![[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}
|
|
|
|
|
||
Vol. 27, Issue 2, 180-187, February 1999
Departments of
Medicinal Chemistry (K.L.K.) and
Pharmaceutics (M.A.G., K.E.T., D.D.S), School of Pharmacy, University
of Washington, Seattle, Washington
The purpose of this study was to compare the kinetics of intestinal
and hepatic cytochrome P-450 3A (CYP3A) inhibition by using
microsomal midazolam 1'-hydroxylation as a marker of enzyme activity.
The effect of two antifungal agents commonly implicated in CYP3A
drug-drug interactions was examined. Inhibition type and affinities
were determined for human liver and intestinal microsomes screened for
the presence or absence of CYP3A4 and CYP3A5, as well as for
cDNA-expressed CYP3A4 and CYP3A5 microsomes. Ketoconazole and
fluconazole were found to be noncompetitive inhibitors of both enzymes.
Ketoconazole exhibited a Ki for
cDNA-expressed CYP3A4 of 26.7 ± 1.71 nM, whereas the
Ki for cDNA expressed CYP3A5 was 109 ± 19.7 nM. Corresponding Ki values for
fluconazole were 9.21 ± 0.51 µM and 84.6 ± 12.9 µM. For
liver and intestinal microsomes that contained only CYP3A4, the average
ketoconazole Ki was found to be 14.9 ± 6.7 nM and 17.0 ± 7.9 nM, respectively, whereas fluconazole yielded mean respective Ki values of
10.7 ± 4.2 µM and 10.4 ± 2.9 µM. Liver and intestinal
microsomes that contained an equal or greater amount of CYP3A5, in
addition to CYP3A4, were less susceptible to inhibition by both
ketoconazole and fluconazole. These findings suggest that there can be
significant differences in the affinity of these two enzymes for
inhibitors. This may further broaden interindividual variability with
respect to the magnitude of in vivo drug-drug interactions. We also
conclude that there is no significant difference in inhibition type and affinity of ketoconazole and fluconazole for hepatic versus intestinal CYP3A4.
This article has been cited by other articles:
|
|
 |
|
  P. Zhao, I. Ragueneau-Majlessi, L. Zhang, J. M. Strong, K. S. Reynolds, R. H. Levy, K. E. Thummel, and S.-M. Huang Quantitative Evaluation of Pharmacokinetic Inhibition of CYP3A Substrates by Ketoconazole: A Simulation Study J. Clin. Pharmacol., March 1, 2009; 49(3): 351 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Sridar, U. M. Kent, K. Noon, A. McCall, B. Alworth, M. Foroozesh, and P. F. Hollenberg Differential Inhibition of Cytochromes P450 3A4 and 3A5 by the Newly Synthesized Coumarin Derivatives 7-Coumarin Propargyl Ether and 7-(4-Trifluoromethyl)coumarin Propargyl Ether Drug Metab. Dispos., November 1, 2008; 36(11): 2234 - 2243. [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]
|
|
|
|
|
|
H.-Y. Ku, H.-J. Ahn, K.-A. Seo, H. Kim, M. Oh, S. K. Bae, J.-G. Shin, J.-H. Shon, and K.-H. Liu The Contributions of Cytochromes P450 3A4 and 3A5 to the Metabolism of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Udenafil, and Vardenafil Drug Metab. Dispos., June 1, 2008; 36(6): 986 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Isoherranen, S. R. Ludington, R. C. Givens, J. K. Lamba, S. N. Pusek, E. C. Dees, D. K. Blough, K. Iwanaga, R. L. Hawke, E. G. Schuetz, et al. The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation Drug Metab. Dispos., January 1, 2008; 36(1): 146 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Treiber, R. Schneiter, S. Hausler, and B. Stieger Bosentan Is a Substrate of Human OATP1B1 and OATP1B3: Inhibition of Hepatic Uptake as the Common Mechanism of Its Interactions with Cyclosporin A, Rifampicin, and Sildenafil Drug Metab. Dispos., August 1, 2007; 35(8): 1400 - 1407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ogasawara, T. Kume, and E. Kazama Effect of Oral Ketoconazole on Intestinal First-Pass Effect of Midazolam and Fexofenadine in Cynomolgus Monkeys Drug Metab. Dispos., March 1, 2007; 35(3): 410 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. O'Donnell, K. Grime, P. Courtney, D. Slee, and R. J. Riley The Development of a Cocktail CYP2B6, CYP2C8, and CYP3A5 Inhibition Assay and a Preliminary Assessment of Utility in a Drug Discovery Setting Drug Metab. Dispos., March 1, 2007; 35(3): 381 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Picard, N. Djebli, F.