Download PDF
Planta Med 2010; 76(1): 62-69
DOI: 10.1055/s-0029-1185949
Pharmacology
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Characterization of in Vitro Pharmacokinetic Properties of Hoodigogenin A from Hoodia gordonii

Vamsi Lakshmi Mohan Madgula1 , Bharathi Avula1 , Rahul S. Pawar1 , Yatin J. Shukla1 , Ikhlas A. Khan1 , 2 , Larry A. Walker1 , 3 , Shabana I. Khan1
  • 1National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, USA
  • 2Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS, USA
  • 3Department of Pharmacology, School of Pharmacy, The University of Mississippi, University, MS, USA
Further Information

Publication History

received April 16, 2009 revised June 4, 2009

accepted June 11, 2009

Publication Date:
28 July 2009 (online)

Also available at
    Permissions and Reprints

Abstract

This study was aimed to predict the pharmacokinetic properties of hoodigogenin A, which is the aglycone of the oxypregnane steroidal glycoside P57AS3 (P57) isolated from Hoodia gordonii. A series of in vitro assays was used to predict its gastric, intestinal and metabolic stability, intestinal and blood brain barrier (BBB) transport, protein binding and interaction with major drug metabolising enzymes. In the simulated gastric fluid, hoodigogenin A was stable (2 % degradation in 60 minutes) whereas P57 was unstable (45 % degradation in 30 minutes). In simulated intestinal fluid, P57 was degraded to an extent of 8 % in 180 minutes, while hoodigogenin A was stable. Hoodigogenin A was efficiently transported by passive diffusion across Caco-2 and MDR1-MDCK monolayers with Papp values in the range of 32 × 10−6 cm/sec and 22 × 10−6 cm/sec, respectively. The compound was metabolically unstable in human liver microsomes and S9 fractions with a CL′int of 71 and 120 mL/min/kg, respectively and was bound to the plasma proteins to an extent of 92 %. The compound strongly inhibited CYP3A4 activity (IC50 3 µM), indicating a possibility of drug-herb/botanical interactions when products containing H. gordonii are used simultaneously with other botanicals/herbs/drugs.

Key words

Hoodia gordonii - Asclepiadaceae - hoodigogenin A - metabolic stability - CYP inhibition - intestinal and blood brain barrier transport

