Allosteric Enzyme- and Transporter-Based Interactions

  • Murali Subramanian
  • Timothy S. Tracy


Allosterism in enzymes and transporters can result in alterations in kinetic profiles and in rates of metabolism and transport. Cooperativity due to allosteric interactions has been observed with drug-metabolizing enzymes such as the cytochromes P450 and the uridine glucuronosyltransferases. In addition, transporters such as P-glycoprotein and breast cancer resistance protein have been demonstrated to also exhibit allosteric interactions resulting in cooperativity. Kinetic profiles such as autoactivation (sigmoidal profile), biphasic and substrate inhibition have been observed to occur due to homotropic cooperativity, and heteroactivation has been observed to occur due to heterocooperativity. Numerous examples of all types of allosteric interactions have been observed in vitro but in vivo examples are limited. The correct kinetic equation should be applied to kinetic profiles to properly estimate kinetic parameters for use in in vitro–in vivo correlations.


Substrate Inhibition Breast Cancer Resistance Protein Kinetic Profile Allosteric Interaction Biphasic Kinetic 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


P450 s

Cytochrome P450 s














uridine diphosphate glucuronic acid




Madin Darby canine kidney-multiple drug resistance


breast cancer resistance protein


human liver microsomes


  1. Andersson T, Miners JO, Veronese ME and Birkett DJ (1994) Diazepam metabolism by human liver-microsomes is mediated by both S-mephenytoin hydroxylase and Cyp3A isoforms. Br J Clin Pharmacol 38:131–137.PubMedGoogle Scholar
  2. Atkins WM, Wang RW and Lu AYH (2001) Allosteric behavior in cytochrome P450-dependent in vitro drug-drug interactions: a prospective based on conformational dynamics. Chem Res Toxicol 14:338–347.CrossRefPubMedGoogle Scholar
  3. Ayesh S, Shao YM and Stein WD (1996) Co-operative, competitive and non-competitive interactions between modulators of P-glycoprotein. Biochim Biophys Acta 1316:8–18.PubMedGoogle Scholar
  4. Baas BJ, Denisov IG and Sliger SG (2004) Homotropic cooperativity of monomeric cytochrome P450 3A4 in a nanoscale native bilayer environment. Arch Biochem Biophys 430:218–228.CrossRefPubMedGoogle Scholar
  5. Backman JT, Wang JS, Wen X, Kivisto KT and Neuvonen PJ (1999) Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam. Clin Pharmacol Ther 66:401–407.CrossRefPubMedGoogle Scholar
  6. Basu NK, Kole L, Kubota S and Owens IS (2004) Human UDP-glucuronosyltransferases show atypical metabolism of mycophenolic acid and inhibition by curcumin. Drug Metab Dispos 32:768–773.CrossRefPubMedGoogle Scholar
  7. Bowalgaha K, Elliot DJ, Mackenzie PI, Knights KM, Swedmark S and Miners JO (2005) S-Naproxen and desmethylnaproxen glucuronidation by human liver microsomes and recombinant human UDP-glucuronosyltransferases (UGT): role of UGT2B7 in the elimination of naproxen. Br J Clin Pharmacol 60:423–433.CrossRefPubMedGoogle Scholar
  8. Calabrese EJ (2008) P-glycoprotein efflux transporter activity often displays biphasic dose-response relationships. Crit Rev Toxicol 38:473–487.CrossRefPubMedGoogle Scholar
  9. Davydov DR and Halpert JR (2008) Allosteric P450 mechanisms: multiple binding sites, multiple conformers or both? Expert Opin Drug Metab Toxicol 4:1523–1535.CrossRefPubMedGoogle Scholar
  10. Dey S, Ramachandra M, Pastan I, Gottesman MM and Ambudkar SV (1997) Evidence for two nonidentical drug-interaction sites in the human P-glycoprotein. Proc Natl Acad Sci U S A 94:10594–10599.CrossRefPubMedGoogle Scholar
