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The Talinolol Double-Peak Phenomenon Is Likely Caused by Presystemic Processing After Uptake from Gut Lumen

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Abstract

Purpose.

Evaluation of the double-peak phenomenon during absorption of the β1-selective blocker talinolol relative to paracetamol, which is well absorbed from all parts of the gut, and relative to vitamin A, which is absorbed via the lymphatic pathway.

Methods.

Talinolol was given with paracetamol and retinyl palmitate in fast-disintegrating, enteric-coated, and rectal soft capsules to 8 fasting male healthy subjects (21–29 years, 68–86 kg). To evaluate whether the talinolol double-peak is associated with processes of food absorption, a breakfast was served 1 h after administration of a fast disintegrating capsule.

Results.

Bioavailability of talinolol in enteric-coated and rectal capsules was significantly reduced by about 50% and 80%, respectively, despite unchanged bioavailability of paracetamol. Double-peaks appeared after 2–3 h and 4–6 h with talinolol given as fast-liberating capsules. Food increased the maximum concentrations significantly (223 ± 76 μg/ml vs. 315 ± 122 μg/ml, p ‹ 0.05) and shifted the second peak of talinolol to shorter tmax values (3.8 ± 1.2 h vs. 2.1 ± 0.6 h, p ‹ 0.05), which was associated with faster absorption of retinyl palmitate. Pharmacokinetic model fits showed that about half of the oral talinolol dose given with and without meal is drained from the intestine via a presystemic storage compartment.

Conclusions.

The double-peak phenomenon of talinolol is likely caused by a presystemic storage compartment, which represents the complex interplay of heterogeneous uptake and kick-back transport processes along the intestinal-hepatic absorption pathway.

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References

  1. 1. P. Macheras and P. Argyrakis. Gastrointestinal drug absorption: Is it time to consider heterogeneity as well as homogeneity? Pharm. Res. 14:842–847 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. 2. H. Zhou. Pharmacokinetic strategies in deciphering atypical drug absorption profiles. J. Clin. Pharmacol. 43:211–227 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. 3. 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. Pharmacokinet. Biopharm. 15:225–239 (1987).

    Article  CAS  PubMed  Google Scholar 

  4. 4. O. Voinchet, R. Farinotti, P. Loirat, and A. Dauphin. Jejunal and ileal absorption of cimetidine in man. Gastroenterology 80:1310A (1981).

    Google Scholar 

  5. 5. J. H. Lin. Pharmacokinetic and pharmacodynamic properties of histamine H2-receptor antagonists. Clin. Pharmacokinet. 20:218–236 (1991).

    CAS  PubMed  Google Scholar 

  6. 6. 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).

    CAS  PubMed  Google Scholar 

  7. 7. 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. Pharmacokinet. Biopharm. 23:267–286 (1995).

    CAS  PubMed  Google Scholar 

  8. 8. H. Lennernas and C. G. Regardh. Evidence for an interaction between the beta-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. 10:879–883 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. 9. S. A. Mostafavi and R. T. Foster. Influence of cimetidine co-administration on the pharmacokinetics of acebutolol enantiomers and its metabolite diacetolol in a rat model: the effect of gastric pH on double-peak phenomena. Int. J. Pharm. 255:81–86 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. 10. K. Westphal, A. Weinbrenner, T. Giessmann, M. Stuhr, G. Franke, M. Zschiesche, R. Oertel, B. Terhaag, H. K. Kroemer, and W. Siegmund. Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P-glycoprotein. Clin. Pharmacol. Ther. 68:6–12 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. 11. M. S. Roberts, B. M. Magnusson, F. J. Burczynski, and M. Weiss. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin. Pharmacokinet. 41:751–790 (2002).

    CAS  PubMed  Google Scholar 

  12. 12. 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. Pharmacokinet. Biopharm. 15:529–544 (1987).

    Article  CAS  PubMed  Google Scholar 

  13. 13. T. Gramatte. E. EL-Desoky, and U. Klotz. Site-dependent small intestinal absorption of ranitidine. Eur. J. Clin. Pharmacol. 46:253–259 (1994).

    CAS  PubMed  Google Scholar 

  14. 14. B. Terhaag, T. Gramatte, K. Richter, J. Voss, and K. Feller. The biliary elimination of the selective beta-receptor blocking drug talinolol in man. Int. J. Clin. Pharmacol. Ther. Toxicol. 27:170–172 (1989).

