Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1991 Sep;32(3):335–340. doi: 10.1111/j.1365-2125.1991.tb03908.x

Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients

A Tartara, CA Galimberti, R Manni, L Parietti, C Zucca, H Baasch, L Caresia, W Mück, N Barzaghi, G Gatti, E Perucca
PMCID: PMC1368527  PMID: 1777370

Abstract

1 The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively.

2 Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven-fold (P < 0.01) in patients taking enzyme-inducing anticonvulsants and increased by about 50% (P < 0.05) in patients taking sodium valproate.

3 Nimodipine half-lives were shorter in enzyme-induced patients than in controls (3.9 ± 2.0 h vs 9.1 ± 3.4 h, means ± s.d., P < 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate-treated patients, half-lives (8.2 ± 1.8 h) were similar to those found in controls.

Keywords: nimodipine, dihydropyridine, calcium channel blockers, pharmacokinetics, anticonvulsants, epilepsy, drug interaction

Full text

PDF
335

Selected References

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

  1. Brandt L., Säveland H., Ljunggren B., Andersson K. E. Control of epilepsy partialis continuans with intravenous nimodipine. Report of two cases. J Neurosurg. 1988 Dec;69(6):949–950. doi: 10.3171/jns.1988.69.6.0949. [DOI] [PubMed] [Google Scholar]
  2. Capewell S., Freestone S., Critchley J. A., Pottage A., Prescott L. F. Reduced felodipine bioavailability in patients taking anticonvulsants. Lancet. 1988 Aug 27;2(8609):480–482. doi: 10.1016/s0140-6736(88)90124-9. [DOI] [PubMed] [Google Scholar]
  3. De Sarro G. B., Meldrum B. S., Nisticó G. Anticonvulsant effects of some calcium entry blockers in DBA/2 mice. Br J Pharmacol. 1988 Feb;93(2):247–256. doi: 10.1111/j.1476-5381.1988.tb11428.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dhillon S., Richens A. Valproic acid and diazepam interaction in vivo. Br J Clin Pharmacol. 1982 Apr;13(4):553–560. doi: 10.1111/j.1365-2125.1982.tb01421.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fine A., Henderson I. S., Morgan D. R., Tilstone W. J. Malabsorption of frusemide caused by phenytoin. Br Med J. 1977 Oct 22;2(6094):1061–1062. doi: 10.1136/bmj.2.6094.1061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Jawad S., Yuen W. C., Peck A. W., Hamilton M. J., Oxley J. R., Richens A. Lamotrigine: single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy. Epilepsy Res. 1987 May;1(3):194–201. doi: 10.1016/0920-1211(87)90041-6. [DOI] [PubMed] [Google Scholar]
  7. Kapetanović I. M., Kupferberg H. J., Porter R. J., Theodore W., Schulman E., Penry J. K. Mechanism of valproate-phenobarbital interaction in epileptic patients. Clin Pharmacol Ther. 1981 Apr;29(4):480–486. doi: 10.1038/clpt.1981.66. [DOI] [PubMed] [Google Scholar]
  8. Klaassen C. D. Studies on the increased biliary flow produced by phenobarbital in rats. J Pharmacol Exp Ther. 1971 Mar;176(3):743–751. [PubMed] [Google Scholar]
  9. Langley M. S., Sorkin E. M. Nimodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cerebrovascular disease. Drugs. 1989 May;37(5):669–699. doi: 10.2165/00003495-198937050-00004. [DOI] [PubMed] [Google Scholar]
  10. Meikle A. W., Jubiz W., Matsukura S., West C. D., Tyler F. H. Effect of diphenylhydantoin on the metabolism of metyrapone and release of ACTH in man. J Clin Endocrinol Metab. 1969 Dec;29(12):1553–1558. doi: 10.1210/jcem-29-12-1553. [DOI] [PubMed] [Google Scholar]
  11. Meyer F. B., Anderson R. E., Sundt T. M., Jr Anticonvulsant effects of dihydropyridine Ca2+ antagonists in electrocortical shock seizures. Epilepsia. 1990 Jan-Feb;31(1):68–74. doi: 10.1111/j.1528-1157.1990.tb05362.x. [DOI] [PubMed] [Google Scholar]
