Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1989 Sep;28(3):362–365. doi: 10.1111/j.1365-2125.1989.tb05439.x

Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes.

J F Tjia 1, D J Back 1, A M Breckenridge 1
PMCID: PMC1379957  PMID: 2789931

Abstract

The effects of four Ca2+ channel antagonists on the metabolism of cyclosporine (CsA) by human liver microsomes (n = 4) in vitro have been examined. Nicardipine produced marked inhibition of both M17 and M21 (IC50 = 7.0 microM) formation. In contrast nifedipine produced less than 20% inhibition of M17 and M21 even at the highest concentration examined (50 microM). Diltiazem data were comparable to those for nifedipine. Verapamil (50 microM) produced 30 and 28% inhibition of M17 and M21 formation, respectively. These findings give a basis to the increase in CsA blood concentrations seen in transplant patients who are also given nicardipine.

Full text

PDF
362

Selected References

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

  1. Abernethy D. R., Egan J. M., Dickinson T. H., Carrum G. Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans. J Pharmacol Exp Ther. 1988 Mar;244(3):994–999. [PubMed] [Google Scholar]
  2. Bourbigot B., Guiserix J., Airiau J., Bressollette L., Morin J. F., Cledes J. Nicardipine increases cyclosporin blood levels. Lancet. 1986 Jun 21;1(8495):1447–1447. doi: 10.1016/s0140-6736(86)91594-1. [DOI] [PubMed] [Google Scholar]
  3. Castelao A. M., Sabaté I., Griñ J. M., Gil-Vernet S., Andrés E., Sabater R., Alsina J. Cyclosporine-drug interactions. Transplant Proc. 1988 Oct;20(5 Suppl 6):66–69. [PubMed] [Google Scholar]
  4. Cockburn I. Cyclosporine A: a clinical evaluation of drug interactions. Transplant Proc. 1986 Dec;18(6 Suppl 5):50–55. [PubMed] [Google Scholar]
  5. Edwards D. J., Lavoie R., Beckman H., Blevins R., Rubenfire M. The effect of coadministration of verapamil on the pharmacokinetics and metabolism of quinidine. Clin Pharmacol Ther. 1987 Jan;41(1):68–73. doi: 10.1038/clpt.1987.11. [DOI] [PubMed] [Google Scholar]
  6. Graham D. J., Dow R. J., Hall D. J., Alexander O. F., Mroszczak E. J., Freedman D. The metabolism and pharmacokinetics of nicardipine hydrochloride in man. Br J Clin Pharmacol. 1985;20 (Suppl 1):23S–28S. doi: 10.1111/j.1365-2125.1985.tb05141.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Griño J. M., Sabate I., Castelao A. M., Alsina J. Influence of diltiazem on cyclosporin clearance. Lancet. 1986 Jun 14;1(8494):1387–1387. doi: 10.1016/s0140-6736(86)91699-5. [DOI] [PubMed] [Google Scholar]
  8. Henricsson S., Lindholm A. Inhibition of cyclosporine metabolism by other drugs in vitro. Transplant Proc. 1988 Apr;20(2 Suppl 2):569–571. [PubMed] [Google Scholar]
  9. Inaba T., Jurima M., Mahon W. A., Kalow W. In vitro inhibition studies of two isozymes of human liver cytochrome P-450. Mephenytoin p-hydroxylase and sparteine monooxygenase. Drug Metab Dispos. 1985 Jul-Aug;13(4):443–448. [PubMed] [Google Scholar]
  10. Kohlhaw K., Wonigeit K., Frei U., Oldhafer K., Neumann K., Pichlmayr R. Effect of the calcium channel blocker diltiazem on cyclosporine A blood levels and dose requirements. Transplant Proc. 1988 Apr;20(2 Suppl 2):572–574. [PubMed] [Google Scholar]
  11. Kronbach T., Fischer V., Meyer U. A. Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther. 1988 Jun;43(6):630–635. doi: 10.1038/clpt.1988.87. [DOI] [PubMed] [Google Scholar]
  12. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  13. Montamat S. C., Abernethy D. R. N-monodesmethyldiltiazem is the predominant metabolite of diltiazem in the plasma of young and elderly hypertensives. Br J Clin Pharmacol. 1987 Aug;24(2):185–189. doi: 10.1111/j.1365-2125.1987.tb03160.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ptachcinski R. J., Venkataramanan R., Burckart G. J. Clinical pharmacokinetics of cyclosporin. Clin Pharmacokinet. 1986 Mar-Apr;11(2):107–132. doi: 10.2165/00003088-198611020-00002. [DOI] [PubMed] [Google Scholar]
  15. Purba H. S., Maggs J. L., Orme M. L., Back D. J., Park B. K. The metabolism of 17 alpha-ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites. Br J Clin Pharmacol. 1987 Apr;23(4):447–453. doi: 10.1111/j.1365-2125.1987.tb03074.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Renton K. W. Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil. Biochem Pharmacol. 1985 Jul 15;34(14):2549–2553. doi: 10.1016/0006-2952(85)90541-6. [DOI] [PubMed] [Google Scholar]
  17. Sawchuk R. J., Cartier L. L. Liquid-chromatographic determination of cyclosporin A in blood and plasma. Clin Chem. 1981 Aug;27(8):1368–1371. [PubMed] [Google Scholar]
  18. Wadhwa N. K., Schroeder T. J., Pesce A. J., Myre S. A., Clardy C. W., First M. R. Cyclosporine drug interactions: a review. Ther Drug Monit. 1987 Dec;9(4):399–406. doi: 10.1097/00007691-198712000-00007. [DOI] [PubMed] [Google Scholar]
  19. Wagner K., Henkel M., Heinemeyer G., Neumayer H. H. Interaction of calcium blockers and cyclosporine. Transplant Proc. 1988 Apr;20(2 Suppl 2):561–568. [PubMed] [Google Scholar]
  20. Yee G. C., Rosano T., Ptachcinski R. Pharmacology: profiles, parameters, interpretations, and drug interactions. Transplant Proc. 1988 Apr;20(2 Suppl 2):715–721. [PubMed] [Google Scholar]

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

RESOURCES