    CAS  PubMed  Google Scholar 

  15. 15. T. Gramatte, R. Oertel, B. Terhaag, and W. Kirch. Direct demonstration of small intestinal secretion and site-dependent absorption of the beta-blocker talinolol in humans. Clin. Pharmacol. Ther. 59:541–549 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. 16. W. Kübler. Kinetic studies on the development of lipid resorption in relation with the lymph flow rate. Monatsschr. Kinderheilkd. 113:308–310 (1965).

    PubMed  Google Scholar 

  17. 17. R. Blomhoff. Transport and metabolism of vitamin A. Nutr. Rev. 52:S13–S23 (1994).

    CAS  PubMed  Google Scholar 

  18. 18. C. J. Porter and W. N. Charman. Intestinal lymphatic drug transport: an update. Adv. Drug Deliv. Rev. 50:61–80 (2001).

    CAS  PubMed  Google Scholar 

  19. 19. E. Naslund, J. Bogefors, P. Gryback, H. Jacobsson, and P. M. Hellstrom. Gastric emptying: comparison of scintigraphic, polyethylene glycol dilution, and paracetamol tracer assessment techniques. Scand. J. Gastroenterol. 35:375–379 (2000).

    CAS  PubMed  Google Scholar 

  20. 20. M. Zschiesche, G. L. Lemma, K. J. Klebingat, G. Franke, and B. Terhaag. A Hoffmann, T. Gramatte, H.K. Kroemer, and W. Siegmund. Stereoselective. disposition of talinolol in man. J. Pharm. Sci. 91:303–311 (2002).

    CAS  PubMed  Google Scholar 

  21. 21. H. A. Akaike. A new look at the statistical model identification. IEEE Trans Automatic Control. 19:716–723 (1974).

    Google Scholar 

  22. 22. T. Gramatte and K. Richter. Paracetamol absorption from different sites in the human small intestine. Br. J. Clin. Pharmacol. 37:608–611 (1994).

    CAS  PubMed  Google Scholar 

  23. 23. I. R. Wilding, J. G. Hardy, R. A. Sparrow, S. S. Davis, P. B. Daly, and J. R. English. In vivo evaluation of enteric-coated naproxen tablets using gamma scintigraphy. Pharm. Res. 9:1436–1441 (1992).

    CAS  PubMed  Google Scholar 

  24. 24. G. T. Ho, F. M. Moodie, and J. Satsangi. Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant of gastrointestinal disease? Gut 52:759–766 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. 25. V. D. Makhey, A. Guo, D. A. Norris, P. Hu, J. Yan, and P. J. Sinko. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Pharm. Res. 15:1160–1167 (1998).

    CAS  PubMed  Google Scholar 

  26. 26. R. Yumoto, T. Murakami, Y. Nakamoto, R. Hasegawa, J. Nagai, and M. Takano. Transport of rhodamine 123, a P-glycoprotein substrate, across rat intestine and Caco-2 cell monolayers in the presence of cytochrome P-450 3A-related compounds. J. Pharmacol. Exp. Ther. 289:149–155 (1999).

    CAS  PubMed  Google Scholar 

  27. 27. R. H. Stephens, J. Tanianis-Hughes, N. B. Higgs, M. Humphrey, and G. Warhurst. Region-dependent modulation of intestinal permeability by drug efflux transporters: In vitro studies in mdr1a(-/-) mouse intestine. J. Pharmacol. Exp. Ther. 303:1095–1101 (2002).

    CAS  PubMed  Google Scholar 

  28. 28. G. Fricker, J. Drewe, J. Huwyler, H. Gutmann, and C. Beglinger. Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro — in vivo correlation. Br. J. Pharmacol. 118:1841–1847 (1996).

    CAS  PubMed  Google Scholar 

  29. 29. S. Mouly and M. F. Paine. P-Glycoprotein increases from proximal to distal regions of human small intestine. Pharm. Res. 20:1595–1599 (2003).

    CAS  PubMed  Google Scholar 

  30. 30. M. Lindell, M. Lang, and H. Lennernäs. Expression of genes encoding for drug metabolising cytochrome P450 enzymes and P-glycoprotein in the rat small intestine; comparison to the liver. Eur. J. Drug Metab. Pharmacokin. 28:41–48 (2003).

