Skip to main content
PMC home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1995 Sep;40(3):231–236. doi: 10.1111/j.1365-2125.1995.tb05778.x

Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk.

C Y Oo 1, R J Kuhn 1, N Desai 1, C E Wright 1, P J McNamara 1
PMCID: PMC1365102  PMID: 8527284

Abstract

1. Alprazolam, a triazolobenzodiazepine, is extensively prescribed for the treatment of anxiety disorders, which predominantly affect women of child-bearing age. The purpose of the present study was to assess the pharmacokinetics of alprazolam and its two hydroxylated metabolites: 4-hydroxy-alprazolam and alpha-hydroxy-alprazolam in lactating human volunteers and to test the predictability of four recently reported models for drug transfer into milk based on physicochemical properties. 2. Multiple milk and serum samples in eight lactating subjects were collected up to 36 h following single oral doses of 0.5 mg alprazolam; suckling of the infant was discontinued after drug administration. 4-Hydroxy-alprazolam was the predominant metabolite in serum samples while alpha-hydroxy-alprazolam was not detected. 3. The mean oral clearance of alprazolam was 1.15 +/- 0.32 ml min-1 kg-1. The time course of alprazolam in milk roughly paralleled the perspective plasma time profile (mean serum residence time = 16.42 +/- 4.69 h; mean milk residence time = 18.93 +/- 7.03 h). The mean terminal half-life in serum was 12.52 +/- 3.53 h. 4. Observed milk/serum concentration ratios were determined in vivo as AUCmilk/AUCserum (mean M/S(obs) = 0.36 +/- 0.11).(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
231

