Skip to main content
SpringerLink
Log in

Appearance of Double Peaks in Plasma Concentration–time Profile after Oral Administration Depends on Gastric Emptying Profile and Weight Function

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

Abstract

Purpose

Mechanism for double-peak occurrence in plasma concentration profile after oral administration of drugs is controversial, although irregular gastric emptying would be an important factor. The objective of this study was to assess the effect of gastric emptying and a weight function, i.e. pharmacokinetics after reaching the systemic circulation, on the double-peak appearance in plasma concentration profiles.

Materials and Methods

Alprazolam, which generates irregular gastric emptying, was orally co-administered with theophylline to rats, and the plasma concentration profiles or absorption rates were compared between the two drugs. Both drugs are highly absorbable, but alprazolam is rapidly eliminated from plasma, while the elimination of theophylline is very slow.

Results

Oral administration of alprazolam generated the irregular gastric emptying profiles, resulting in multiple peaks in the absorption rate profiles of both drugs. The double peaks in the absorption rate profiles led to the double peaks in plasma concentration profiles for alprazolam, but not necessarily for theophylline. Simulation study clearly indicated that the slower elimination from plasma made the first peak less recognizable.

Conclusions

The irregular gastric emptying could be a main reason for the double peaks in plasma concentration profiles. However, the frequency of double-peak occurrence depends on the weight function, particularly the elimination rate, of each drug.

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

Fig.  1
Fig.  2
Fig.  3
Fig.  4
Fig.  5
Fig.  6
Fig.  7
Fig.  8

Similar content being viewed by others

References

  1. K. Higaki, S. Yamashita, and G. L. Amidon. Time-dependent oral absorption models. J. Pharmacokin. Phrmacodyn. 28:109–128 (2001).

    Article  CAS  Google Scholar 

  2. T. Kimura, and K. Higaki. Gastrointestinal transit and drug absorption. Biol. Pharm. Bull. 25:149–164 (2002).

    Article  PubMed  CAS  Google Scholar 

  3. J. A. Clements, R. C. Heading, W. S. Nimmo, and L. F. Prescott. Kinetics of acetaminophen absorption and gastric emptying in man. Clin. Pharmacol. Ther. 24:420–431 (1978).

    PubMed  CAS  Google Scholar 

  4. W. D. Mason, N. Winer, G. Kochak, I. Cohen, and R. Bell. Kinetics and absolute bioavailability of atenolol. Clin. Pharmacol. 25:408–415 (1979).

    CAS  Google Scholar 

  5. W. N. Charman, M. C. Rogge, A. W. Boddy, W. H. Barr, and B. M. Berger. Absorption of danazol after administration to different sites of the gastrointestinal tract and the relationship to single- and double-peak phenomena in the plasma profiles. J. Clin. Pharmacol. 33:1207–1213 (1993).

    PubMed  CAS  Google Scholar 

  6. J. B. Dressman, R. R. Berardi, G. H. Elta, T. M. Gray, P. A. Montgomery, H. S. Lau, K. L. Pelekoudas, G. J. Szpunar, and J. G. Wabner. Absorption of flurbiprofen in the fed and fasted states. Pharm. Res. 9:901–907 (1992).

    Article  PubMed  CAS  Google Scholar 

  7. J-P. Reymond, J-L. Steimer, and W. Niederberger. On the dose dependency of cyclosporin A absorption and disposition in healthy volunteers. J. Pharmacokin. Biopharm. 16:331–353 (1988).

    Article  CAS  Google Scholar 

  8. E. Lipka, I-D. Lee, P. Langguth, H. Spahn-Langguth, E. Mutschler, and G. L. Amidon. Celiprolol double-peak occurrence and gastric motility: nonlinear mixed effects modeling of bioavailability data obtained in dogs. J. Pharmacokin. Biopharm. 23:267–286 (1995).

    Article  CAS  Google Scholar 

  9. G. A. Digenis, E. P. Sandefer, R. C. Page, and W. J. Doll. Gamma scintigraphy: an evolving technology in pharmaceutical formulation development—Part 2. Pharm. Sci. Technol. Today 1:160–165 (1998).

    Article  CAS  Google Scholar 

  10. H. Lennernäs, and C-G. Regårdh. Evidence for an interaction between the β-blocker pafenolol and bile salts in the intestinal lumen of the rat leading to dose-dependent oral absorption and double peaks in the plasma concentration–time profile. Pharm. Res. 10:879–88 (1993).

    Article  Google Scholar 

  11. T. Yamaguchi, T. Oida, C. Ikeda, and Y. Sekine. Intestinal absorption of a β-adrenergic blocking agent nadolol. . Chem. Pharm. Bull. 34:4259–4264 (1986).

