Skip to main content
SpringerLink
Log in

Relationship Between Loperamide-Induced Sedative Effect and Digoxin Pharmacokinetics in Healthy Japanese Subjects

  • Research Papers
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

No Heading

Purpose.

Loperamide-induced suppressive effects on central nervous system closely relate to a lack of or decline in the P-glycoprotein (P-gp) function. The aim of this study was to determine the loperamide-induced sedative effect quantitatively and to investigate possible alterations in the pharmacokinetics of digoxin, a substrate for P-gp, in Japanese subjects.

Methods.

Loperamide hydrochloride (2 mg) was administered orally to 26 subjects and the critical flicker-fusion frequency threshold (CFF) values were measured every 30 min separately by portable instrument. Further, digoxin (0.25 mg) was administered to 8 subjects, and the plasma concentration was determined.

Results.

In five subjects who complained of drowsiness, the CFF values more remarkably decreased compared with those in the other subjects. The Tmax and mean residence time (MRT) values of digoxin pharmacokinetics in four subjects with drowsiness were significantly lower and Cmax was higher than those in four subjects with marginal effect. Moreover, there were good correlations between the CFF value-time profile and the Cmax, Tmax, and MRT of digoxin.

Conclusions.

The determination of the CFF value after oral administration of loperamide will be useful for evaluating varied P-gp function and for anticipating individual variations in the disposition of P-gp substrates in humans.

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

Abbreviations

AUC:

area under the digoxin concentration curve

Cmax:

maximum plasma concentration

CFF:

critical flicker-fusion frequency threshold

CLtot/F:

total clearance divided by bioavailability

CNS:

central nervous system

CYP:

cytochrome P-450

ΔCFF-AUC:

area under the ΔCFF curve

Ka:

absorption constant

Ke:

elimination constant

MRT:

mean residence time

P-gp:

P-glycoprotein

Tmax:

time at maximum plasma concentration

References

  1. 1. P. Oelkers, L. C. Kirby, J. E. Heubi, and P. A. Dawson. Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2). J. Clin. Invest. 99:1880–1887 (1997).

    Google Scholar 

  2. 2. E. M. Wright. Genetic disorders of membrane transport I. Glucose galactose malabsorption. Am. J. Physiol. 275:G879–G882 (1998).

    Google Scholar 

  3. 3. H. Tsujii, J. Konig, D. Rost, B. Stockel, U. Leuschner, and D. Keppler. Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. Gastroenterology 117:653–660 (1999).

    Google Scholar 

  4. 4. L. R. Schiller, C. A. Santa Ana, S. G. Morawski, and J. S. Fordtran. Mechanism of the antidiarrheal effect of loperamide. Gastroenterology 86:1475–1480 (1984).

    Google Scholar 

  5. 5. J. Heykants, M. Michiels, A. Knaeps, and J. Brugmans. Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 5: the pharmacokinetics of loperamide in rats and man. Arzneimittelforschung 24:1649–1653 (1974).

    Google Scholar 

  6. 6. A. H. Schinkel, E. Wagenaar, C. A. Mol, and L. van Deemter. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:2517–2524 (1996).

    Google Scholar 

  7. 7. A. J. Sadeque, C. Wandel, H. He, S. Shah, and A. J. Wood. Increased drug delivery to the brain by P-glycoprotein inhibition. Clin. Pharmacol. Ther. 68:231–237 (2000).

    Google Scholar 

  8. 8. I. Hindmarch and A. C. Parrott. A repeated dose comparison of the side effects of five antihistamines on objective assessments of psychomotor performance, central nervous system arousal and subjective appraisals of sleep and early morning behaviour. Arzneimittelforschung 28:483–486 (1978).

    Google Scholar 

  9. 9. I. Hindmarch and Z. Subhan. The effects of midazolam in conjunction with alcohol on sleep, psychomotor performance and car driving ability. Int. J. Clin. Pharmacol. Res. 3:323–329 (1983).

    Google Scholar 

  10. 10. Z. Subhan and I. Hindmarch. The effects of lormetazepam on aspects of sleep and early morning performance. Eur. J. Clin. Pharmacol. 25:47–51 (1983).

    Google Scholar 

  11. 11. J. L. Pretorius, M. Phillips, R. W. Langley, E. Szabadi, and C. M. Bradshaw. Comparison of clozapine and haloperidol on some autonomic and psychomotor functions, and on serum prolactin concentration, in healthy subjects. Br. J. Clin. Pharmacol. 52:322–326 (2001).

    Google Scholar 

  12. 12. J. A. Endicott and V. Ling. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu. Rev. Biochem. 58:137–171 (1989).

    Google Scholar 

  13. 13. S. F. Su and J. D. Huang. Inhibition of the intestinal digoxin absorption and exsorption by quinidine. Drug Metab. Dispos. 24:142–147 (1996).

    Google Scholar 

  14. 14. Y. Tanigawara, N. Okamura, M. Hirai, M. Yasuhara, K. Ueda, N. Kioka, T. Komano, and R. Hori. Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J. Pharmacol. Exp. Ther. 263:840–845 (1992).

    Google Scholar 

  15. 15. C. Marzolini, E. Paus, T. Buclin, and R. B. Kim. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin. Pharmacol. Ther. 75:13–33 (2004).

    Google Scholar 

  16. 16. S. Hoffmeyer, O. Burk, O. von Richter, H. P. Arnold, J. Brockmoller, A. Johne, I. Cascorbi, T. Gerloff, I. Roots, M. Eichelbaum, and U. Brinkmann. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. USA 97:3473–3478 (2000).