References

  • 1 South African National Biodiversity Institute .Plants of Southern Africa. Available at www.plantzafrica.com. Accessed April 4, 2009
  • 2 Rubin D I, Cawthorne M A, Bindra J S. Extracts, compounds and pharmaceutical compositions having anti-diabetic activity and their uses. US Patent 7416744B2 2008
    Search in Google Scholar
  • 3 Rubin D I, Cawthorne M A, Bindra J S. Extracts, compounds and pharmaceutical compositions having anti-diabetic activity and their use. Euro Patent 1166792 2002
    Search in Google Scholar
  • 4 Pawar R S, Shukla Y J, Khan S I, Avula B, Khan I A. New oxypregnane glycosides from appetite suppressant herbal supplement Hoodia gordonii.  Steroids. 2007;  72 524-534
    CrossrefPubMedSearch in Google Scholar
  • 5 van Heerden F R, Marthinus Horak R, Maharaj V J, Vleggaar R, Senabe J V, Gunning P J. An appetite suppressant from Hoodia species.  Phytochemistry. 2007;  68 2545-2553
    CrossrefPubMedSearch in Google Scholar
  • 6 MacLean D B, Luo L G. Increased ATP content/production in the hypothalamus may be a signal for energy-sensing of satiety: studies of the anorectic mechanism of a plant steroidal glycoside.  Brain Res. 2004;  1020 1-11
    CrossrefPubMedSearch in Google Scholar
  • 7 Madgula V L, Avula B, Pawar R S, Shukla Y J, Khan I A, Walker L A, Khan S I. In vitro metabolic stability and intestinal transport of P57AS3 (P57) from Hoodia gordonii and its interaction with drug metabolizing enzymes.  Planta Med. 2008;  74 1269-1275
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Gee J M, DuPont M S, Day A J, Plumb G W, Williamson G, Johnson I T. Intestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway.  J Nutr. 2000;  130 2765-2771
    PubMedSearch in Google Scholar
  • 9 Day A J, Canada F J, Diaz J C, Kroon P A, McLauchlan R, Faulds C B, Plumb G W, Morgan M R, Williamson G. Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase.  FEBS Lett. 2000;  468 166-170
    CrossrefPubMedSearch in Google Scholar
  • 10 Day A J, DuPont M S, Ridley S, Rhodes M, Rhodes M J, Morgan M R, Williamson G. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver beta-glucosidase activity.  FEBS Lett. 1998;  436 71-75
    CrossrefPubMedSearch in Google Scholar
  • 11 Andlauer W, Kolb J, Furst P. Isoflavones from tofu are absorbed and metabolized in the isolated rat small intestine.  J Nutr. 2000;  130 3021-3027
    PubMedSearch in Google Scholar
  • 12 Liu Y, Hu M. Absorption and metabolism of flavonoids in the caco-2 cell culture model and a perused rat intestinal model.  Drug Metab Dispos. 2002;  30 370-377
    CrossrefPubMedSearch in Google Scholar
  • 13 Walgren R A, Karnaky Jr K J, Lindenmayer G E, Walle T. Efflux of dietary flavonoid quercetin 4′-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance-associated protein-2.  J Pharmacol Exp Ther. 2000;  294 830-836
    PubMedSearch in Google Scholar
  • 14 Brown J E, Khodr H, Hider R C, Rice-Evans C A. Structural dependence of flavonoid interactions with Cu2+ ions: implications for their antioxidant properties.  Biochem J. 1998;  330 (Pt 3) 1173-1178
    PubMedSearch in Google Scholar
  • 15 Kay C D. Aspects of anthocyanin absorption, metabolism and pharmacokinetics in humans.  Nutr Res Rev. 2006;  19 137-146
    CrossrefPubMedSearch in Google Scholar
  • 16 Gumbleton M, Audus K L. Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier.  J Pharm Sci. 2001;  90 1681-1698
    CrossrefPubMedSearch in Google Scholar
  • 17 Wang Q, Rager J D, Weinstein K, Kardos P S, Dobson G L, Li J, Hidalgo I J. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier.  Int J Pharm. 2005;  288 349-359
    CrossrefPubMedSearch in Google Scholar
  • 18 The United States Pharmacopeia XXXI/The National Formulary 26 .Solutions/Test solutions. Rockville; The United States Pharmacopeial Convention 2008: 817
    Search in Google Scholar
  • 19 Asafu-Adjaye E B, Faustino P J, Tawakkul M A, Anderson L W, Yu L X, Kwon H, Volpe D A. Validation and application of a stability-indicating HPLC method for the in vitro determination of gastric and intestinal stability of venlafaxine.  J Pharm Biomed Anal. 2007;  43 1854-1859
    CrossrefPubMedSearch in Google Scholar
  • 20 Madgula V L, Avula B, Reddy V L N, Khan I A, Khan S I. Transport of decursin and decursinol angelate across Caco-2 and MDR-MDCK cell monolayers: in vitro models for intestinal and blood-brain barrier permeability.  Planta Med. 2007;  73 330-335
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Madgula V L, Avula B, Choi Y W, Pullela S V, Khan I A, Walker L A, Khan S I. Transport of Schisandra chinensis extract and its biologically-active constituents across Caco-2 cell monolayers – an in-vitro model of intestinal transport.  J Pharm Pharmacol. 2008;  60 363-370