-L. Sauvage, and P. Marquet Metabolism of Sirolimus in the Presence or Absence of Cyclosporine by Genotyped Human Liver Microsomes and Recombinant Cytochromes P450 3A4 and 3A5 Drug Metab. Dispos., March 1, 2007; 35(3): 350 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-c. Lin, C. Fang, S. Benetton, G.-f. Xu, and L.-T. Yeh Metabolic Activation of Pradefovir by CYP3A4 and Its Potential as an Inhibitor or Inducer. Antimicrob. Agents Chemother., September 1, 2006; 50(9): 2926 - 2931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Polsky-Fisher, H. Cao, P. Lu, and C. R. Gibson EFFECT OF CYTOCHROMES P450 CHEMICAL INHIBITORS AND MONOCLONAL ANTIBODIES ON HUMAN LIVER MICROSOMAL ESTERASE ACTIVITY Drug Metab. Dispos., August 1, 2006; 34(8): 1361 - 1366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Kamdem, F. Streit, U. M. Zanger, J. Brockmoller, M. Oellerich, V. W. Armstrong, and L. Wojnowski Contribution of CYP3A5 to the in Vitro Hepatic Clearance of Tacrolimus Clin. Chem., August 1, 2005; 51(8): 1374 - 1381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. R. Winter and J. D. Unadkat IDENTIFICATION OF CYTOCHROME P450 AND ARYLAMINE N-ACETYLTRANSFERASE ISOFORMS INVOLVED IN SULFADIAZINE METABOLISM Drug Metab. Dispos., July 1, 2005; 33(7): 969 - 976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. McCune, L. J. Risler, B. R. Phillips, K. E. Thummel, D. Blough, and D. D. Shen CONTRIBUTION OF CYP3A5 TO HEPATIC AND RENAL IFOSFAMIDE N-DECHLOROETHYLATION Drug Metab. Dispos., July 1, 2005; 33(7): 1074 - 1081. [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]
|
|
|
|
|
|
P. Zhao, K. L. Kunze, and C. A. Lee EVALUATION OF TIME-DEPENDENT INACTIVATION OF CYP3A IN CRYOPRESERVED HUMAN HEPATOCYTES Drug Metab. Dispos., June 1, 2005; 33(6): 853 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Wang, D. R. Jones, and S. D. Hall DIFFERENTIAL MECHANISM-BASED INHIBITION OF CYP3A4 AND CYP3A5 BY VERAPAMIL Drug Metab. Dispos., May 1, 2005; 33(5): 664 - 671. [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]
|
|
|
|
|
|
R. L. Walsky, E. A. Gaman, and R. S. Obach Examination of 209 Drugs for Inhibition of Cytochrome P450 2C8 J. Clin. Pharmacol., January 1, 2005; 45(1): 68 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. McConn II, Y. S. Lin, K. Allen, K. L. Kunze, and K. E. Thummel DIFFERENCES IN THE INHIBITION OF CYTOCHROMES P450 3A4 AND 3A5 BY METABOLITE-INHIBITOR COMPLEX-FORMING DRUGS Drug Metab. Dispos., October 1, 2004; 32(10): 1083 - 1091. [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]
|
|
|
|
|
|
B. Lalovic, B. Phillips, L. L. Risler, W. Howald, and D. D. Shen QUANTITATIVE CONTRIBUTION OF CYP2D6 AND CYP3A TO OXYCODONE METABOLISM IN HUMAN LIVER AND INTESTINAL MICROSOMES Drug Metab. Dispos., April 1, 2004; 32(4): 447 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Williams, J. Cook, and S. I. Hurst A SIGNIFICANT DRUG-METABOLIZING ROLE FOR CYP3A5? Drug Metab. Dispos., December 1, 2003; 31(12): 1526 - 1530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-A. Kim and J.-Y. Park INHIBITORY EFFECT OF GLYBURIDE ON HUMAN CYTOCHROME P450 ISOFORMS IN HUMAN LIVER MICROSOMES Drug Metab. Dispos., September 1, 2003; 31(9): 1090 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C. Patki, L. L. von Moltke, and D. J. Greenblatt IN VITRO METABOLISM OF MIDAZOLAM, TRIAZOLAM, NIFEDIPINE, AND TESTOSTERONE BY HUMAN LIVER MICROSOMES AND RECOMBINANT CYTOCHROMES P450: ROLE OF CYP3A4 AND CYP3A5 Drug Metab. Dispos., July 1, 2003; 31(7): 938 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Yuan, S. Madani, X.