedCrossRefGoogle Scholar
  28. 28.
    Pentikäinen PJ, Välisalmi L, Himberg J-J, et al. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol 1989; 29: 272–7PubMedGoogle Scholar
  29. 29.
    Ræder JC, Nilsen OG, Hole A. Pharmacokinetics of midazolam and alfentanil in outpatient general anaesthesia: a study with concomitant thiopentone, flumazenil or placebo administration. Acta Anaesthesiol Scand 1988; 32: 467–72PubMedCrossRefGoogle Scholar
  30. 30.
    Sànchez-Alcaraz A, Sangrador G, Laguarda M, et al. Pharmacokinetics of intravenous midazolam during epidural anaesthesia. J Clin Pharm Ther 1991; 16: 209–14PubMedCrossRefGoogle Scholar
  31. 31.
    Servin F, Enriquez I, Fournett M, et al. Pharmacokinetics of midazolam used as an intravenous induction agent for patients over 80 years of age. Eur J Anaesthesiol 1987; 4: 1–7PubMedGoogle Scholar
  32. 32.
    Sjövall S, Kanto J, Himberg J-J, et al. CSF penetration and pharmacokinetics of midazolam. Eur J Clin Pharmacol 1983; 25: 247–51PubMedCrossRefGoogle Scholar
  33. 33.
    Smith MT, Eadie MJ, O’Rourke Brophy T. The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol 1981; 19: 271–8PubMedCrossRefGoogle Scholar
  34. 34.
    Trouvin J-H, Farinotti R, Haberer J-P, et al. Pharmacokinetics of midazolam in anaesthetized cirrhotic patients. Br J Anaesth 1988; 60: 762–7PubMedCrossRefGoogle Scholar
  35. 35.
    Lacroix M, Varin F, Donati F. Pharmacokinetics of mivacurium isomers in anesthetized patients [abstract no. PI-80]. Clin Pharmacol Ther 1994; 55: 143Google Scholar
  36. 36.
    Mastey V, Panneton A-C, Donati F, et al. Determination of midazolam and two of its metabolites in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl 1994; 655: 305–10PubMedCrossRefGoogle Scholar
  37. 37.
    Gibaldi M, Perrier D. Pharmacokinetics, 2nd rev. ed. New York: Marcel Dekker Inc, 1982: 409–17, 445-9Google Scholar
  38. 38.
    Dundee JW, Halliday NJ, Harper KW, et al. Midazolam: a review of its pharmacological properties and therapeutic use. Drugs 1984; 28: 519–43PubMedCrossRefGoogle Scholar
  39. 39.
    Grayson J. Responses of the microcirculation to hot and cold environments. Pharmacol Ther 1988; 38: 201–14PubMedCrossRefGoogle Scholar
  40. 40.
    Tozer TN. Concepts basic to pharmacokinetics. Pharmacol Ther 1981; 12: 109–31PubMedCrossRefGoogle Scholar
  41. 41.
    Upton RN, Mather LE, Runciman WB, et al. The use of mass balance principles to describe regional drug distribution and elimination. J Pharmacokinet Biopharm 1988; 16: 13–29PubMedGoogle Scholar
  42. 42.
    Upton RN. Regional pharmacokinetics I: physiological and physicochemical basis. Biopharm Drug Dispos 1990; 11: 647–62PubMedCrossRefGoogle Scholar
  43. 43.
    Kienlen J, du Cailar J. Pharmacologie du midazolam. Ann Fr Anesth Réanim 1987; 6: 439–52PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • V. Mastey
    • 1
  • F. Donati
    • 2
  • F. Varin
    • 1
  1. 1.Faculté de PharmacieUniversité de MontréalMontréalCanada
  2. 2.Department of AnaesthesiaMcGill UniversityMontrealCanada

Personalised recommendations