    CrossrefPubMedSearch in Google Scholar
  • 22 Obach R S. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes.  Drug Metab Dispos. 1999;  27 1350-1359
    PubMedSearch in Google Scholar
  • 23 Crespi C L, Miller V P, Penman B W. Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450.  Anal Biochem. 1997;  248 188-190
    CrossrefPubMedSearch in Google Scholar
  • 24 Harvard Bioscience Inc. .Guide to equilibrium dialysis. Southborough; The Nest Group, Inc. 2008
    Search in Google Scholar
  • 25 Food and Drug Administration .Guidance for industry, waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on biopharmaceutical classification system. Rockville; CDER, Department of Health and Human Services 2000
    Search in Google Scholar
  • 26 Gres M C, Julian B, Bourrie M, Meunier V, Roques C, Berger M, Boulenc X, Berger Y, Fabre G. Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line: comparison with the parental Caco-2 cell line.  Pharm Res. 1998;  15 726-733
    CrossrefPubMedSearch in Google Scholar
  • 27 Stewart B H, Chan O H, Lu R H, Reyner E L, Schmid H L, Hamilton H W, Steinbaugh B A, Taylor M D. Comparison of intestinal permeabilities determined in multiple in vitro and in situ models: relationship to absorption in humans.  Pharm Res. 1995;  12 693-699
    CrossrefPubMedSearch in Google Scholar
  • 28 Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells.  Biochem Biophys Res Commun. 1991;  175 880-885
    CrossrefPubMedSearch in Google Scholar
  • 29 Garberg P, Ball M, Borg N, Cecchelli R, Fenart L, Hurst R D, Lindmark T, Mabondzo A, Nilsson J E, Raub T J, Stanimirovic D, Terasaki T, Oberg J O, Osterberg T. In vitro models for the blood-brain barrier.  Toxicol In Vitro. 2005;  19 299-334
    CrossrefPubMedSearch in Google Scholar
  • 30 Camenisch G, Alsenz J, van de Waterbeemd H, Folkers G. Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs' lipophilicity and molecular weight.  Eur J Pharm Sci. 1998;  6 317-324
    PubMedSearch in Google Scholar
  • 31 Obach R S, Baxter J G, Liston T E, Silber B M, Jones B C, MacIntyre F, Rance D J, Wastall P. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data.  J Pharmacol Exp Ther. 1997;  283 46-58
    PubMedSearch in Google Scholar
  • 32 Butterweck V, Derendorf H, Gaus W, Nahrstedt A, Schulz V, Unger M. Pharmacokinetic herb-drug interactions: are preventive screenings necessary and appropriate?.  Planta Med. 2004;  70 784-791
    Thieme ConnectPubMedSearch in Google Scholar
  • 33 CDER .Drug interaction studies: study design data analysis, and implications for dosing and labelling. Rockville; Food and Drug Administration 2004
    Search in Google Scholar
  • 34 Liu Y, Yang L. Early metabolism evaluation making traditional Chinese medicine effective and safe therapeutics.  J Zhejiang Univ Sci B. 2006;  7 99-106
    CrossrefPubMedSearch in Google Scholar
  • 35 Barone G W, Gurley B J, Ketel B L, Lightfoot M L, Abul-Ezz S R. Drug interaction between St. John's wort and cyclosporine.  Ann Pharmacother. 2000;  34 1013-1016
    CrossrefPubMedSearch in Google Scholar
  • 36 Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract.  N Engl J Med. 1997;  336 1108
    CrossrefPubMedSearch in Google Scholar
  • 37 Usia T, Iwata H, Hiratsuka A, Watabe T, Kadota S, Tezuka Y. CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants.  Phytomedicine. 2006;  13 67-73
    PubMedSearch in Google Scholar
  • 38 Huang J D, Oie S. Effect of altered disopyramide binding on its pharmacologic response in rabbits.  J Pharmacol Exp Ther. 1982;  223 469-471
    PubMedSearch in Google Scholar
  • 39 Qin M, Nilsson M, Oie S. Decreased elimination of drug in the presence of alpha-1-acid glycoprotein is related to a reduced hepatocyte uptake.  J Pharmacol Exp Ther. 1994;  269 1176-1181
    PubMedSearch in Google Scholar
  • 40 Shand D G, Cotham R H, Wilkinson G R. Perfusion-limited of plasma drug binding on hepatic drug extraction.  Life Sci. 1976;  19 125-130
    CrossrefPubMedSearch in Google Scholar
  • 41 Jansen J A. Influence of plasma protein binding kinetics on hepatic clearance assessed from a “tube” model and a “well-stirred” model.  J Pharmacokinet Biopharm. 1981;  9 15-26
    CrossrefPubMedSearch in Google Scholar

Shabana I. Khan

School of Pharmacy
National Center for Natural Products Research
University of Mississippi

University, MS 38677

USA

Phone: + 01 66 29 15 10 41

Fax: + 01 66 29 15 70 62

Email: skhan@olemiss.edu