    CAS  Google Scholar 

  31. 31. U. Wetterich, H. Spahn-Langguth, E. Mutschler, B. Terhaag, W. Rosch, and P. Langguth. Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration- and dose-dependent absorption in vitro and in vivo. Pharm. Res. 13:514–522 (1996).

    CAS  PubMed  Google Scholar 

  32. 32. T. Gramatte and R. Oertel. Intestinal secretion of intravenous talinolol is inhibited by luminal R-verapamil. Clin. Pharmacol. Ther. 66:239–245 (1999).

    CAS  PubMed  Google Scholar 

  33. 33. B. Trausch, R. Oertel, K. Richter, and T. Gramatte. Disposition and bioavailability of the beta 1-adrenoceptor antagonist talinolol in man. Biopharm. Drug Dispos. 16:403–414 (1995).

    CAS  PubMed  Google Scholar 

  34. 34. L. S. Gan, P. H. Hsyu, J. F. Pritchard, and D. Thakker. Mechanism of intestinal absorption of ranitidine and ondansetron: transport across Caco-2 cell monolayers. Pharm. Res. 10:1722–1725 (1993).

    CAS  PubMed  Google Scholar 

  35. 35. H. Lennernäs, O. Ahrenstedt, and A. L. Ungell. Intestinal drug absorption during induced net water absorption in man; a mechanistic study using antipyrine, atenolol and enalapril. Br. J. Clin. Pharmacol. 37:589–596 (1994).

    PubMed  Google Scholar 

  36. 36. B. Terhaag, H. Sahre, U. Lange, K. Richer, and K. Feller. Zum Einfluss der Nahrung auf die Absorption von Talinolol (Cordanum®) am gesunden Probanden. Z. Klin. Med. 46:1021–1023 (1991).

    CAS  Google Scholar 

  37. 37. S. G. Barnwell, T. Laudanski, M. Dwyer, M. J. Story, P. Guard, S. Cole, and D. Attwood. Reduced bioavailability of atenolol in man: the role of bile acids. Int. J. Pharm. 89:245–250 (1993).

    CAS  Google Scholar 

  38. 38. E. H. Harrison and M. M. Hussain. Mechanisms involved in the intestinal digestion and absorption of dietary vitamin A. J. Nutr. 131:1405–1408 (2001).

    CAS  PubMed  Google Scholar 

  39. 39. E. Li and P. Tso. Vitamin A uptake from foods. Curr. Opin. Lipidol. 14:241–247 (2003).

    CAS  PubMed  Google Scholar 

  40. 40. K. M. Wasan. The role of lymphatic transport in enhancing oral protein and peptide drug delivery. Drug Dev. Ind. Pharm. 28:1047–1058 (2002).

    CAS  PubMed  Google Scholar 

  41. 41. K. A. Milton, G. Edwards, S. A. Ward, M. L. Orme, and A. M. Breckenridge. Pharmacokinetics of halofantrine in man: effects of food and dose size. Br. J. Clin. Pharmacol. 28:71–77 (1989).

    CAS  PubMed  Google Scholar 

  42. 42. M. D. Robertson, M. Parkes, B. F. Warren, D. J. Ferguson, K. G. Jackson, D. P. Jewell, and K. N. Frayn. Mobilisation of enterocyte fat stores by oral glucose in humans. Gut 52:834–839 (2003).

    CAS  PubMed  Google Scholar 

  43. 43. L. M. S. Chan, S. Lowes, and B. H. Hirst. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur. J. Pharm. Sci. 21:25–51 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. 44. P. Chandra and K. L. R. Brouwer. The complexities of hepatic drug transport: Current knowledge and emerging concepts. Pharm. Res. 21:719–735 (2004).

    CAS  PubMed  Google Scholar 

  45. 45. J. W. Jonker and A. H. Schinkel. Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J. Pharmacol. Exp. Ther. 308:2–9 (2004).

    CAS  PubMed  Google Scholar 

  46. 46. H. Koepsel. Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol. Sci. 25:375–381 (2004).