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atkinson H. C., Begg E. J. Prediction of drug distribution into human milk from physicochemical characteristics. Clin Pharmacokinet. 1990 Feb;18(2):151–167. doi: 10.2165/00003088-199018020-00005. [DOI] [PubMed] [Google Scholar]
  2. Atkinson H. C., Begg E. J. Relationship between human milk lipid-ultrafiltrate and octanol-water partition coefficients. J Pharm Sci. 1988 Sep;77(9):796–798. doi: 10.1002/jps.2600770916. [DOI] [PubMed] [Google Scholar]
  3. Begg E. J., Atkinson H. C. Modelling of the passage of drugs into milk. Pharmacol Ther. 1993 Sep;59(3):301–310. doi: 10.1016/0163-7258(93)90072-l. [DOI] [PubMed] [Google Scholar]
  4. Brandt R. Passage of diazepam and desmethyldiazepam into breast milk. Arzneimittelforschung. 1976;26(3):454–457. [PubMed] [Google Scholar]
  5. Buist A., Norman T. R., Dennerstein L. Breastfeeding and the use of psychotropic medication: a review. J Affect Disord. 1990 Jul;19(3):197–206. doi: 10.1016/0165-0327(90)90092-m. [DOI] [PubMed] [Google Scholar]
  6. Ciraulo D. A., Antal E. J., Smith R. B., Olson D. R., Goldberg D. A., Rand E. H., Raskin R. B., Phillips J. P., Shader R. I., Greenblatt D. J. The relationship of alprazolam dose to steady-state plasma concentrations. J Clin Psychopharmacol. 1990 Feb;10(1):27–32. doi: 10.1097/00004714-199002000-00005. [DOI] [PubMed] [Google Scholar]
  7. Dehlin O., Kullingsjö H., Lidén A., Agrell B., Moser G., Olsen I. Pharmacokinetics of alprazolam in geriatric patients with neurotic depression. Pharmacol Toxicol. 1991 Feb;68(2):121–124. doi: 10.1111/j.1600-0773.1991.tb02048.x. [DOI] [PubMed] [Google Scholar]
  8. Erkkola R., Kanto J. Diazepam and breast-feeding. Lancet. 1972 Jun 3;1(7762):1235–1236. doi: 10.1016/s0140-6736(72)90954-3. [DOI] [PubMed] [Google Scholar]
  9. Fleishaker J. C., Desai N., McNamara P. J. Factors affecting the milk-to-plasma drug concentration ratio in lactating women: physical interactions with protein and fat. J Pharm Sci. 1987 Mar;76(3):189–193. doi: 10.1002/jps.2600760302. [DOI] [PubMed] [Google Scholar]
  10. Fleishaker J. C., McNamara P. J. Effect of altered serum protein binding on propranolol distribution into milk in the lactating rabbit. J Pharmacol Exp Ther. 1988 Mar;244(3):925–928. [PubMed] [Google Scholar]
  11. Fleishaker J. C., McNamara P. J. In vivo evaluation in the lactating rabbit of a model for xenobiotic distribution into breast milk. J Pharmacol Exp Ther. 1988 Mar;244(3):919–924. [PubMed] [Google Scholar]
  12. Fleishaker J. C., Phillips J. P., Eller M. G., Smith R. B. Pharmacokinetics and pharmacodynamics of alprazolam following single and multiple oral doses of a sustained-release formulation. J Clin Pharmacol. 1989 Jun;29(6):543–549. doi: 10.1002/j.1552-4604.1989.tb03379.x. [DOI] [PubMed] [Google Scholar]
  13. Garzone P. D., Kroboth P. D. Pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet. 1989 Jun;16(6):337–364. doi: 10.2165/00003088-198916060-00002. [DOI] [PubMed] [Google Scholar]
  14. Greenblatt D. J., Arendt R. M., Abernethy D. R., Giles H. G., Sellers E. M., Shader R. I. In vitro quantitation of benzodiazepine lipophilicity: relation to in vivo distribution. Br J Anaesth. 1983 Oct;55(10):985–989. doi: 10.1093/bja/55.10.985. [DOI] [PubMed] [Google Scholar]
  15. Greenblatt D. J., Wright C. E. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet. 1993 Jun;24(6):453–471. doi: 10.2165/00003088-199324060-00003. [DOI] [PubMed] [Google Scholar]
  16. Hilbert J. M., Gural R. P., Symchowicz S., Zampaglione N. Excretion of quazepam into human breast milk. J Clin Pharmacol. 1984 Oct;24(10):457–462. doi: 10.1002/j.1552-4604.1984.tb01819.x. [DOI] [PubMed] [Google Scholar]
  17. Hümpel M., Stoppelli I., Milia S., Rainer E. Pharmacokinetics and biotransformation of the new benzodiazepine, lormetazepam, in man. III. Repeated administration and transfer to neonates via breast milk. Eur J Clin Pharmacol. 1982;21(5):421–425. doi: 10.1007/BF00542330. [DOI] [PubMed] [Google Scholar]
  18. Ito S., Blajchman A., Stephenson M., Eliopoulos C., Koren G. Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am J Obstet Gynecol. 1993 May;168(5):1393–1399. doi: 10.1016/s0002-9378(11)90771-6. [DOI] [PubMed] [Google Scholar]
  19. Kroboth P. D., McAuley J. W., Smith R. B. Alprazolam in the elderly: pharmacokinetics and pharmacodynamics during multiple dosing. Psychopharmacology (Berl) 1990;100(4):477–484. doi: 10.1007/BF02243999. [DOI] [PubMed] [Google Scholar]
  20. Lawrence R. A. Breastfeeding and medical disease. Med Clin North Am. 1989 May;73(3):583–603. doi: 10.1016/s0025-7125(16)30659-9. [DOI] [PubMed] [Google Scholar]
  21. Matheson I., Lunde P. K., Bredesen J. E. Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects. Br J Clin Pharmacol. 1990 Dec;30(6):787–793. doi: 10.1111/j.1365-2125.1990.tb05443.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. McNamara P. J., Burgio D., Yoo S. D. Pharmacokinetics of cimetidine during lactation: species differences in cimetidine transport into rat and rabbit milk. J Pharmacol Exp Ther. 1992 Jun;261(3):918–923. [PubMed] [Google Scholar]
  23. Michels R., Marzuk P. M. Progress in psychiatry (2). N Engl J Med. 1993 Aug 26;329(9):628–638. doi: 10.1056/NEJM199308263290908. [DOI] [PubMed] [Google Scholar]
  24. Patrick M. J., Tilstone W. J., Reavey P. Diazepam and breast-feeding. Lancet. 1972 Mar 4;1(7749):542–543. doi: 10.1016/s0140-6736(72)90216-4. [DOI] [PubMed] [Google Scholar]
  25. Schotter A., Müller R., Günther C., Hausleiter H. J., Achtert G. Transfer of metaclazepam and its metabolites into breast milk. Arzneimittelforschung. 1989 Nov;39(11):1468–1470. [PubMed] [Google Scholar]
  26. Sheiner L. B., Beal S. L. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm. 1981 Aug;9(4):503–512. doi: 10.1007/BF01060893. [DOI] [PubMed] [Google Scholar]
  27. Smith R. B., Kroboth P. D. Influence of dosing regimen on alprazolam and metabolite serum concentrations and tolerance to sedative and psychomotor effects. Psychopharmacology (Berl) 1987;93(1):105–112. doi: 10.1007/BF02439595. [DOI] [PubMed] [Google Scholar]
  28. Stebler T., Guentert T. W. Studies on the excretion of diazepam and nordazepam into milk for the prediction of milk-to-plasma drug concentration ratios. Pharm Res. 1992 Oct;9(10):1299–1305. doi: 10.1023/a:1015809418284. [DOI] [PubMed] [Google Scholar]
  29. Whitelaw A. G., Cummings A. J., McFadyen I. R. Effect of maternal lorazepam on the neonate. Br Med J (Clin Res Ed) 1981 Apr 4;282(6270):1106–1108. doi: 10.1136/bmj.282.6270.1106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wilson J. T., Brown R. D., Hinson J. L., Dailey J. W. Pharmacokinetic pitfalls in the estimation of the breast milk/plasma ratio for drugs. Annu Rev Pharmacol Toxicol. 1985;25:667–689. doi: 10.1146/annurev.pa.25.040185.003315. [DOI] [PubMed] [Google Scholar]
  31. Wretlind M. Excretion of oxazepam in breast milk. Eur J Clin Pharmacol. 1987;33(2):209–210. doi: 10.1007/BF00544570. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES