Download PDF
Planta Med 2018; 84(11): 795-805
DOI: 10.1055/s-0044-100401
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

In Vitro and In Situ Absorption and Metabolism of Sesquiterpenes from Petasites hybridus Extracts

Lucia Disch
1   Max Zeller Söhne AG, Romanshorn, Switzerland
,
Kristina Forsch
1   Max Zeller Söhne AG, Romanshorn, Switzerland
,
Beate Siewert
1   Max Zeller Söhne AG, Romanshorn, Switzerland
,
Jürgen Drewe
1   Max Zeller Söhne AG, Romanshorn, Switzerland
,
Gert Fricker
2   Ruprecht-Karls-University, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

received 11 October 2017
revised 28 November 2017

accepted 30 December 2017

Publication Date:
16 January 2018 (online)

    Permissions and Reprints

Abstract

Petasites hybridus extract is used in the treatment of seasonal allergic rhinitis. The aim of this study was to evaluate the active constituent petasin and its isomers isopetasin and neopetasin (petasins) in the P. hybridus extract Ze 339 for liberation, dissolution, absorption, and metabolism. The determination of pH-dependent thermodynamic solubility was performed via the shake-flask method. Petasins exhibited a low solubility that was pH independent. In vivo, the concentration of solute drugs is decreased continuously by intestinal absorption. Therefore, low solubility is not assumed to be critical for in vivo performance. Additionally, dissolution of an herbal medicinal product containing P. hybridus extract Ze 339 was assessed. Furthermore, high permeability through Caco-2 monolayers was evident. Using an in situ rat model, absorption capacity for petasins was found in all tested intestinal segments, namely, duodenum, jejunum, and ileum. Besides, high metabolism was evident both in Caco-2 monolayers and in the rat intestine. To compare intestinal and hepatic metabolism of petasins, in vitro enzyme assays using liver and intestinal cytosol and microsomes (S9 fraction) of rats and humans were performed. A significantly higher metabolic rate was found in the liver S9 fraction of both species compared with the intestinal S9 fraction.

Key words

Asteraceae - Petasites hybridus - petasin - BCS - Caco-2 - dissolution - intestinal absorption - metabolism

Supporting Information

    Results of pH-dependent thermodynamic solubility and enzyme assays, LC parameters of all used analytical methods as well as graphical illustration of efflux ratios and mass transfer (Caco-2 assay) and AUCphys (in situ rat study) are available as Supporting Information.