  11. Domanski TL, He YA, Harlow GR and Halpert JR (2000) Dual role of human cytochrome P450 3A4 residue phe-304 in substrate specificity and cooperativity. J Pharmacol Exp Ther 293:585–591.PubMedGoogle Scholar
  12. Domanski TL, He YA, Khan KK, Roussel F, Wang QM and Halpert JR (2001) Phenylalanine and tryptophan scanning mutagenesis of CYP3A4 substrate recognition site residues and effect on substrate oxidation and cooperativity. Biochemistry 40:10150–10160.CrossRefPubMedGoogle Scholar
  13. Domanski TL, Liu JP, Harlow GR and Halpert JR (1998) Analysis of four residues within substrate recognition site 4 of human cytochrome p450 3A4: role in steroid hydroxylase activity and α-naphthoflavone stimulation. Arch Biochem Biophys 350:223–232.CrossRefPubMedGoogle Scholar
  14. Egnell AC, Houston B and Boyer S (2003) In vivo CYP3A4 heteroactivation is a possible mechanism for the drug interaction between felbamate and carbamazepine. J Pharmacol Exp Ther 305:1251–1262.CrossRefPubMedGoogle Scholar
  15. Ekroos M and Sjogren T (2006) Structural basis for ligand promiscuity in cytochrome P450 3A4. Proc Natl Acad Sci U S A 103:13682–13687.CrossRefPubMedGoogle Scholar
  16. Emoto C, Yamazaki H, Iketaki H, Yamasaki S, Satoh T, Shimizu R, Suzuki S, Shimada N, Nakajima M and Yokoi T (2001) Cooperativity of α -naphthoflavone in cytochrome P450 3A-dependent drug oxidation activities in hepatic and intestinal microsomes from mouse and human. Xenobiotica 31:265–275.CrossRefPubMedGoogle Scholar
  17. Fisher MB, Campanale K, Ackermann BL, Vandenbranden M and Wrighton SA (2000) In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab Dispos 28:560–566.PubMedGoogle Scholar
  18. Galetin A, Clarke SE and Houston JB (2002) Quinidine and haloperidol as modifiers of CYP3A4 activity: multisite kinetic model approach. Drug Metab Dispos 30:1512–1522.CrossRefPubMedGoogle Scholar
  19. Garrigos M, Mir LM and Orlowski S (1997) Competitive and non-competitive inhibition of the multidrug-resistance-associated P-glycoprotein ATPase – Further experimental evidence for a multisite model. Eur J Biochem 244:664–673.CrossRefPubMedGoogle Scholar
  20. Garrigues A, Nugier J, Orlowski S and Ezan E (2002) A high-throughput screening microplate test for the interaction of drugs with P-glycoprotein. Anal Biochem 305:106–114.CrossRefPubMedGoogle Scholar
  21. Ghosal A, Satoh H, Thomas PE, Bush E and Moore D (1996) Inhibition and kinetics of cytochrome P4503A activity in microsomes from rat, human, and cDNA-expressed human cytochrome P450. Drug Metab Dispos 24:940–947.PubMedGoogle Scholar
  22. Giri N, Agarwal S, Shaik N, Pan G, Chen Y and Elmquist GF (2009) Substrate-dependent breast cancer resistance protein (Bcrp1/Abcg2)-mediated interactions: consideration of multiple binding sites in in vitro assay design. Drug Metab Dispos 37:560–570.CrossRefPubMedGoogle Scholar
  23. Gottesman MM, Pastan I and Ambudkar SV (1996) P-glycoprotein and multidrug resistance. Curr Opin Genet Dev 6:610–617.CrossRefPubMedGoogle Scholar
  24. Graves NM, Holmes GB, Fuerst RH and Leppik IE (1989) Effect of felbamate on phenytoin and carbamazepine serum concentrations. Epilepsia 30:225–229.CrossRefPubMedGoogle Scholar
  25. Hallifax D, Galetin A and Houston JB (2008) Prediction of metabolic clearance using fresh human hepatocytes: comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines. Xenobiotica 38:353–367.CrossRefPubMedGoogle Scholar
  26. Henshall J, Galetin A, Harrison A and Houston JB (2008) Comparative analysis of CYP3A heteroactivation by steroid hormones and flavonoids in different in vitro systems and potential in vivo implications. Drug Metab Dispos 36:1332–1340.CrossRefPubMedGoogle Scholar
  27. Houston JB and Galetin A (2005) Modelling atypical CYP3A4 kinetics: principles and pragmatism. Arch Biochem Biophys 433:351–360.CrossRefPubMedGoogle Scholar
  28. Hummel MA, Gannett PM, Aguilar JS and Tracy TS (2004) Effector-mediated alteration of substrate orientation in cytochrorne P4502C9. Biochemistry 43:7207–7214.CrossRefPubMedGoogle Scholar
  29. Hutzler JM, Frye RF, Korzekwa KR, Branch RA, Huang SM and Tracy TS (2001a) Minimal in vivo activation of CYP2C9-mediated flurbiprofen metabolism by dapsone. Eur J Pharma Sci 14:47–52.CrossRefGoogle Scholar
  30. Hutzler JM, Hauer MJ and Tracy TS (2001b) Dapsone activation of CYP2C9-mediated metabolism: Evidence for activation of multiple substrates and a two-site model. Drug Metab Dispos 29:1029–1034.PubMedGoogle Scholar
  31. Hutzler JM and Tracy TS (2002) Atypical kinetic profiles in drug metabolism reactions. Drug Metab Dispos 30:355–362.CrossRefPubMedGoogle Scholar
  32. Hutzler JM, Wienkers LC, Wahlstrom JL, Carlson TJ and Tracy TS (2003) Activation of cytochrome P4502C9-mediated metabolism: mechanistic evidence in support of kinetic observations. Arch Biochem Biophys 410:16–24.CrossRefPubMedGoogle Scholar
  33. Inouye K, Mizokawa T, Saito A, Tonomura B and Ohkawa H (2000) Biphasic kinetic behavior of rat cytochrome P-4501A1-dependent monooxygenation in recombinant yeast microsomes. Biochim Biophys Acta-Protein Struct Mol Enzymol 1481:265–272.CrossRefGoogle Scholar
  34. Iwuchukwu OF and Nagar S (2008) Resveratrol (trans-resveratrol, 3,5,4 '-trihydroxy-trans-stilbene) glucuronidation exhibits atypical enzyme kinetics in various protein sources. Drug Metab Dispos 36:322–330.CrossRefPubMedGoogle Scholar
  35. Iyer LV, Ho MN, Shinn WM, Bradford WW, Tanga MJ, Nath SS and Green CE (2003) Glucuronidation of 1-hydroxyestragole (1-HE) by human UDP-glucuronosyltransferases UGT2B7 and UGT1A9. Toxicol Sci 73:36–43.CrossRefPubMedGoogle Scholar
  36. Jushchyshyn MI, Hutzler JM, Schrag ML and Wienkers LC (2005) Catalytic turnover of pyrene by CYP3A4: evidence that cytochrome b(5) directly induces positive cooperativity. Arch Biochem Biophys 438:21–28.CrossRefPubMedGoogle Scholar
  37. Kenworthy KE, Bloomer JC, Clarke SE and Houston JB (1999) CYP3A4 drug interactions: correlation of 10 in vitro probe substrates. Br J Clin Pharmacol 48:716–727.CrossRefPubMedGoogle Scholar
  38. Kenworthy KE, Clarke SE, Andrews J and Houston JB (2001) Multisite kinetic models for CYP3A4: simultaneous activation and inhibition of diazepam and testosterone metabolism. Drug Metab Dispos 29:1644–1651.PubMedGoogle Scholar
  39. Kerlan V, Dreano Y, Bercovici JP, Beaune PH, Floch HH and Berthou F (1992) Nature of cytochromes P450 involved in the 2-/4-hydroxylations of estradiol in human liver-microsomes. Biochem Pharmacol 44:1745–1756.CrossRefPubMedGoogle Scholar
  40. Kerr BM, Thummel KE, Wurden CJ, Klein SM, Kroetz DL, Gonzalez FJ and Levy RH (1994) Human liver carbamazepine metabolism – role of Cyp3A4 and Cyp2C8 in 10,11-epoxide formation. Biochem Pharmacol 47:1969–1979.CrossRefPubMedGoogle Scholar
  41. Kirkwood LC, Nation RL and Somogyi AA (1998) Glucuronidation of dihydrocodeine by human liver microsomes and the effect of inhibitors. Clin Exp Pharmacol Physiol 25:266–270.CrossRefPubMedGoogle Scholar
  42. Korzekwa KR, Krishnamachary N, Shou M, Ogai A, Parise RA, Rettie AE, Gonzalez FJ and Tracy TS (1998) Evaluation of atypical cytochrome P450 kinetics with two-substrate models: evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry 37:4137–4147.CrossRefPubMedGoogle Scholar
  43. Kronbach T, Mathys D, Umeno M, Gonzalez FJ and Meyer UA (1989) Oxidation of midazolam and triazolam by human-liver cytochrome P450Iiia4. Mol Pharmacol 36:89–96.PubMedGoogle Scholar
  44. Kumar V, Wahlstrom JL, Rock DA, Warren CJ, Gorman LA and Tracy TS (2006) CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metab Dispos 34:1966–1975.CrossRefPubMedGoogle Scholar
  45. Lee CA, Kadwell SH, Kost TA and SerabjitSingh CJ (1995) Cyp3A4 expressed by insect cells infected with a recombinant baculovirus containing both Cyp3A4 and human Nadph-cytochrome P450 reductase is catalytically similar to human liver microsomal Cyp3A4. Arch Biochem Biophys 319:157–167.CrossRefPubMedGoogle Scholar
  46. Lin Y, Lu P, Tang C, Mei Q, Sandig G, Rodrigues AD, Rushmore TH and Shou M (2001) Substrate inhibition kinetics for cytochrome P450-catalyzed reactions. Drug Metab Dispos 29:368–374.PubMedGoogle Scholar
  47. Litman T, Zeuthen T, Skovsgaard T and Stein WD (1997) Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity. Biochim Biophys Acta 1361:169–176.PubMedGoogle Scholar
  48. Liu Y, Apak TI, Lehmler HJ, Robertson LW and Duffel MW (2006) Hydroxylated polychlorinated biphenyls are substrates and inhibitors of human hydroxysteroid sulfotransferase SULT2A1. Chemical Research in Toxicology 19:1420–1425.Google Scholar
  49. Ludwig E, Schmid J, Beschke K and Ebner T (1999) Activation of human cytochrome P-450 3A4-catalyzed meloxicam 5-methylhydroxylation by quinidine and hydroquinidine in vitro. J Pharmacol Exp Ther 290:1–8.PubMedGoogle Scholar
  50. Lugo MR and Sharom FJ (2005) Interaction of LDS-751 and rhodamine 123 with P-glycoprotein: evidence for simultaneous binding of both drugs. Biochemistry 44:14020–14029.CrossRefPubMedGoogle Scholar
  51. Martin C, Berridge G, Higgins CF, Mistry P, Charlton P and Callaghan R (2000) Communication between multiple drug binding sites on P-glycoprotein. Mol Pharmacol 58:624–632.PubMedGoogle Scholar
  52. McMasters DR, Torres RA, Crathern SJ, Dooney DL, Nachbar RB, Sheridan RP and Korzekwa KR (2007) Inhibition of recombinant cytochrome p450 isoforms 2D6 and 2C9 by diverse drug-like molecules. J Med Chem 50:3205–3213.CrossRefPubMedGoogle Scholar
  53. Miksits M, Maier-Salamon A, Aust S, Thalhammer T, Reznicek G, Kunert O, Haslinger E, Szekeres T and Jaeger W (2005) Sulfation of resveratrol in human liver: Evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1. Xenobiotica 35:1101–1119.Google Scholar
  54. Miller GP and Guengerich FP (2001) Binding and oxidation of alkyl 4-nitrophenyl ethers by rabbit cytochrome P450 1A2: evidence for two binding sites. Biochemistry 40:7262–7272.CrossRefPubMedGoogle Scholar
  55. Miners JO, Lillywhite KJ, Matthews AP, Jones ME and Birkett DJ (1988) Kinetic and inhibitor studies of 4-methylumbelliferone and 1-naphthol glucuronidation in human-liver microsomes. Biochem Pharmacol 37:665–671.CrossRefPubMedGoogle Scholar
  56. Nakajima M, Tanaka E, Kobayashi T, Ohashi N, Kume T and Yokoi T (2002) Imipramine N-glucuronidation in human liver microsomes: biphasic kinetics and characterization of UDP-glucuronosyltransferase isoforms. Drug Metab Dispos 30:636–642.CrossRefPubMedGoogle Scholar
  57. Nakamura H, Torimoto N, Ishii I, Ariyoshi N, Nakasa H, Ohmori S and Kitada M (2003) CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids. Drug Metab Dispos 31:432–438.CrossRefPubMedGoogle Scholar
  58. Ngui JS, Chen Q, Shou MG, Wang RW, Stearns RA, Baillie TA and Tang W (2001) In vitro stimulation of warfarin metabolism by quinidine: Increases in the formation of 4- and 10-hydroxywarfarin. Drug Metab Dispos 29:877–886.PubMedGoogle Scholar