-X. Wei, K. Reynolds, and S.-M. Huang Evaluation of Cytochrome P450 Probe Substrates Commonly Used by the Pharmaceutical Industry to Study in Vitro Drug Interactions Drug Metab. Dispos., December 1, 2002; 30(12): 1311 - 1319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Wienkers and M. A. Wynalda Multiple Cytochrome P450 Enzymes Responsible for the Oxidative Metabolism of the Substituted (S)-3-Phenylpiperidine, (S,S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine Hydrochloride, in Human Liver Microsomes Drug Metab. Dispos., December 1, 2002; 30(12): 1372 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. H. Tran, L. L. von Moltke, K. Venkatakrishnan, B. W. Granda, M. A. Gibbs, R. S. Obach, J. S. Harmatz, and D. J. Greenblatt Microsomal Protein Concentration Modifies the Apparent Inhibitory Potency of CYP3A Inhibitors Drug Metab. Dispos., December 1, 2002; 30(12): 1441 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yasuda, L.-b. Lan, D. Sanglard, K. Furuya, J. D. Schuetz, and E. G. Schuetz Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 323 - 332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Khan, Y. Q. He, M. A. Correia, and J. R. Halpert Differential Oxidation of Mifepristone by Cytochromes P450 3A4 and 3A5: Selective Inactivation of P450 3A4 Drug Metab. Dispos., September 1, 2002; 30(9): 985 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yu and R. L. Haining Comparative Contribution to Dextromethorphan Metabolism by Cytochrome P450 Isoforms in Vitro: Can Dextromethorphan Be Used as a Dual Probe for Both CYP2D6 and CYP3A Activities? Drug Metab. Dispos., November 1, 2001; 29(11): 1514 - 1520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Obach, Q.-Y. Zhang, D. Dunbar, and L. S. Kaminsky Metabolic Characterization of the Major Human Small Intestinal Cytochrome P450s Drug Metab. Dispos., March 1, 2001; 29(3): 347 - 352. [Abstract] [Full Text]
|
|
|
|
|
|
M. L. Schrag and L. C. Wienkers Triazolam Substrate Inhibition: Evidence of Competition for Heme-Bound Reactive Oxygen Within the CYP3A4 Active Site Drug Metab. Dispos., January 1, 2001; 29(1): 70 - 75. [Abstract] [Full Text]
|
|
|
|
|
|
M. A. Wynalda, M. J. Hauer, and L. C. Wienkers Oxidation of the Novel Oxazolidinone Antibiotic Linezolid in Human Liver Microsomes Drug Metab. Dispos., September 1, 2000; 28(9): 1014 - 1017. [Abstract] [Full Text]
|
|
|
|
|
|
V. P. Hosagrahara, L. K. Hansen, and R. P. Remmel Induction of the Metabolism of Midazolam by Rifampin in Cultured Porcine Hepatocytes: Preliminary Evidence for CYP3A Isoforms in Pigs Drug Metab. Dispos., December 1, 1999; 27(12): 1512 - 1518. [Abstract] [Full Text]
|
|
|
|
|
|
A. E. M. Vickers, J. R. Sinclair, M. Zollinger, F. Heitz, U. Glänzel, L. Johanson, and V. Fischer Multiple Cytochrome P-450s Involved in the Metabolism of Terbinafine Suggest a Limited Potential for Drug-Drug Interactions Drug Metab. Dispos., September 1, 1999; 27(9): 1029 - 1038. [Abstract] [Full Text]
|
|
|
|
|
|
M. A. Gibbs, K. L. Kunze, W. N. Howald, and K. E. Thummel Effect of Inhibitor Depletion on Inhibitory Potency: Tight Binding Inhibition of CYP3A by Clotrimazole Drug Metab. Dispos., May 1, 1999; 27(5): 596 - 599. [Abstract] [Full Text]
|
|
|
|
|
|
J. M. Fisher, S. A. Wrighton, P. B. Watkins, P. Schmiedlin-Ren, J. C. Calamia, D. D. Shen, K. L. Kunze, and K. E. Thummel First-Pass Midazolam Metabolism Catalyzed by 1alpha ,25-Dihydroxy Vitamin D3-Modified Caco-2 Cell Monolayers J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 1134 - 1142. [Abstract] [Full Text]
|
|
|
|
|
|
M. F. Paine, P. Schmiedlin-Ren, and P. B. Watkins Cytochrome P-450 1A1 Expression in Human Small Bowel: Interindividual Variation and Inhibition by Ketoconazole Drug Metab. Dispos., March 1, 1999; 27(3): 360 - 364. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