  12. Meyer F. B., Anderson R. E., Sundt T. M., Jr, Yaksh T. L., Sharbrough F. W. Suppression of pentylenetetrazole seizures by oral administration of a dihydropyridine Ca2+ antagonist. Epilepsia. 1987 Jul-Aug;28(4):409–414. doi: 10.1111/j.1528-1157.1987.tb03666.x. [DOI] [PubMed] [Google Scholar]
  13. Meyer H., Wehinger E., Bossert F., Scherling D. Nimodipine: synthesis and metabolic pathway. Arzneimittelforschung. 1983;33(1):106–112. doi: 10.1002/chin.198320206. [DOI] [PubMed] [Google Scholar]
  14. Morocutti C., Pierelli F., Sanarelli L., Stefano E., Peppe A., Mattioli G. L. Antiepileptic effects of a calcium antagonist (nimodipine) on cefazolin-induced epileptogenic foci in rabbits. Epilepsia. 1986 Sep-Oct;27(5):498–503. doi: 10.1111/j.1528-1157.1986.tb03574.x. [DOI] [PubMed] [Google Scholar]
  15. Paczynski R. P., Meyer F. B., Anderson R. E. Effects of the dihydropyridine Ca2+ channel antagonist nimodipine on kainic acid-induced limbic seizures. Epilepsy Res. 1990 May-Jun;6(1):33–38. doi: 10.1016/0920-1211(90)90006-h. [DOI] [PubMed] [Google Scholar]
  16. Perucca E., Hebdige S., Frigo G. M., Gatti G., Lecchini S., Crema A. Interaction between phenytoin and valproic acid: plasma protein binding and metabolic effects. Clin Pharmacol Ther. 1980 Dec;28(6):779–789. doi: 10.1038/clpt.1980.235. [DOI] [PubMed] [Google Scholar]
  17. Perucca E., Hedges A., Makki K. A., Ruprah M., Wilson J. F., Richens A. A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients. Br J Clin Pharmacol. 1984 Sep;18(3):401–410. doi: 10.1111/j.1365-2125.1984.tb02482.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Perucca E. Pharmacokinetic interactions with antiepileptic drugs. Clin Pharmacokinet. 1982 Jan-Feb;7(1):57–84. doi: 10.2165/00003088-198207010-00004. [DOI] [PubMed] [Google Scholar]
  19. Perucca E., Richens A. Reduction of oral bioavailability of lignocaine by induction of first pass metabolism in epileptic patients. Br J Clin Pharmacol. 1979 Jul;8(1):21–31. doi: 10.1111/j.1365-2125.1979.tb05904.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pirttiaho H. I., Sotaniemi E. A., Pelkonen R. O., Pitkänen U. Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants. Eur J Clin Pharmacol. 1982;22(5):441–445. doi: 10.1007/BF00542550. [DOI] [PubMed] [Google Scholar]
  21. Pisani F., Perucca E., Di Perri R. Clinically relevant anti-epileptic drug interactions. J Int Med Res. 1990 Jan-Feb;18(1):1–15. doi: 10.1177/030006059001800102. [DOI] [PubMed] [Google Scholar]
  22. Riegelman S., Rowland M., Epstein W. L. Griseofulvin-phenobarbital interaction in man. JAMA. 1970 Jul 20;213(3):426–431. [PubMed] [Google Scholar]
  23. Rowland M., Gupta S. K. Cyclosporin-phenytoin interaction: re-evaluation using metabolite data. Br J Clin Pharmacol. 1987 Sep;24(3):329–334. doi: 10.1111/j.1365-2125.1987.tb03177.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rämsch K. D., Ahr G., Tettenborn D., Auer L. M. Overview on pharmacokinetics of nimodipine in healthy volunteers and in patients with subarachnoid hemorrhage. Neurochirurgia (Stuttg) 1985 May;28 (Suppl 1):74–78. doi: 10.1055/s-2008-1054107. [DOI] [PubMed] [Google Scholar]
  25. Rämsch K. D., Graefe K. H., Scherling D., Sommer J., Ziegler R. Pharmacokinetics and metabolism of calcium-blocking agents nifedipine, nitrendipine, and nimodipine. Am J Nephrol. 1986;6 (Suppl 1):73–80. doi: 10.1159/000167224. [DOI] [PubMed] [Google Scholar]
  26. Schmidt D., Ried S. Klinische Relevanz von Calcium-Antagonisten in der Behandlung von Epilepsien. Arzneimittelforschung. 1989 Jan;39(1A):156–158. [PubMed] [Google Scholar]

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

RESOURCES