    Google Scholar 

  17. 17. A. Johne, K. Kopke, T. Gerloff, I. Mai, S. Rietbrock, C. Meisel, S. Hoffmeyer, R. Kerb, M. F. Fromm, U. Brinkmann, M. Eichelbaum, J. Brockmoller, I. Cascorbi, and I. Roots. Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin. Pharmacol. Ther. 72:584–594 (2002).

    Google Scholar 

  18. 18. Y. Kurata, I. Ieiri, M. Kimura, T. Morita, S. Irie, A. Urae, S. Ohdo, H. Ohtani, Y. Sawada, S. Higuchi, and K. Otsubo. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin. Pharmacol. Ther. 72:209–219 (2002).

    Google Scholar 

  19. 19. C. Verstuyft, S. Strabach, H. El-Morabet, R. Kerb, U. Brinkmann, L. Dubert, P. Jaillon, C. Funck-Brentano, G. Trugnan, and L. Becquemont. Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition. Clin. Pharmacol. Ther. 73:51–60 (2003).

    Google Scholar 

  20. 20. T. Sakaeda, T. Nakamura, M. Horinouchi, M. Kakumoto, N. Ohmoto, T. Sakai, Y. Morita, T. Tamura, N. Aoyama, M. Hirai, M. Kasuga, and K. Okumura. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm. Res. 18:1400–1404 (2001).

    Google Scholar 

  21. 21. T. Nakamura, T. Sakaeda, M. Horinouchi, T. Tamura, N. Aoyama, T. Shirakawa, M. Matsuo, M. Kasuga, and K. Okumura. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin. Pharmacol. Ther. 71:297–303 (2002).

    Google Scholar 

  22. 22. T. Gerloff, M. Schaefer, A. Johne, K. Oselin, C. Meisel, I. Cascorbi, and I. Roots. MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males. Br. J. Clin. Pharmacol. 54:610–616 (2002).

    Google Scholar 

  23. 23. K. Yamaoka, Y. Tanigawara, T. Nakagawa, and T. Uno. A pharmacokinetic analysis program (multi) for microcomputer. J. Pharmacobiodyn. 4:879–885 (1981).

    Google Scholar 

  24. 24. K. Tabata, K. Yamaoka, A. Kaibara, S. Suzuki, M. Terakawa, and T. Hata. Moment analysis program available on Microsoft Excel®. Xenobio Metabol. Dispos. 14:286–293 (1999).

    Google Scholar 

  25. 25. K. Lauritsen, L. S. Laursen, and J. Rask-Madsen. Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (Part II). Clin. Pharmacokinet. 19:94–125 (1990).

    Google Scholar 

  26. 26. Y. Tayrouz, B. Ganssmann, R. Ding, A. Klingmann, R. Aderjan, J. Burhenne, W. E. Haefeli, and G. Mikus. Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement. Clin. Pharmacol. Ther. 70:405–414 (2001).

    Google Scholar 

  27. 27. C. Wandel, R. Kim, M. Wood, and A. Wood. Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology 96:913–920 (2002).

    CAS  PubMed  Google Scholar 

  28. 28. L. Becquemont, C. Verstuyft, R. Kerb, U. Brinkmann, M. Lebot, P. Jaillon, and C. Funck-Brentano. Effect of grapefruit juice on digoxin pharmacokinetics in humans. Clin. Pharmacol. Ther. 70:311–316 (2001).

    Google Scholar 

  29. 29. P. Pauli-Magnus, J. Feiner, C. Brett, E. Lin, and D. L. Kroetz. No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects. Clin. Pharmacol. Ther. 74:487–498 (2003).

    Google Scholar 

  30. 30. N. Morita, T. Yasumori, and K. Nakayama. Human MDR1 polymorphism: G2677T/A and C3435T have not effect on MDR1 transport activity. Biochem. J. 65:1843–1852 (2003).

    Google Scholar 

  31. 31. B. Greiner, M. Eichelbaum, P. Fritz, H. P. Kreichgauer, O. von Richter, J. Zundler, and H. K. Kroemer. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J. Clin. Invest. 104:147–153 (1999).

    Google Scholar 

  32. 32. D. Dürr, B. Stieger, G. A. Kullak-Ublick, K. M. Rentsch, H. C. Steinert, P. J. Meier, and K. Fattinger. St John’s Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin. Pharmacol. Ther. 68:598–604 (2000).

    Google Scholar 

  33. 33. A. Yamauchi, I. Ieiri, Y. Kataoka, M. Tanabe, T. Nishizaki, R. Oishi, S. Higuchi, K. Otsubo, and K. Sugimachi. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 74:571–572 (2002).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan

    Michiya Kobayashi, Hiroshi Saitoh & Michiko Yamaguchi

  2. Laboratory of Environmental Biology, Department of Preventive Medicine, Division of Social Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Takeshi Saito & Hiroyoshi Fujita

  3. Department of Hospital Pharmacy & Pharmacology, Asahikawa Medical College, Asahikawa, Japan

    Manabu Suno & Kazuo Matsubara

  4. Absorption Systems, Exton, Pennsylvania, USA

    Bruce J. Aungst

Authors
  1. Michiya Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Saitoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michiko Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takeshi Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroyoshi Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manabu Suno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuo Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bruce J. Aungst
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroshi Saitoh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kobayashi, M., Saitoh, H., Yamaguchi, M. et al. Relationship Between Loperamide-Induced Sedative Effect and Digoxin Pharmacokinetics in Healthy Japanese Subjects. Pharm Res 22, 413–418 (2005). https://doi.org/10.1007/s11095-004-1879-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-004-1879-6

Key Words:

Search

Navigation