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. 1985 Apr;19(4):495–501. doi: 10.1111/j.1365-2125.1985.tb02675.x

Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation.

J Säwe, L Kager, J O Svensson Eng, A Rane
PMCID: PMC1463820  PMID: 3994897

Abstract

The kinetics of morphine and formation of the main metabolite, morphine-3-glucuronide (M3G) after single and intravenous doses of morphine were studied in six cancer patients and compared with the formation rate of M3G in vitro in microsomes isolated from liver biopsies obtained from the same patients at palliative laparotomy. The results showed that high formation rates of M3G in vitro in microsomes isolated from liver biopsies were associated both with high apparent oral clearance values and high M3G/morphine AUC (area under the concentration vs time curve) ratios as measured in vivo in the same patients. In accordance with previous results marked interindividual differences were seen in the kinetics of morphine; the oral bioavailability varied between 30 and 69% and the systemic plasma clearance between 18.6 and 34.0 ml min-1 kg-1. This variation correlated with the variation in morphine metabolism as assessed in vitro. In vivo, a high M3G/morphine AUC ratio predicted a high oral clearance. Hepatic UDP-glucuronyl transferase activity is thus an important determinant of the in vivo kinetics of orally administered morphine.

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Selected References

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  1. Back D. J., Breckenridge A. M., MacIver M., Orme M., Purba H. S., Rowe P. H., Taylor I. The gut wall metabolism of ethinyloestradiol and its contribution to the pre-systemic metabolism of ethinyloestradiol in humans. Br J Clin Pharmacol. 1982 Mar;13(3):325–330. doi: 10.1111/j.1365-2125.1982.tb01382.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bock K. W., Brunner G., Hoensch H., Huber E., Josting D. Determination of microsomal UDP-glucuronyltransferase in needle-biopsy specimens of human liver. Eur J Clin Pharmacol. 1978 Dec 18;14(5):367–373. doi: 10.1007/BF00611908. [DOI] [PubMed] [Google Scholar]
  3. Boerner U. The metabolism of morphine and heroin in man. Drug Metab Rev. 1975;4(1):39–73. doi: 10.3109/03602537508993748. [DOI] [PubMed] [Google Scholar]
  4. Boobis A. R., Brodie M. J., Kahn G. C., Toverud E. L., Blair I. A., Murray S., Davies D. S. Comparison of the in vivo and in vitro rates of formation of the three main oxidative metabolites of antipyrine in man. Br J Clin Pharmacol. 1981 Dec;12(6):771–777. doi: 10.1111/j.1365-2125.1981.tb01305.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brunk S. F., Delle M. Morphine metabolism in man. Clin Pharmacol Ther. 1974 Jul;16(1):51–57. doi: 10.1002/cpt1974161part151. [DOI] [PubMed] [Google Scholar]
  6. Dahlström B. E., Paalzow L. K. Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat. J Pharmacokinet Biopharm. 1978 Dec;6(6):505–519. doi: 10.1007/BF01062106. [DOI] [PubMed] [Google Scholar]
  7. Iwamoto K., Klaassen C. D. First-pass effect of morphine in rats. J Pharmacol Exp Ther. 1977 Jan;200(1):236–244. [PubMed] [Google Scholar]
  8. Mahon W. A., Inaba T., Stone R. M. Metabolism of flurazepam by the small intestine. Clin Pharmacol Ther. 1977 Aug;22(2):228–233. doi: 10.1002/cpt1977222228. [DOI] [PubMed] [Google Scholar]
  9. Mount B. M., Melzack R., MacKinnon K. J. The management of intractable pain in patients with advanced malignant disease. J Urol. 1978 Dec;120(6):720–725. doi: 10.1016/s0022-5347(17)57340-1. [DOI] [PubMed] [Google Scholar]
  10. Neumann P. B., Henriksen H., Grosman N., Christensen C. B. Plasma morphine concentrations during chronic oral administration in patients with cancer pain. Pain. 1982 Jul;13(3):247–252. doi: 10.1016/0304-3959(82)90014-8. [DOI] [PubMed] [Google Scholar]
  11. Nies A. S., Shand D. G., Wilkinson G. R. Altered hepatic blood flow and drug disposition. Clin Pharmacokinet. 1976;1(2):135–155. doi: 10.2165/00003088-197601020-00005. [DOI] [PubMed] [Google Scholar]
  12. Pacifici G. M., Säwe J., Kager L., Rane A. Morphine glucuronidation in human fetal and adult liver. Eur J Clin Pharmacol. 1982;22(6):553–558. doi: 10.1007/BF00609630. [DOI] [PubMed] [Google Scholar]
  13. Sloan T. P., Lancaster R., Shah R. R., Idle J. R., Smith R. L. Genetically determined oxidation capacity and the disposition of debrisoquine. Br J Clin Pharmacol. 1983 Apr;15(4):443–450. doi: 10.1111/j.1365-2125.1983.tb01528.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Svensson J. O., Rane A., Säwe J., Sjöqvist F. Determination of morphine, morphine-3-glucuronide and (tentatively) morphine-6-glucuronide in plasma and urine using ion-pair high-performance liquid chromatography. J Chromatogr. 1982 Jul 9;230(2):427–432. doi: 10.1016/s0378-4347(00)80494-6. [DOI] [PubMed] [Google Scholar]
  15. Säwe J., Dahlström B., Paalzow L., Rane A. Morphine kinetics in cancer patients. Clin Pharmacol Ther. 1981 Nov;30(5):629–635. doi: 10.1038/clpt.1981.214. [DOI] [PubMed] [Google Scholar]
  16. Säwe J., Pacifici G. M., Kager L., von Bahr C., Rane A. Glucuronidation of morphine in human liver and interaction with oxazepam. Acta Anaesthesiol Scand Suppl. 1982;74:47–51. doi: 10.1111/j.1399-6576.1982.tb01845.x. [DOI] [PubMed] [Google Scholar]
  17. Säwe J., Svensson J. O., Rane A. Morphine metabolism in cancer patients on increasing oral doses--no evidence for autoinduction or dose-dependence. Br J Clin Pharmacol. 1983 Jul;16(1):85–93. doi: 10.1111/j.1365-2125.1983.tb02148.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Yeh S. Y. Urinary excretion of morphine and its metabolites in morphine-dependent subjects. J Pharmacol Exp Ther. 1975 Jan;192(1):201–210. [PubMed] [Google Scholar]
  19. von Bahr C., Birgersson C., Blanck A., Göransson M., Mellström B., Nilsell K. Correlation between nortriptyline and debrisoquine hydroxylation in the human liver. Life Sci. 1983 Aug 15;33(7):631–636. doi: 10.1016/0024-3205(83)90251-5. [DOI] [PubMed] [Google Scholar]

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