![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (A.G., J.B.H.); and Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, The Frythe, Welwyn, Hertfordshire, United Kingdom (S.E.C.)
The potential of substrates and modifiers of CYP3A4 to show differential
effects, attributed to the existence of multiple binding sites, confounds the
straightforward prediction of in vivo drug-drug interactions from in vitro
data. A set of in vitro interaction studies was performed in human
lymphoblast-expressed CYP3A4 involving representatives of two CYP3A4
subclasses, midazolam (MDZ) and testosterone (TST); a distinct subgroup,
nifedipine (NIF); and its structural analog, felodipine (FEL). Mechanistic
insight into the interaction of each pair of substrates was provided by
employing a range of multisite kinetic models; most were subtypes of a generic
two-site model, but a three-site model was required for TST interactions. The
complexity of the inhibition profiles and the selection of the kinetic model
with appropriate interaction factors were dependent upon the kinetics of
substrates involved (hyperbolic, substrate inhibition, or sigmoidal for
MDZ/FEL, NIF, and TST, respectively). In no case was a simple reciprocity seen
between pairs of substrates. The interaction profiles observed between TST,
MDZ, NIF, and FEL involved several atypical inhibition features (partial,
cooperative, concentration-dependent loss of characteristic homotropic
behavior) and pathway-differential effects reflecting an 80-fold difference in
Ki values and a 
factor (defining the alteration in
the binding affinity in the presence of a modifier) ranging from 0.04 to 2.3.
The conclusions from the multisite kinetic analysis performed support the
hypothesis of distinct binding domains for each substrate subgroup.
Furthermore, the analysis of intersubstrate interactions strongly indicates
the existence of a mutual binding domain common to each of the three CYP3A4
substrate subclasses.
This article has been cited by other articles:
|
|
 |
|
  Y. Kapelyukh, M. J. I. Paine, J.-D. Marechal, M. J. Sutcliffe, C. R. Wolf, and G. C. K. Roberts Multiple Substrate Binding by Cytochrome P450 3A4: Estimation of the Number of Bound Substrate Molecules Drug Metab. Dispos., October 1, 2008; 36(10): 2136 - 2144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Uchaipichat, A. Galetin, J. B. Houston, P. I. Mackenzie, J. A. Williams, and J. O. Miners 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., October 1, 2008; 74(4): 1152 - 1162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Henshall, A. Galetin, A. Harrison, and J. B. Houston Comparative Analysis of CYP3A Heteroactivation by Steroid Hormones and Flavonoids in Different in Vitro Systems and Potential in Vivo Implications Drug Metab. Dispos., July 1, 2008; 36(7): 1332 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zhou, L. Xia, and J. Wang Metformin Transport by a Newly Cloned Proton-Stimulated Organic Cation Transporter (Plasma Membrane Monoamine Transporter) Expressed in Human Intestine Drug Metab. Dispos., October 1, 2007; 35(10): 1956 - 1962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lu, P. Li, R. Gallegos, V. Uttamsingh, C. Q. Xia, G. T. Miwa, S. K. Balani, and L.-S. Gan Comparison of Intrinsic Clearance in Liver Microsomes and Hepatocytes from Rats and Humans: Evaluation of Free Fraction and Uptake in Hepatocytes Drug Metab. Dispos., September 1, 2006; 34(9): 1600 - 1605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Galetin and J. B. Houston Intestinal and Hepatic Metabolic Activity of Five Cytochrome P450 Enzymes: Impact on Prediction of First-Pass Metabolism J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1220 - 1229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Zhou, L. Afzelius, S. W. Grimm, T. B. Andersson, R. J. Zauhar, and I. Zamora COMPARISON OF METHODS FOR THE PREDICTION OF THE METABOLIC SITES FOR CYP3A4-MEDIATED METABOLIC REACTIONS Drug Metab. Dispos., June 1, 2006; 34(6): 976 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-i. Fujita, Y. Ando, M. Narabayashi, T. Miya, F. Nagashima, W. Yamamoto, K. Kodama, K. Araki, H. Endo, and Y. Sasaki GEFITINIB (IRESSA) INHIBITS THE CYP3A4-MEDIATED FORMATION OF 7-ETHYL-10-(4-AMINO-1-PIPERIDINO)CARBONYLOXYCAMPTOTHECIN BUT ACTIVATES THAT OF 7-ETHYL-10-[4-N-(5-AMINOPENTANOIC ACID)-1-PIPERIDINO]CARBONYLOXYCAMPTOTHECIN FROM IRINOTECAN Drug Metab. Dispos., December 1, 2005; 33(12): 1785 - 1790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Galetin, K. Ito, D. Hallifax, and J. B. Houston CYP3A4 Substrate Selection and Substitution in the Prediction of Potential Drug-Drug Interactions J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 180 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Krauser and F. P. Guengerich Cytochrome P450 3A4-catalyzed Testosterone 6{beta}-Hydroxylation Stereochemistry, Kinetic Deuterium Isotope Effects, and Rate-limiting Steps J. Biol. Chem., May 20, 2005; 280(20): 19496 - 19506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Klees, P. Sheffels, O. Dale, and E. D. Kharasch METABOLISM OF ALFENTANIL BY CYTOCHROME P4503A (CYP3A) ENZYMES Drug Metab. Dispos., March 1, 2005; 33(3): 303 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-C. Egnell, J. B. Houston, and C. S. Boyer Predictive Models of CYP3A4 Heteroactivation: In Vitro-in Vivo Scaling and Pharmacophore Modeling J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 926 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Paine, A. B. Criss, and P. B. Watkins Two Major Grapefruit Juice Components Differ in Time to Onset of Intestinal CYP3A4 Inhibition J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 1151 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Galetin, C. Brown, D. Hallifax, K. Ito, and J. B. Houston UTILITY OF RECOMBINANT ENZYME KINETICS IN PREDICTION OF HUMAN CLEARANCE: IMPACT OF VARIABILITY, CYP3A5, AND CYP2C19 ON CYP3A4 PROBE SUBSTRATES Drug Metab. Dispos., December 1, 2004; 32(12): 1411 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shitara, M. Hirano, H. Sato, and Y. Sugiyama Gemfibrozil and Its Glucuronide Inhibit the Organic Anion Transporting Polypeptide 2 (OATP2/OATP1B1:SLC21A6)-Mediated Hepatic Uptake and CYP2C8-Mediated Metabolism of Cerivastatin: Analysis of the Mechanism of the Clinically Relevant Drug-Drug Interaction between Cerivastatin and Gemfibrozil J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 228 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Paine, A. B. Criss, and P. B. Watkins TWO MAJOR GRAPEFRUIT JUICE COMPONENTS DIFFER IN INTESTINAL CYP3A4 INHIBITION KINETIC AND BINDING PROPERTIES Drug Metab. Dispos., October 1, 2004; 32(10): 1146 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Walsky and R. S. Obach VALIDATED ASSAYS FOR HUMAN CYTOCHROME P450 ACTIVITIES Drug Metab. Dispos., June 1, 2004; 32(6): 647 - 660. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
