Skip to main content
SpringerLink
Log in

The disposition kinetics of diazepam in pregnant women at parturition

  • Originals
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Summary

The disposition of diazepam has been studied in pregnant women at parturition. The plasma concentration of diazepam was monitored for at least 3 days in 18 women who received a single intravenous injection of 10 mg during the 10 h-period prior to delivery. Fourteen mothers had uneventful puerperia (Group I) and in 13 of these cases there was a pronounced postnatal increase in the plasma concentration of diazepam. The terminal phase half-life (t1/2) was significantly greater for Group I (mean = 65 h; range = 24–114 h) than for age-matched non-pregnant patients (mean = 29 h; range = 18–44 h from literature). The prolonged t1/2 appeared to be related to changes in the distribution of diazepam and not to a reduction in hepatic elimination since the total plasma clearance (Cltp) in these 14 pregnant patients (mean = 28 ml/min; range = 18–43 ml/min) was not reduced compared to that reported for non-pregnant controls (mean = 30 ml/min; range = 22–45 ml/min). Four mothers underwent postnatal surgery for tubal ligation (Group II) and the plasma concentration-time profiles for this group did not show the same postnatal phenomenon as did the profiles obtained for Group I. The t1/2 for Group II was shorter (mean = 31 h; range = 24–37 h) than for Group I and similar to that for the non-pregnant controls. The Cltp for Group II was greater (mean = 56 ml/min; range = 48–63 ml/min) than for both Group I and non-pregnant controls. These results suggest that delivery alters the disposition of diazepam and is generally associated with a postnatal re-distribution of diazepam into the systemic circulation. The blood/plasma concentration ratio was determined in 9 patients (mean = 0.62; range = 0.54–0.77). There was no difference in the total blood clearance between the pregnant patients of Group I and the non-pregnant controls. In most cases the umbilical venous plasma concentration (Cpuv) of diazepam was greater than the peripheral maternal venous plasma concentration (Cpmv) at delivery. The foetus appears to constitute a slowly equilibrating tissue-group in which diazepam does not reach equilibrium with the maternal systemic circulation for at least 5–10 h at which time the diazepam concentration in maternal and foetal plasma is similar.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Andreasen, P. B., Hendel, J., Greisen, G., Hvidberg, E. F.: Pharmacokinetics of diazepam in disordered liver function. Europ. J. clin. Pharmacol.10, 115–120 (1976)

    Google Scholar 

  • Baird, E.S., Hailey, D.M.: Delayed recovery from a sedative: Correlation of the plasma levels of diazepam with clinical effects after oral and intravenous administration. Brit. J. Anaesth.44, 830–808 (1972)

    Google Scholar 

  • Blaschke, T.F.: Protein binding and kinetics of drugs in liver diseases. Clin. Pharmacokinetics2, 32–44 (1977)

    Google Scholar 

  • Bonica, J.J.: Obstetric analgesia-anaesthesia. Clin. Obstet. Gynecol.2, 469–497 (1975)

    Google Scholar 

  • Branch, R.A., Morgan, M.H., James, J., Read, A.E.: Intravenous administration of diazepam in patients with chronic liver disease. Gut17, 975–983 (1976)

    Google Scholar 

  • Cavanagh, D., Condo, C.S.: Diazepam — a pilot study of drug concentrations in maternal blood, amniotic fluid and cord blood. Curr. Ther. Res.6, 122–126 (1964)

    Google Scholar 

  • Cree, J.E., Meyer, J., Hailey, D.M.: Diazepam in labour: Its metabolism and effect on the clinical condition and thermogenesis of the newborn. Br. Med. J.1973 IV, 251–255

    Google Scholar 

  • De Silva, J.A.F., D'Arconte, L., Kaplan, J.: The determination of blood levels and the placental transfer of diazepam in humans. Curr. Ther. Res.6, 115–121 (1964)

    Google Scholar 

  • De Silva, J.A.F., Koechlin, B.A., Bader, G.: Blood level distribution patterns of diazepam and its major metabolite in man. J. Pharm. Sci.55, 692–702 (1966)

    Google Scholar 

  • DeSilva, J.A.F., Puglisi, C.V.: Determination of medazepam (Nobrium), diazepam (Valium) and their major biotransformation products in blood and urine by electron capture gas-liquid chromatography. Anal. Chem.42, 1725–1736 (1970)

    Google Scholar 

  • Eliot, B.W., Hill, J.G., Cole, A.P., Hailey, D.M. Continuous pethidine/diazepam infusion during labour and its effects on the newborn. Br. J. Obstet. Gynaecol.82, 126–131 (1975)

    Google Scholar 

  • Erkkola, R., Kangas, L., Pekkarinen, A.: The transfer of diazepam across the placenta during labour. Acta Obstet. Gynecol. Scand.52, 167–170 (1973)

    Google Scholar 

  • Gutová, M., Borgå, O., Rane, A.: Kinetics of phenytoin in pregnant and nonpregnant rats. Acta pharmacol. toxicol.38, 254–259 (1976)

