Advertisement

Stereoselective Hepatic Disposition of Model Diastereomeric Acyl Glucuronides

  • David M. Shackleford
  • Roger L. Nation
  • R.W. Milne
  • P.J. Hayball
  • Allan M. EvansEmail author
Article

Abstract

Numerous studies have previously been conducted with the impulse-response isolated perfused rat liver (IR-IPRL) to establish the role of both physiological and physicochemical factors in determining solutes' pattern of hepatic disposition, however the impact of optical isomerism on hepatic disposition has hardly been studied using this methodology. In this study, the IR-IPRL was used to assess the extent of stereoselectivity exhibited by the kinetic processes involved in the hepatic disposition of the diastereomeric acyl glucuronides of (R)- and (S)-2-phenylpropionic acid (i.e. (R)- and (S)-PPAG). Moment and model-dependent (distributed model and axial dispersion model) analyses were conducted of the hepatic outflow profiles generated upon bolus administration of (R)-14C-PPAG, or (S)-14C-PPAG and 3H-Sucrose (used as a marker of the hepatic vascular space) into the portal inflow of isolated perfused livers of male Sprague–Dawley rats (n=4). Significant differences between (R)- and (S)-PPAG were apparent in the pharmacokinetic parameters defining the total hepatic disposition of the two diastereomers, the most marked being the hepatic availabilities, where the value for (S)-PPAG (0.721±0.059) was significantly lower than that of (R)-PPAG (0.909±0.042). The distributed and axial dispersion model analyses suggested that the more extensive hepatic extraction of (S)-PPAG was (at least in part) due to the higher sinusoidal membrane permeability-surface area product (PSupt) of that diastereomer, and this has been considered in light of the emerging evidence regarding the role of hepatocellular membrane transport mechanisms. Furthermore, given the potential immunogenicity of acyl glucuronides (through covalent binding to plasma and intracellular proteins), the results of this study suggest that diastereomeric glucuronides may exhibit differing toxicity due to differences in their access to intracellular proteins.