  • Supporting Information
 

  • References

  • 1 Schapowal A. Petasites Study Group. Butterbur Ze339 for the treatment of intermittent allergic rhinitis: dose-dependent efficacy in a prospective, randomized, double-blind, placebo-controlled study. Arch Otolaryngol Head Neck Surg 2004; 130: 1381-1386
    CrossrefPubMedGoogle Scholar
  • 2 Käufeler R, Polasek W, Brattström A, Koetter U. Efficacy and safety of butterbur herbal extract Ze 339 in seasonal allergic rhinitis: postmarketing surveillance study. Adv Ther 2006; 23: 373-384
    CrossrefPubMedGoogle Scholar
  • 3 Schapowal A. Petasites Study Group. Randomised controlled trial of butterbur and cetirizine for treating seasonal allergic rhinitis. BMJ 2002; 324: 144-146
    CrossrefPubMedGoogle Scholar
  • 4 Schapowal A. Petasites Study Group. Treating intermittent allergic rhinitis: a prospective, randomized, placebo and antihistamine-controlled study of Butterbur extract Ze 339. Phytother Res 2005; 19: 530-537
    CrossrefPubMedGoogle Scholar
  • 5 Dumitru AF, Shamji M, Wagenmann M, Hindersin S, Scheckenbach K, Greve J, Klenzner T, Hess L, Nebel S, Zimmermann C, Zahner C, Schmidt-Weber CB, Chaker AM. Petasol butenoate complex (Ze 339) relieves allergic rhinitis-induced nasal obstruction more effectively than desloratadine. J Allergy Clin Immunol 2011; 127: 1515-1521.e6
    CrossrefPubMedGoogle Scholar
  • 6 National Toxicology Program National Institute of Environmental Health Sciences, National Institutes of Health U.S Department of Health and Human Services, Research Triangle Park, NC. NTP (2009) Chemical Information Review Document for Butterbur (Petasites hybridus, ext.) [CAS No. 90082-63-6]. Services USDoHaH. National Toxicology Program. Available at. https://ntp.niehs.nih.gov/ntp/noms/support_docs/butterbur_nov2009.pdf Accessed January 11, 2018
    PubMedGoogle Scholar
  • 7 Schenk A, Siewert B, Toff S, Drewe J. UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339). J Chromatogr B Analyt Technol Biomed Life Sci 2015; 997: 23-29
    CrossrefPubMedGoogle Scholar
  • 8 Wichtl M. Teedrogen und Phytopharmaka – Ein Handbuch für die Praxis. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH; 2015
    Google Scholar
  • 9 U.S. Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER). FDA (2017) Guidance for Industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System, Guidance for Industry. Available at. https://www.fda.gov/downloads/Drugs/Guidances/ucm070246.pdf Accessed January 11, 2018
    PubMedGoogle Scholar
  • 10 European Medicines Agency (EMA). Guideline on Specifications: Test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products; EMA/HPMC/162241/2005 Rev. 2; Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency. London, UK: HMPC, EMA; 2011
    Google Scholar
  • 11 Tam D, Sun H, Pang KS. Influence of P-glycoprotein, transfer clearances, and drug binding on intestinal metabolism in Caco-2 cell monolayers or membrane preparations: a theoretical analysis. Drug Metab Dispos 2003; 31: 1214-1226
    CrossrefPubMedGoogle Scholar
  • 12 Sun H, Pang KS. Permeability, transport, and metabolism of solutes in Caco-2 cell monolayers: a theoretical study. Drug Metab Dispos 2008; 36: 102-123
    CrossrefPubMedGoogle Scholar
  • 13 Bourdet DL, Pollack GM, Thakker DR. Intestinal absorptive transport of the hydrophilic cation ranitidine: a kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs. transcellular transport in Caco-2 cells. Pharm Res 2006; 23: 1178-1187
    CrossrefPubMedGoogle Scholar
  • 14 Avdeef A, Tam KY. How well can the Caco-2/Madin-Darby canine kidney models predict effective human jejunal permeability?. J Med Chem 2010; 53: 3566-3584
    CrossrefPubMedGoogle Scholar
  • 15 Dressman JB, Amidon GL, Reppas C, Shah VP. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm Res 1998; 15: 11-22
    CrossrefPubMedGoogle Scholar
  • 16 McConnell EL, Basit AW, Murdan S. Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in-vivo experiments. J Pharm Pharmacol 2008; 60: 63-70
    CrossrefPubMedGoogle Scholar
  • 17 Parrott N, Lukacova V, Fraczkiewicz G, Bolger MB. Predicting pharmacokinetics of drugs using physiologically based modeling – application to food effects. AAPS J 2009; 11: 45-53
    CrossrefPubMedGoogle Scholar
  • 18 Shen Q, Lin Y, Handa T, Doi M, Sugie M, Wakayama K, Okada N, Fujita T, Yamamoto A. Modulation of intestinal P-glycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies. Int J Pharm 2006; 313: 49-56
    CrossrefPubMedGoogle Scholar
  • 19 Schulze JD, Peters EE, Vickers AW, Staton JS, Coffin MD, Parsons GE, Basit AW. Excipient effects on gastrointestinal transit and drug absorption in beagle dogs. Int J Pharm 2005; 300: 67-75
    CrossrefPubMedGoogle Scholar
  • 20 Basit AW, Podczeck F, Newton JM, Waddington WA, Ell PJ, Lacey LF. Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine. Pharm Res 2002; 19: 1368-1374
    CrossrefPubMedGoogle Scholar
  • 21 Beig A, Miller JM, Lindley D, Carr RA, Zocharski P, Agbaria R, Dahan A. Head-to-head comparison of different solubility-enabling formulations of etoposide and their consequent solubility-permeability interplay. J Pharm Sci 2015; 104: 2941-2947
    CrossrefPubMedGoogle Scholar
  • 22 Duffus JH, Nordberg M, Templeton DM. Glossary of terms used in toxicology, 2nd Edition. Pure Appl Chem 2007; 79: 1153-1344
    CrossrefPubMedGoogle Scholar
  • 23 Mishra DS, Yalkowsky SH. Ideal solubility of a solid solute: effect of heat capacity assumptions. Pharm Res 1992; 9: 958-959
    CrossrefPubMedGoogle Scholar
  • 24 Artursson P. Epithelial transport of drugs in cell culture. I: A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells. J Pharm Sci 1990; 79: 476-482
    CrossrefPubMedGoogle Scholar
  • 25 Artursson P, Borchardt RT. Intestinal drug absorption and metabolism in cell cultures: Caco-2 and beyond. Pharm Res 1997; 14: 1655-1658
    CrossrefPubMedGoogle Scholar
  • 26 Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev 2001; 46: 27-43
    CrossrefPubMedGoogle Scholar