    PubMed  Google Scholar 

  47. 47. U. I. Schwarz, T. Gramatte, J. Krappweis, A. Berndt, R. Oertel, O. von Richter, and W. Kirch. Unexpected effect of verapamil on oral bioavailability of the beta-blocker talinolol in humans. Clin. Pharmacol. Ther. 65:283–290 (1999).

    CAS  PubMed  Google Scholar 

  48. 48. U. I. Schwarz, G. K. Dresser, R. Oertel, and R. B. Kim. Talinolol-verapamil interaction is not solely due to P-glycoprotein inhibition. Clin. Pharmacol. Ther. 69:PIII–86 (2001).

    Google Scholar 

  49. 49. R. J. Ott and K. M. Giacomini. Stereoselective interactions of organic cations with the organic cation transporter in OK cells. Pharm. Res. 10:1169–1173 (1993).

    CAS  PubMed  Google Scholar 

  50. 50. A. J. Dudley, K. Bleasby, and C. D. Brown. The organic cation transporter OCT2 mediates the uptake of beta-adrenoceptor antagonists across the apical membrane of renal LLC-PK(1) cell monolayers. Br. J. Pharmacol. 131:71–79 (2000).

    CAS  PubMed  Google Scholar 

  51. 51. D. Kobayashi, T. Nozawa, K. Imai, J. Nezu, A. Tsuji, and I. Tamai. Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J. Pharmacol. Exp. Ther. 306:703–708 (2003).

    CAS  PubMed  Google Scholar 

  52. 52. M. Niemi, E. Schaeffeler, T. Lang, M. F. Fromm, M. Neuvonen, C. Kyrklund, J. T. Backman, R. Kerb, M. Schwab, P. J. Neuvonen, M. Eichelbaum, and K. T. Kivisto. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14:429–440 (2004).

    CAS  PubMed  Google Scholar 

  53. 53. J. Mwinyi, A. Johne, S. Bauer, I. Roots, and T. Gerloff. Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin. Pharmacol. Ther. 75:415–421 (2004).

    CAS  PubMed  Google Scholar 

  54. 54. K. Westphal, A. Weinbrenner, M. Zschiesche, G. Franke, M. Knoke, R. Oertel, P. Fritz, O. von Richter, R. Warzok, T. Hachenberg, H. M. Kauffmann, D. Schrenk, B. Terhaag, H. K. Kroemer, and W. Siegmund. Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction. Clin. Pharmacol. Ther. 68:345–355 (2000).

    CAS  PubMed  Google Scholar 

  55. 55. W. Siegmund, S. Altmannsberger, A. Paneitz, U. Hecker, M. Zschiesche, G. Franke, W. Meng, R. Warzok, E. Schroeder, B. Sperker, B. Terhaag, I. Cascorbi, and H. K. Kroemer. Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition. Clin. Pharmacol. Ther. 72:256–264 (2002).

    CAS  PubMed  Google Scholar 

  56. 56. T. Giessmann, K. May, C. Modess, D. Wegner, U. Hecker, M. Zschiesche, P. Dazert, M. Grube, E. Schroeder, W. Warzok, I. Cascorbi, H.K. Kroemer, and W. Siegmund. Carbamazepine regulates intestinal p-glycoprotein and mrp2 and influences disposition of talinolol in man. Clin. Pharmacol. Ther. 76:192–200 (2004).

    CAS  PubMed  Google Scholar 

  57. 57. U. I. Schwarz, T. Gramatte, J. Krappweis, R. Oertel, and W. Kirch. P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans. Int. J. Clin. Pharmacol. Ther. 38:161–167 (2000).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biopharmacy and Pharmaceutical Technology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt University, Greifswald, Germany

    Werner Weitschies, Vera Hartmann & Stefan Nagel

  2. Department of Clinical Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt University, Greifswald, Germany

    Annika Bernsdorf, Thomas Giessmann, Michael Zschiesche, Christiane Modess, Claudia Mrazek, Danilo Wegner & Werner Siegmund

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  1. Werner Weitschies
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  2. Annika Bernsdorf
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Weitschies, W., Bernsdorf, A., Giessmann, T. et al. The Talinolol Double-Peak Phenomenon Is Likely Caused by Presystemic Processing After Uptake from Gut Lumen. Pharm Res 22, 728–735 (2005). https://doi.org/10.1007/s11095-005-2588-5

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