    PubMed  CAS  Google Scholar 

  12. J-E. Peris-Ribera, F. Torres-Molina, M. C. Garcia-Carbonell, J. C. Aristorena, and J. M. Pla-Delfina. Pharmacokinetics and bioavailability of diclofenac in the rat. J. Pharmacokin. Biopharm. 14:615–633 (1986).

    Article  Google Scholar 

  13. R. F. Bergstrom, D. R. Kay, T. M. Harkcom, and J. G. Wagner. Penicillamine kinetics in normal subjects. Clin. Pharmacol. Ther. 30:404–413 (1981).

    Article  PubMed  CAS  Google Scholar 

  14. Y. Plusquellec, G. Campistron, S. Staveris, J. Barre, L. Jung, J. P. Tillement, and G. Houin. A double-peak phenomenon in the pharmacokinetics of veralipride after oral administration: a double-site model for drug absorption. J. Pharmacokin. Biopharm. 15:225–239 (1987).

    Article  CAS  Google Scholar 

  15. D. Brockmeier, H. G. Grigoleit, and H. Leonhardt. The absorption of piretanide from the gastrointestinal tract is site-dependent. Eur. J. Clin. Pharmacol. 30:79–82 (1986).

    Article  PubMed  CAS  Google Scholar 

  16. H. Lennern+//0Aw//9AKQ-s, and C. G. Reg+//0Aw//9AKU-rdh. Regional gastrointestinal absorption of the beta-blocker pafenolol in the rat and intestinal transit rate determined by movement of 14C-PEG 4000. Pharm. Res. 10:130–135 (1993).

    Article  Google Scholar 

  17. R. Miller. Pharmacokinetics and bioavailability of ranitidine in humans. J. Pharm. Sci. 73:1376–1379 (1984).

    Article  PubMed  CAS  Google Scholar 

  18. R. L. Oberle, and G. L. Amidon. The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon. J. Pharmacokin. Biopharm. 15:529–544 (1987).

    Article  CAS  Google Scholar 

  19. P. Veng-Pedersen, and R. Miller. Pharmacokinetics and bioavailability of cimetidine in humans. J. Pharm. Sci. 69:394–398 (1980).

    Article  Google Scholar 

  20. N. Piyapolrungroj, Y. S. Zhou, C. Li, G. Liu, E. Zimmermann, and D. Fleisher. Cimetidine absorption and elimination in rat small intestine. Drug Metab. Dispos. 28:65–72 (2000).

    PubMed  CAS  Google Scholar 

  21. G. Mullersman, V. P. Gotz, W. L. Russell, and H. Derendorf. Lack of clinically significant in vitro and in vivo interactions between ranitidine and sucralfate. J. Pharm. Sci. 75:995–998 (1986).

    Article  PubMed  CAS  Google Scholar 

  22. A. B. Suttle, and K. L. R. Brouwer. Gastrointestinal transit and distribution of ranitidine in the rat. Pharm. Res. 12:1316–1322 (1995).

    Article  PubMed  CAS  Google Scholar 

  23. K. S. Reynolds, M. H. Song, W. D. Heizer, C. B. Burns, D. A. Sica, and K. L. R. Brouwer. Effect of pancreatico-biliary secretions and GI tract time on the absorption and pharmacokinetic profile of ranitidine in humans. Pharm. Res. 15:1281–1285 (1998).

    Article  PubMed  CAS  Google Scholar 

  24. V. Mummaneni, G. L. Amidon, and J. B. Dressman. Gastric pH influences the appearance of double peaks in the plasma concentration–time profiles of cimetidine after oral administration in dogs. Pharm. Res. 12:780–786 (1995).

    Article  PubMed  CAS  Google Scholar 

  25. G. L. Amidon, H. Lennernäs, V. P. Shar, and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413–420 (1995).

    Article  PubMed  CAS  Google Scholar 

  26. R. L. Oberle, T-S. Chen, C. Lloyd, J. L. Barnett, C. Owyang, J. Meyer, and G. L. Amidon. The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids. Gastroenterol. 99:1275–1282 (1990).

    CAS  Google Scholar 

  27. N. Takamatsu, L. S. Welage, Y. Hayashi, R. Yamamoto, J. L. Barnett, V. P. Shah, L. J. Lesko, C. Ramachandran, and G. L. Amidon. Variability in cimetidine absorption and plasma double peaks following oral administration in the fasted state in humans: correlation with antral gastric motility. Eur. J. Pharm. Biopharm. 53:37–47 (2002).