Hepatic Disposition distereomers acyl glucuronides stereo selectivity transport hepatocyte perfused liver impulse-response 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    C.¡H.¡ Chou,¡A.¡J.¡ McLachlan,and¡M.¡ Rowland.¡Membrane-permeability¡and¡lipophilicity¡in¡the¡isolated-perfused¡rat-liver—5-ethyl¡barbituric-acid¡and¡other¡compounds.¡J.¡Pharmacol.¡Exp.¡Ther.¡275:933-940¡(1995).Google Scholar
  2. 2.
    C.¡H.¡ Chou,¡A.¡M.¡ Evans,¡G.¡ Fornasini,¡and¡M.¡ Rowland.¡Relationship¡between¡lipophilicity¡and¡hepatic¡dispersion¡and¡distribution¡for¡a¡homologous¡series¡of¡barbiturates¡in¡the¡isolated¡perfused¡insitu¡rat¡liver.¡Drug¡Metab.¡Dispos.¡21:933-938¡(1993).Google Scholar
  3. 3.
    G.¡D.¡ Mellick¡and¡M.¡S.¡ Roberts.¡Structure-hepatic¡disposition¡relationships¡for¡phenolic¡compounds.¡Toxicol.¡Appl.¡Pharmacol.¡158:50-60¡(1999).Google Scholar
  4. 4.
    D.¡Y.¡ Hung,¡G.¡D.¡ Mellick,¡Y.¡G.¡ Anissimov,¡M.¡ Weiss,¡and¡M.¡S.¡ Roberts.¡Hepatic¡structure-pharmacokinetic¡relationships:¡The¡hepatic¡disposition¡and¡metabolite¡kinetics¡of¡a¡homologous¡series¡of¡O-acyl¡derivatives¡of¡salicylic¡acid.¡Br.¡J.¡Pharmacol.¡124:1475-1483¡(1998).Google Scholar
  5. 5.
    D.¡Y.¡ Hung,¡G.¡D.¡ Mellick,¡Y.¡G.¡ Anissimov,¡M.¡ Weiss,¡and¡M.¡S.¡ Roberts.¡Hepatic¡disposition¡and¡metabolite¡kinetics¡of¡a¡homologous¡series¡of¡diflunisal¡esters.¡J.¡Pharmaceut.¡Sci.¡87:943-951¡(1998).Google Scholar
  6. 6.
    D.¡M.¡ Shackleford,¡P.¡J.¡ Hayball,¡G.¡D.¡ Reynolds,¡D.¡P.¡G.¡ Hamon,¡A.¡M.¡ Evans,¡R.¡W.¡ Milne,¡and¡R.¡L.¡ Nation.¡A¡small-scale¡synthesis¡and¡enantiomeric¡resolution¡of¡(RS)-[1-C-14]-2-phenylpropionic¡acid¡and¡biosynthesis¡of¡its¡diastereomeric¡acyl¡glucuronides.¡J.¡Labelled¡Comp.¡Rad.¡44:225-234¡(2001).Google Scholar
  7. 7.
    A.¡M.¡ Evans¡and¡K.¡ Shanahan.¡The¡disposition¡of¡morphine¡and¡Its¡metabolites¡in¡the¡in-situ¡rat¡isolated¡perfused¡liver.¡J.¡Pharm.¡Pharmacol.¡47:333-339¡(1995).Google Scholar
  8. 8.
    Y.¡ Nakamura¡and¡T.¡ Yamaguchi.¡Stereoselective¡metabolism¡of¡2-phenylpropionic¡acid¡in¡rat¡.1.¡Invitro¡studies¡on¡the¡stereoselective¡isomerization¡and¡glucuronidation¡of¡2¡phenylpropionic¡acid.¡Drug¡Metabol.¡Dispos.¡15:529-534¡(1987).Google Scholar
  9. 9.
    K.¡ Akira,¡H.¡ Hasegawa,¡Y.¡ Shinohara,¡M.¡ Imachi,¡and¡T.¡ Hashimoto.¡Stereoselective¡internal¡acyl¡migration¡of¡1¡beta-O-acyl¡glucuronides¡of¡enantiomeric¡2-phenylpropionic¡acids.¡Biol.¡Pharmaceut.¡Bull.¡23:506-510¡(2000).Google Scholar
  10. 10.
    C.¡A.¡ Goresky,¡G.¡G.¡ Bach,¡and¡B.¡E.¡ Nadeau.¡On¡the¡uptake¡of¡materials¡by¡the¡intact¡liver:¡The¡concentrative¡transport¡of¡Rubidium-86.¡J.¡Clin.¡Invest.¡52:975-990¡(1973).Google Scholar
  11. 11.
    M.¡S.¡ Roberts¡and¡M.¡ Rowland.¡A¡dispersion¡model¡of¡hepatic¡elimination:¡1.¡Formulation¡of¡the¡model¡and¡bolus¡considerations.¡J.¡Pharmacokinet.¡Biopharm.¡14:227-260¡(1986).Google Scholar
  12. 12.
    A.¡M.¡ Evans,¡Z.¡ Hussein,¡and¡M.¡ Rowland.¡A¡2-compartment¡dispersion¡model¡describes¡the¡hepatic¡outflow¡profile¡of¡diclofenac¡in¡the¡presence¡of¡Its¡binding-protein.¡J.¡Pharm.¡Pharmacol.¡43:709-714¡(1991).Google Scholar
  13. 13.
    Y.¡ Yano,¡K.¡ Yamaoka,¡and¡H.¡ Tanaka.¡A¡nonlinear¡least-squares¡program,¡Multi(Filt),¡based¡on¡fast¡inverse¡laplace¡transform¡for¡microcomputers.¡Chem.¡Pharmaceut.¡Bull.¡37:1035-1038¡(1989).Google Scholar
  14. 14.
    Y.¡ Giroud,¡P.-ACarrupt,¡A.¡ Pagliara,¡B.¡ Testa,¡and¡R.¡G.¡ Dickinson.¡Intrinsic¡and¡intramolecular¡lipophilicity¡effects¡in¡O-glucuronides.¡Helv.¡Chim.¡Acta¡81:330-341¡(1998).Google Scholar
  15. 15.
    C.¡A.¡ Goresky,¡G.¡G.¡ Bach,¡A.¡ Simard,¡A.¡J.¡ Schwab,¡and¡A.¡ Bracht.¡Uptake¡of¡lactate¡by¡the¡liver:¡Effect¡of¡red¡blood¡cell¡carriage.¡Am.¡J.¡Physiol.—Gastr.¡Liver¡Physiol.¡278:G775-G788¡(2000).Google Scholar
  16. 16.
    W.¡P.¡ Geng,¡A.¡J.¡ Schwab,¡C.¡A.¡ Goresky,¡and¡K.¡S.¡ Pang.¡Carrier-mediated¡uptake¡and¡excretion¡of¡bromosulfophthalein–glutathione¡in¡perfused¡rat¡liver—a¡multiple¡indicator¡dilution¡study.¡Hepatology¡22:1188-1207¡(1995).Google Scholar
  17. 17.
    C.¡A.¡ Goresky,¡K.¡S.¡ Pang,¡A.¡J.¡ Schwab,¡F.¡ Barker,¡W.¡F.¡ Cherry,¡and¡G.¡G.¡ Bach.¡Uptake¡of¡a¡protein-bound¡polar¡compound,¡acetaminophen¡sulfate,¡by¡perfused-rat-liver.¡Hepatology¡16:173-190¡(1992).Google Scholar
  18. 18.
    Z.¡ Hussein,¡A.¡J.¡ McLachlan,¡and¡M.¡ Rowland.¡Distribution¡kinetics¡of¡salicylic¡acid¡in¡the¡isolated¡perfused¡rat¡liver¡assessed¡using¡moment¡analysis¡and¡the¡two-compartment¡axial¡dispersion¡model.¡Pharmaceut.¡Res.¡11:1337-1345¡(1994).Google Scholar
  19. 19.
    S.¡ Miyauchi,¡Y.¡ Sugiyama,¡T.¡ Iga,¡and¡M.¡ Hanano.¡Membrane-limited¡hepatic¡transport¡of¡the¡conjugative¡metabolites¡of¡4-methylumbelliferone¡in¡rats.¡J.¡Pharmaceut.¡Sci.¡77:688-692¡(1988).Google Scholar
  20. 20.
    S.¡ Miyauchi,¡Y.¡ Sugiyama,¡T.¡ Iga,¡and¡M.¡ Hanano.¡The¡conjugative¡metabolism¡of¡4-methylumbelliferone¡and¡deconjugation¡to¡the¡parent¡drug¡examined¡by¡isolated¡perfused¡liver¡and¡in¡vivo¡liver¡homogenate¡of¡rats.¡Chem.¡Pharmaceut.¡Bull.¡37:475-480¡(1989).Google Scholar
  21. 21.
    S.¡ Ratna,¡M.¡ Chiba,¡L.¡ Bandyopadhyay,¡and¡K.¡S.¡ Pang.¡Futile¡cycling¡between¡4-methylumbelliferone¡and¡its¡conjugates¡in¡perfused-rat-liver.¡Hepatology¡17:838-853¡(1993).Google Scholar
  22. 22.
    H.¡ Suzuki¡and¡Y.¡ Sugiyama.¡Transport¡of¡drugs¡across¡the¡hepatic¡sinusoidal¡membrane:¡Sinusoidal¡drug¡influx¡and¡efflux¡in¡the¡liver.¡Semin.¡Liver¡Dis.¡20:251-263¡(2000).Google Scholar
  23. 23.
    I.¡ Tamai,¡H.¡ Takanaga,¡H.¡ Maeda,¡Y.¡ Sai,¡T.¡ Ogihara,¡H.¡ Higashida,¡and¡A.¡ Tsuji.¡Participation¡of¡a¡proton-cotransporter,¡MCT1,¡in¡the¡intestinal¡transport¡of¡monocarboxylic¡acids.¡Biochem.¡Biophys.¡Res.¡Commun.214:482-489¡(1995).Google Scholar
  24. 24.
    T.¡ Ogihara,¡I.¡ Tamai,¡and¡A.¡ Tsuji.¡Structural¡requirements¡of¡substrates¡for¡stereoselective¡monocarboxylate¡transport¡in¡caco-cells.¡Pharm.¡Pharmacol.¡Commun.¡6:161-165¡(2000).Google Scholar
  25. 25.
    M.¡S.¡ Roberts,¡S.¡ Fraser,¡A.¡ Wagner,¡and¡L.¡ McLeod.¡Residence¡time¡distributions¡of¡solutes¡in¡the¡perfused¡rat¡liver¡using¡a¡dispersion¡model¡of¡hepatic¡elimination.¡Part¡2.¡Effect¡of¡pharmacological¡agents,¡retrograde¡perfusions,¡and¡enzyme¡inhibition¡on¡Evans¡blue,¡sucrose,¡water,¡and¡taurocholate.¡J.¡Pharmacokinet.¡Biop.¡18:235-258¡(1990).Google Scholar
  26. 26.
    K.¡S.¡ Pang,¡W.¡F.¡ Lee,¡W.¡F.¡ Cherry,¡V.¡ Yuen,¡and¡C.¡A.¡ Goresky¡et¡al.¡Effects¡of¡perfusate¡flow¡rate¡on¡measured¡blood¡volume,¡disse¡space,¡intracellular¡water¡space,¡and¡drug¡extraction¡in¡the¡perfused¡rat¡liver¡preparation:¡Characterization¡by¡the¡multiple¡indicator¡dilution¡technique.¡J.¡Pharmacokinet.¡Biop.¡16:595-632¡(1988).Google Scholar
  27. 27.
    S.¡ Iwakawa,¡H.¡ Spahn,¡L.¡Z.¡ Benet,¡and¡E.¡T.¡ Lin.¡Stereoselective¡binding¡of¡the¡glucuronide¡conjugates¡of¡carprofen¡enantiomers¡to¡human¡serum¡albumin.¡Biochem.¡Pharmacol.¡39:949-953¡(1990).Google Scholar
  28. 28.
    P.¡J.¡ Hayball,¡R.¡L.¡ Nation,¡and¡F.¡ Bochner.¡Stereoselective¡interactions¡of¡ketoprofen¡glucuronides¡with¡human¡plasma¡protein¡and¡serum¡albumin.¡Biochem.¡Pharmacol.¡44:291-299¡(1992).Google Scholar
  29. 29.
    A.¡ Bischer,¡P.¡ Zia-Amirhosseini,¡M.¡ Iwaki,¡A.¡F.¡ McDonagh,¡and¡L.¡Z.¡ Benet.¡Stereoselective¡binding¡properties¡of¡naproxen¡glucuronide¡diastereomers¡to¡protein.¡J.¡Pharmackinet.¡Biop.¡23:379-395¡(1995).Google Scholar
  30. 30.
    M.¡H.¡ Devries,¡G.¡J.¡ Mulder,¡G.¡M.¡M.¡ Groothuis,¡and¡D.¡K.¡F.¡ Meijer.¡Secretion¡of¡harmol¡sulfate¡from¡liver¡Into¡blood—evidence¡for¡a¡carrier-mediated¡mechanism.¡Hepatology¡4:771(1984).Google Scholar
  31. 31.