  59. Ngui JS, Tang W, Stearns RA, Shou MG, Miller RR, Zhang Y, Lin JH and Baillie TA (2000) Cytochrome P450 3A4-mediated interaction of diclofenac and quinidine. Drug Metab Dispos 28:1043–1050.PubMedGoogle Scholar
  60. Niwa T, Murayama N and Yamazaki H (2008a) Heterotropic cooperativity in oxidation mediated by cytochrome P450. Curr Drug Metab 9:453–462.CrossRefPubMedGoogle Scholar
  61. Niwa T, Okada K, Hiroi T, Imaoka S, Narimatsu S and Funae Y (2008b) Effect of psychotropic drugs on the 21-hydroxylation of neurosteroids, progesterone and allopregnanolone, catalyzed by rat CYP2D4 and human CYP2D6 in the brain. Biol Pharmaceut Bull 31:348–351.CrossRefGoogle Scholar
  62. Niwa T, Shiraga T, Yamasaki S, Ishibashi K, Ohno Y and Kagayama A (2003) In vitro activation of 7-benzyloxyresorufin O-debenzylation and nifedipine oxidation in human liver microsomes. Xenobiotica 33:717–729.CrossRefPubMedGoogle Scholar
  63. Orlowski S, Mir LM, Belehradek J and Garrigos M (1996) Effects of steroids and verapamil on P-glycoprotein ATPase activity: progesterone, desoxycorticosterone, corticosterone and verapamil are mutually non-exclusive modulators. Biochem J 317:515–522.PubMedGoogle Scholar
  64. Pascaud C, Garrigos M and Orlowski S (1998) Multidrug resistance transporter P-glycoprotein has distinct but interacting binding sites for cytotoxic drugs and reversing agents. Biochem J 333:351–358.PubMedGoogle Scholar
  65. Pfeiffer E, Treiling CR, Hoehle SI and Metzler M (2005) Isoflavones modulate the glucuronidation of estradiol in human liver microsomes. Carcinogenesis 26:2172–2178.CrossRefPubMedGoogle Scholar
  66. Ramamoorthy Y, Tyndale RF and Sellers EM (2001) Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates. Pharmacogenetics 11:477–487.CrossRefPubMedGoogle Scholar
  67. Riches Z, Bloomer JC and Coughtrie MWH (2007) Comparison of 2-aminophenol and 4-nitrophenol as in vitro probe substrates for the major human hepatic sulfotransferase, SULT1A1, demonstrates improved selectivity with 2-aminophenol. Biochemical Pharmacology 74:352–358.Google Scholar
  68. Ring BJ, Eckstein JA, Gillespie JS, Binkley SN, Vandenbranden M and Wrighton SA (2001) Identification of the human cytochromes P450 responsible for in vitro formation of R- and S-norfluoxetine. J Pharmacol Exp Ther 297:1044–1050.PubMedGoogle Scholar
  69. Romsicki Y and Sharom FJ (1999) The membrane lipid environment modulates drug interactions with the P-glycoprotein multidrug transporter. Biochemistry 38:6887–6896.CrossRefPubMedGoogle Scholar
  70. Safa AR (2004) Identification and characterization of the binding sites of P-glycoprotein for multidrug resistance-related drugs and modulators. Curr Med Chem Anticancer Agents 4:1–17.CrossRefPubMedGoogle Scholar
  71. Schmider J, Greenblatt DJ, VonMoltke LL, Harmatz JS and Shader RI (1995) N-demethylation of amitriptyline in-vitro – role of cytochrome-P-450 3A (Cyp3A) isoforms and effect of metabolic-inhibitors. J Pharmacol Exp Ther 275:592–597.PubMedGoogle Scholar
  72. Schoch GA, Yano JK, Wester MR, Griffin KJ, Stout CD and Johnson EF (2004) Structure of human microsomal cytochrome P4502C8 – evidence for a peripheral fatty acid binding site. J Biol Chem 279:9497–9503.CrossRefPubMedGoogle Scholar
  73. Schrag ML and Wienkers LC (2001) Triazolam substrate inhibition: evidence of competition for heme-bound reactive oxygen within the CYP3A4 active site. Drug Metab Dispos 29:70–75.PubMedGoogle Scholar
  74. Shapiro AB and Ling V (1997) Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur J Biochem 250:130–137.CrossRefPubMedGoogle Scholar
  75. Shaw PM, Hosea NA, Thompson DV, Lenius JM and Guengerich FP (1997) Reconstitution premixes for assays using purified recombinant human cytochrome P450, NADPH-cytochrome P450 reductase, and cytochrome b(5). Arch Biochem Biophys 348:107–115.CrossRefPubMedGoogle Scholar