    Article  PubMed  CAS  Google Scholar 

  28. S. K. Sarna. Cyclic motor activity; Migrating motor complex. Gastroenterol. 89:894–913 (1985).

    CAS  Google Scholar 

  29. H. C. Kutchai. The gastrointestinal system. In R. M. Berne, and M. N. Levy (eds.), Physiology, 4th ed, Mosby, St. Louis, 1998, pp. 589–674.

    Google Scholar 

  30. G. S. Hebbard, W. M. Sun, F. Bochner, and M. Horowitz. Pharmacokinetic considerations in gastrointestinal motor disorders. Clin. Pharmacokinet. 28:41–66 (1995).

    Article  PubMed  CAS  Google Scholar 

  31. L. A. Houghton, Y. F. Mangnall, and N. W. Read. Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers. Gut 31:1226–1229 (1990).

    Article  PubMed  CAS  Google Scholar 

  32. C. Feinle, D. Grundy, B. Otto, and M. Fried. Relationship between increasing duodenal lipid doses, gastric perception, and plasma hormone levels in humans. Am. J. Physiol. 278:R1217–1223 (2000).

    CAS  Google Scholar 

  33. J. T. McLaughlin, L. E. A. Troncon, J. Barlow, L. J. Heggie, and D. G. Thompson. Evidence for a lipid specific effect in nutrient induced human proximal gastric relaxation. Gut 43:248–251 (1998).

    Article  PubMed  CAS  Google Scholar 

  34. S. Haruta, N. Iwasaki, K. Ogawara, K. Higaki, and T. Kimura. Absorption behavior of orally administered drugs in rats treated with propantheline. J. Pharm. Sci. 87:1081–1085 (1998).

    Article  PubMed  CAS  Google Scholar 

  35. M. J. Fargeas, J. Fioramonti, and L. Bueno. Time-related effects of benzodiazepines on intestinal motility in conscious dogs Journal. J. Pharm. Pharmacol. 36:130–132 (1984).

    PubMed  CAS  Google Scholar 

  36. Y. Wang, A. Roy, L. Sun, and C. E. Lau. A double-peak phenomenon in the pharmacokinetics of alprazolam after oral administration. Drug Metab. Dispos. 27:855–859 (1999).

    PubMed  CAS  Google Scholar 

  37. S. Y. Yu, H. C. Chung, E. J. Kim, S. H. Kim, I. Lee, S. G. Kim, and M. G. Lee. Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of intravenous theophylline in rats: the role of CYP2E1 induction in 1,3-demethyluric acid formation. J. Pharm. Pharmacol. 54:1687–19692 (2002).

    Article  PubMed  CAS  Google Scholar 

  38. L. S. Schanker, P. A. Shore, B. B. Brodie, and C. A. M. Hogben. Absorption of drugs from the stomach. I. The rat. J. Pharmacol. Exp. Ther. 120:528–539 (1957).

    PubMed  CAS  Google Scholar 

  39. K. Yamaoka, Y. Tanigawara, Y. Nakagawa, and T. Uno. A pharmacokinetic analysis program (MULTI) for microcomputer. J. Pharmacobio-Dyn. 4:879–855 (1981).

    PubMed  CAS  Google Scholar 

  40. J.C.K. Loo, and S. Riegelman. New method for calculating the intrinsic absorption rate of drugs. J. Pharm. Sci. 57:918–928 (1968).

    Article  PubMed  CAS  Google Scholar 

  41. K. Yamaoka and Y. Tanigawara. Deconvolution. In: Introduction to Pharmacokinetic Analysis by Microcomputer, Nankodo, Tokyo, 1984, pp. 91–112.

  42. L. L. von Moltke, D. J. Greenblatt, J. S. Harmatz, and R. I. Shader. Alprazolam metabolism in vitro: studies of human, monkey, mouse, and rat liver microsomes. Pharmacol. 47:268–276 (1993).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama, 700-8530, Japan

    Yukiko Metsugi, Yoshihiro Miyaji, Ken-ichi Ogawara, Kazutaka Higaki & Toshikiro Kimura

Authors
  1. Yukiko Metsugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshihiro Miyaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ken-ichi Ogawara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazutaka Higaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshikiro Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshikiro Kimura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Metsugi, Y., Miyaji, Y., Ogawara, Ki. et al. Appearance of Double Peaks in Plasma Concentration–time Profile after Oral Administration Depends on Gastric Emptying Profile and Weight Function. Pharm Res 25, 886–895 (2008). https://doi.org/10.1007/s11095-007-9469-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-007-9469-z

Key words

Search

Navigation