    Google Scholar 

  • Kleijn, E. van der, Rossum, J.M. van, Muskens, E.T.J.M., Rijntjes, N.V.M.: Pharmacokinetics of diazepam in dogs, mice and humans. Acta pharmacol. toxicol.29, 109–127 (1971)

    Google Scholar 

  • Klotz, U., Antonin, K.H., Bieck, P.R.: Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Europ. J. clin. Pharmacol.10, 121–126 (1976a)

    Google Scholar 

  • Klotz, U., Antonin, K.H., Bieck, P.R.: Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat. J. Pharmacol. exp. Ther.199, 67–73 (1976b)

    Google Scholar 

  • Klotz, U., Avant, G.R., Hoyumpa, A., Schenker, S., Wilkinson, G.R.: The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J. Clin. Invest.55, 347–359 (1975)

    Google Scholar 

  • Korttila, K., Kangas, L.: Unchanged protein binding and the increase of serum diazepam levels after food intake. Acta pharmacol. toxicol.40, 241–246 (1977)

    Google Scholar 

  • Kvetina, J., Marcucci, F., Fanelli, R.: Metabolism of diazepam in isolated perfused liver of rat and mouse. J. Pharm. Pharmacol.20, 807–808 (1968)

    Google Scholar 

  • Lander, C.M., Edwards, V.E., Eadie, M.J., Tyrer, J.H.: Plasma anticonvulsant concentrations during pregnancy. Neurology (Minneap.)27, 128–131 (1977)

    Google Scholar 

  • Levy, G., Hayton, W.L.: Pharmacokinetic aspects of placental drug transfer. In: Fetal pharmacology (ed. L. Boréus), pp. 29–39. New York: Raven Press 1973

    Google Scholar 

  • Linnoila, M., Korttila, K., Mattila, M.J.: Effect of food and repeated injections on diazepam serum levels. Acta pharmacol. toxicol.36, 181–186 (1975)

    Google Scholar 

  • Mahon, W.A., Inaba, T., Umeda, T., Tsutsumi, E., Stone, R.: Biliary elimination of diazepam in man. Clin. Pharmacol. Ther.19, 443–450 (1976)

    Google Scholar 

  • Mandelli, M., Morselli, P.L., Nordio, S., Pardi, G., Principi, N., Sereni, F., Tognoni, G.: Placental transfer of diazepam and its disposition in the newborn. Clin. Pharmacol. Ther.17, 564–572 (1975)

    Google Scholar 

  • Marcucci, F., Fanelli, R., Mussini, E., Garattini, S.: The metabolism of diazepam by liver microsomal enzymes of rats and mice. Europ. J. Pharmacol.7, 307–313 (1969)

    Google Scholar 

  • Mygind, K.I., Dam, M., Christiansen, J.: Phenytoin and phenobarbitone plasma clearance during pregnancy. Acta neurol. scand.54, 160–166 (1976)

    Google Scholar 

  • Rane, A., Garle, M., Borgå, O., Sjöqvist, F.: Plasma disappearance of transplacentally transferred diphenylhydantoin in the newborn studied by mass fragmentography. Clin. Pharmacol. Ther.15, 39–45 (1974)

    Google Scholar 

  • Rowland, M., Benet, L.Z., Graham, G.G.: Clearance concepts in pharmacokinetics. J. Pharmacokinet. Biopharm.1, 123–136 (1973)

    Google Scholar 

  • Scher, J., Hailey, D.M., Beard, R.W.: The effects of diazepam on the fetus. J. Obstet. Gynaecol. Br. Commonw.79, 635–638 (1972)

    Google Scholar 

  • Schwartz, M.A., Koechlin, B.A., Postma, E., Palmer, S., Krol, G.: Metabolism of diazepam in rat, dog, and man. J. Pharmacol. exp. Ther.149, 423–435 (1965)

    Google Scholar 

  • Shannon, R.W., Frazer, G.P., Aitken, R.G., Harper, J.R.: Diazepam in preeclamptic toxaemia with special reference to its effect on the newborn infant. Br. J. Clin. Pract.26, 271–275 (1972)

    Google Scholar 

  • Swartz, R.D., Sidell, F.R., Cucinell, S.A.: Effects of physical stress on the disposition of drugs eliminated by the liver in man. J. Pharmacol. exp. Ther.188, 1–7 (1974)

    Google Scholar 

  • Walters, W.A.W., MacGregor, W.G., Hills, M.: Cardiac output at rest during pregnancy and the peurperium. Clin. Sci.30, 1–11 (1966)

    Google Scholar 

  • Wilkinson, G.R., Shand, D.G.: A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther.18, 377–390 (1975)

    Google Scholar 

  • Zingales, I.A.: Diazepam metabolism during chronic medication unbound fraction in plasma, erythrocytes and urine. J. Chromatogr.75, 55–78 (1973)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Foetal Pharmacology Laboratory, Foundation 41, The Women's Hospital, Crown Street, Sydney, Australia

    R. G. Moore & W. G. McBride

Authors
  1. R. G. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. G. McBride
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moore, R.G., McBride, W.G. The disposition kinetics of diazepam in pregnant women at parturition. Eur J Clin Pharmacol 13, 275–284 (1978). https://doi.org/10.1007/BF00716363

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00716363

Key words

Search

Navigation