  76. Shimada T, Yamazaki H, Mimura M, Inui Y and Guengerich FP (1994) Interindividual variations in human liver cytochrome-P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic-chemicals – studies with liver-microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414–423.PubMedGoogle Scholar
  77. Shou M, Grogan J, Mancewicz JA, Krausz KW, Gonzalez FJ, Gelboin HV and Korzekwa KR (1994) Activation of Cyp3A4 – evidence for the simultaneous binding of 2 substrates in a cytochrome-P450 active-site. Biochemistry 33:6450–6455.CrossRefPubMedGoogle Scholar
  78. Shou M, Lin Y, Lu P, Tang C, Mei Q, Cui D, Tang W, Ngui JS, Lin CC, Singh R, Wong BK, Yergey JA, Lin JH, Pearson PG, Baillie TA, Rodrigues AD and Rushmore TH (2001) Enzyme kinetics of cytochrome P450-mediated reactions. Curr Drug Metab 2:17–36.CrossRefPubMedGoogle Scholar
  79. Shou MG, Mei Q, Ettore MW, Dai RK, Baillie TA and Rushmore TH (1999) Sigmoidal kinetic model for two co-operative substrate-binding sites in a cytochrome P450 3A4 active site: an example of the metabolism of diazepam and its derivatives. Biochem J 340:845–853.CrossRefPubMedGoogle Scholar
  80. Spoelstra EC, Westerhoff HV, Pinedo HM, Dekker H and Lankelma J (1994) The multidrug-resistance-reverser verapamil interferes with cellular P-glycoprotein-mediated pumping of daunorubicin as a non-competing substrate. Eur J Biochem 221:363–373.CrossRefPubMedGoogle Scholar
  81. Sreeramulu K, Liu R and Sharom FJ (2007) Interaction of insecticides with mammalian P-glycoprotein and their effect on its transport function. Biochim Biophys Acta 1768: 1750–1757.CrossRefPubMedGoogle Scholar
  82. Stevens JC and Wrighton SA (1993) Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes-P450. J Pharmacol Exp Ther 266:964–971.PubMedGoogle Scholar
  83. Stone AN, Mackenzie PI, Galetin A, Houston JB and Miners JO (2003) Isoform selectivity and kinetics of morphine 3-and 6-glucuronidation by human UDP-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7. Drug Metab Dispos 31:1086–1089.CrossRefPubMedGoogle Scholar
  84. Stresser DM, Blanchard AP, Turner SD, Erve JCL, Dandeneau AA, Miller VP and Crespi CL (2000) Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates. Drug Metab Dispos 28:1440–1448.PubMedGoogle Scholar
  85. Tabrett CA and Coughtrie MWH (2003) Phenol sulfotransferase 1A1 activity in human liver: kinetic properties, interindividual variation and re-evaluation of the suitability of 4-nitrophenol as a probe substrate. Biochemical Pharmacology 66:2089–2097.Google Scholar
  86. Tamai I and Safa AR (1991) Azidopine noncompetitively interacts with vinblastine and cyclosporine-A binding to P-glycoprotein in multidrug resistant cells. J Biol Chem 266:16796–16800.PubMedGoogle Scholar
  87. Tang W, Stearns RA, Kwei GY, Iliff SA, Miller RR, Egan MA, Yu NX, Dean DC, Kumar S, Shou MG, Lin JH and Baillie TA (1999) Interaction of diclofenac and quinidine in monkeys: stimulation of diclofenac metabolism. J Pharmacol Exp Ther 291:1068–1074.PubMedGoogle Scholar
  88. Taub ME, Podila L, Ely D and Almeida I (2005) Functional assessment of multiple P-glycoprotein (P-gp) probe substrates: influence of cell line and modulator concentration on P-GP activity. Drug Metab Dispos 33:1679–1687.CrossRefPubMedGoogle Scholar
  89. Tracy TS (2003) Atypical enzyme kinetics: their effect on in vitro-in vivo pharmacokinetic predictions and drug interactions. Curr Drug Metab 4:341–346.CrossRefPubMedGoogle Scholar
  90. Tracy TS (2006) Atypical cytochrome P450 kinetics, implications for drug discovery. Drugs R D 7:349–363.CrossRefPubMedGoogle Scholar