    L.¡ Sabordo,¡B.¡C.¡ Sallustio,¡A.¡M.¡ Evans,¡and¡R.¡L.¡ Nation.¡Hepatic¡disposition¡of¡the¡acyl¡glucuronide1-O-gemfibrozil-beta-D-glucuronide:¡Effects¡of¡dibromosulfophthalein¡on¡membrane¡transport¡and¡aglycone¡formation¡[In¡Process¡Citation].¡J.¡Pharmacol.¡Exp.¡Ther.¡288:414-420¡(1999).Google Scholar
  32. 32.
    L.¡ Sabordo,¡B.¡C.¡ Sallustio,¡A.¡M.¡ Evans,¡and¡R.¡L.¡ Nation.¡Hepatic¡disposition¡of¡the¡acyl¡glucuronide¡1-O-gemfibrozil-β-D-glucuronide:¡Effects¡of¡Clofibric¡Acid,¡acetaminophen,¡and¡acetaminophen¡glucuronide.¡J.¡Pharm.¡Exp.¡Ther.¡295:44-50¡(2000).Google Scholar
  33. 33.
    H.¡ Sasabe,¡Y.¡ Kato,¡A.¡ Tsuji,¡and¡Y.¡ Sugiyama.¡Stereoselective¡hepatobiliary¡transport¡of¡the¡quinolone¡antibiotic¡grepafloxacin¡and¡its¡glucuronide¡in¡the¡rat.¡J.¡Pharm.¡Exp.¡Ther.¡284:661-668¡(1998).Google Scholar
  34. 41.
    M.¡ Murata,¡I.¡ Tamai,¡Y.¡ Sai,¡O.¡ Nagata,¡H.¡ Kato,¡Y.¡ Sugiyama,¡and¡A.¡ Tsuji.¡Hepatobiliary¡transport¡kinetics¡of¡HSR-903,¡a¡new¡quinolone¡antibacterial¡agent.¡Drug¡Metabol.¡Dispos.¡26:1113-1119¡(1998).Google Scholar
  35. 34.
    H.¡ Suzuki.¡Analysis¡of¡xenobiotic¡detoxification¡system¡mediated¡by¡efflux¡transporters.¡Yakugaku¡Zasshi—J.¡Pharmaceut.¡Soc.¡Jpn.¡119:822-834¡(1999).Google Scholar
  36. 35.
    K.¡ Ogawa,¡H.¡ Suzuki,¡T.¡ Hirohashi,¡T.¡ Ishikawa,¡P.¡J.¡ Meier,¡K.¡ Hirose,¡T.¡ Akizawa,¡M.¡ Yoshioka,¡and¡Y.¡ Sugiyama.¡Characterization¡of¡inducible¡nature¡of¡MRP3¡in¡rat¡liver.¡Am.¡J.¡Physiol.¡Gastr.¡Liver¡Physiol.278:G438-G446¡(2000).Google Scholar
  37. 35.
    P.¡J.¡ Hayball.¡Formation¡and¡reactivity¡of¡acyl¡glucuronides—the¡influence¡of¡chirality.¡Chirality 7:1-9¡(1995).Google Scholar
  38. 36.
    Y.¡ Yano,¡K.¡ Yamaoka,¡Y.¡ Aoyama,¡and¡H.¡ Tanaka.¡Two-compartment¡dispersion¡model¡for¡analysis¡of¡organ¡perfusion¡system¡of¡drugs¡by¡fast¡inverse¡laplace¡transform¡(FILT).¡J.¡Pharmacokinet.¡Biop.¡12:179-202¡(1989).Google Scholar
  39. 37.
    M.¡S.¡ Roberts,¡J.¡D.¡ Donaldson,¡and¡M.¡ Rowland.¡Models¡of¡hepatic¡elimination:¡Comparison¡of¡stochastic¡models¡to¡describe¡residence¡time¡distributions¡and¡to¡predict¡the¡influence¡of¡drug¡distribution,¡enzyme¡heterogeneity,¡and¡systemic¡recycling¡on¡hepatic¡elimination.¡J.¡Pharmacokinet.¡Biop.¡16:41-83¡(1988).Google Scholar

Copyright information

© Plenum Publishing Corporation 2004

Authors and Affiliations

  • David M. Shackleford
    • 1
  • Roger L. Nation
    • 1
  • R.W. Milne
    • 1
  • P.J. Hayball
    • 1
  • Allan M. Evans
    • 1
    Email author
  1. 1.Centre for Pharmaceutical Research, School of Pharmaceutical, Molecular and Biomedical SciencesUniversity of South AustraliaAdelaideAustralia

Personalised recommendations