  91. Tracy TS and Hummel MA (2004) Modeling kinetic data from in vitro drug metabolism enzyme experiments. Drug Metab Rev 36:231–242.CrossRefPubMedGoogle Scholar
  92. Tsoutsikos P, Miners JO, Stapleton A, Thomas A, Sallustio BC and Knights KM (2004) Evidence that unsaturated fatty acids are potent inhibitors of renal UDP-glucuronosyltransferases (UGT): kinetic studies using human kidney cortical microsomes and recombinant UGT1A9 and UGT2B7. Biochem Pharmacol 67:191–199.CrossRefPubMedGoogle Scholar
  93. Uchaipichat V, Galetin A, Houston JB, Mackenzie PI, Williams JA and Miners JO (2008) Kinetic modeling of the interactions between 4-methylumbelliferone, 1-naphthol, and zidovudine glucuronidation by UDP-glucuronosyltransferase 2B7 (UGT2B7) provides evidence for multiple substrate binding and effector sites. Mol Pharmacol 74:1152–1162.CrossRefPubMedGoogle Scholar
  94. Ueng YF, Kuwabara T, Chun YJ and Guengerich FP (1997) Cooperativity in oxidations catalyzed by cytochrome P450 3A4. Biochemistry 36:370–381.CrossRefPubMedGoogle Scholar
  95. Venkatakrishnan K, von Moltke LL, Duan SX, Fleishaker JC, Shader RI and Greenblatt DJ (1998) Kinetic characterization and identification of the enzymes responsible for the hepatic biotransformation of adinazolam and N-desmethyladinazolam in man. J Pharm Pharmacol 50:265–274.PubMedGoogle Scholar
  96. Wang EJ, Casciano CN, Clement RP and Johnson WW (2000a) Cooperativity in the inhibition of P-glycoprotein-mediated daunorubicin transport: Evidence for half-of-the-sites reactivity. Arch Biochem Biophys 383:91–98.CrossRefPubMedGoogle Scholar
  97. Wang EJ, Casciano CN, Clement RP and Johnson WW (2000b) Two transport binding sites of P-glycoprotein are unequal yet contingent: initial rate kinetic analysis by ATP hydrolysis demonstrates intersite dependence. Biochim Biophys Acta-Protein Struct Mol Enzymol 1481:63–74.CrossRefGoogle Scholar
  98. Wang EJ, Casciano CN, Clement RP and Johnson WW (2001) Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Comm 289:580–585.CrossRefPubMedGoogle Scholar
  99. Wang RW, Newton DJ, Liu N, Atkins WM and Lu AYH (2000c) Human cytochrome P-450 3A4: in vitro drug-drug interaction patterns are substrate-dependent. Drug Metab Dispos 28:360–366.PubMedGoogle Scholar
  100. Watanabe Y, Nakajima M and Yokoi T (2002) Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. Drug Metab Dispos 30:1462–1469.CrossRefPubMedGoogle Scholar
  101. Williams JA, Ring BJ, Cantrell VE, Campanale K, Jones DR, Hall SD and Wrighton SA (2002) Differential modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzed estradiol-3-glucuronidation by the addition of UGT1A1 substrates and other compounds to human liver microsomes. Drug Metab Dispos 30:1266–1273.CrossRefPubMedGoogle Scholar
  102. Williams PA, Cosme J, Vinkovic DM, Ward A, Angove HC, Day PJ, Vonrhein C, Tickle IJ and Jhoti H (2004) Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science 305:683–686.CrossRefPubMedGoogle Scholar
  103. Yan Z, Caldwell GW, Gauthier D, Leo GC, Mei J, Ho CY, Jones WJ, Masucci JA, Tuman RW, Galemmo RA and Johnson DL (2006) N-glucuronidation of the platelet-derived growth factor receptor tyrosine kinase inhibitor 6,7-(dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine by human UDP-glucuronosyltransferases. Drug Metab Dispos 34:748–755.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Experimental and Clinical PharmacologyUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Experimental and Clinical PharmacologyCollege of Pharmacy, University of MinnesotaMinneapolisUSA

Personalised recommendations