![[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. 30, Issue 8, 883-891, August 2002
Department of Drug Disposition, Lilly Research Laboratories, Eli
Lilly and Company, Indianapolis, Indiana (J.A.W., B.J.R., V.E.C., J.E.,
K.R., S.A.W.); and Department of Clinical Pharmacology, Indiana
University School of Medicine, Indianapolis, Indiana (D.R.J., M.A.H.,
S.D.H.)
The human cytochromes P450 (P450) CYP3A contribute to the
biotransformation of 50% of oxidatively metabolized drugs. The
predominant hepatic form is CYP3A4, but recent evidence indicates that
CYP3A5 contributes more significantly to the total liver CYP3A than was originally thought. CYP3A7 is the major fetal form and is rarely expressed in adults. To compare the metabolic capabilities of CYP3A
forms for 10 substrates, incubations were performed using a consistent
molar ratio (1:7:9) of recombinant CYP3A, P450 reductase, and
cytochrome b5. A wide range of substrate concentrations was examined to
determine the best fit to kinetic models for metabolite formation. In
general, Km or
S50 values for the substrates were 3 to 4 times lower for CYP3A4 than for CYP3A5 or CYP3A7. For a more direct
comparison of these P450 forms, clearance to the metabolites was
determined as a linear relationship of rate of metabolite formation for
the lowest substrate concentrations examined. The clearance for
1'-hydroxy midazolam formation at low substrate concentrations was
similar for CYP3A4 and CYP3A5. For CYP3A5 versus CYP3A4, clearance
values at low substrate concentrations were 2 to 20 times lower for the
other biotransformations. The clearance values for CYP3A7-catalyzed
metabolite formation at low substrate concentrations were substantially
lower than for CYP3A4 or CYP3A5, except for clarithromycin, 4-OH
triazolam, and N-desmethyl diltiazem (CYP3A5 
CYP3A7). The CYP3A forms demonstrated regioselective differences in
some of the biotransformations. These results demonstrate an equal or
reduced metabolic capability for CYP3A5 compared with CYP3A4 and a
significantly lower capability for CYP3A7.
This article has been cited by other articles:
|
|
 |
|
  A. K. Riffel, E. Schuenemann, and C. A. Vyhlidal Regulation of the CYP3A4 and CYP3A7 Promoters by Members of the Nuclear Factor I Transcription Factor Family Mol. Pharmacol., November 1, 2009; 76(5): 1104 - 1114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, Y. Cui, S. N. Hart, C. D. Klaassen, and X.-b. Zhong Dynamic Patterns of Histone Methylation Are Associated with Ontogenic Expression of the Cyp3a Genes during Mouse Liver Maturation Mol. Pharmacol., May 1, 2009; 75(5): 1171 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Dennison, M. A. Mohutsky, R. J. Barbuch, S. A. Wrighton, and S. D. Hall Apparent High CYP3A5 Expression Is Required for Significant Metabolism of Vincristine by Human Cryopreserved Hepatocytes J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 248 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Prakash, W. Wang, T. O'Connell, and K. A. Johnson CYP2C8- and CYP3A-Mediated C-Demethylation of (3-{[(4-tert-Butylbenzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic Acid (CP-533,536), an EP2 Receptor-Selective Prostaglandin E2 Agonist: Characterization of Metabolites by High-Resolution Liquid Chromatography-Tandem Mass Spectrometry and Liquid Chromatography/Mass Spectrometry-Nuclear Magnetic Resonance Drug Metab. Dispos., October 1, 2008; 36(10): 2093 - 2103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. T. Williams, K. O. Jones, G. D. Ponsler, S. M. Lowery, E. J. Perkins, S. A. Wrighton, K. J. Ruterbories, M. Kazui, and N. A. Farid The Biotransformation of Prasugrel, a New Thienopyridine Prodrug, by the Human Carboxylesterases 1 and 2 Drug Metab. Dispos., July 1, 2008; 36(7): 1227 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Williams, T. Andersson, T. B. Andersson, R. Blanchard, M. O. Behm, N. Cohen, T. Edeki, M. Franc, K. M. Hillgren, K. J. Johnson, et al. PhRMA White Paper on ADME Pharmacogenomics J. Clin. Pharmacol., July 1, 2008; 48(7): 849 - 889. [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]
|
|
|
|
|
|
R. A. B. van Waterschoot, A. E. van Herwaarden, J. S. Lagas, R. W. Sparidans, E. Wagenaar, C. M. M. van der Kruijssen, J. A. Goldstein, D. C. Zeldin, J. H. Beijnen, and A. H. Schinkel Midazolam Metabolism in Cytochrome P450 3A Knockout Mice Can Be Attributed to Up-Regulated CYP2C Enzymes Mol. Pharmacol., March 1, 2008; 73(3): 1029 - 1036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Lee, S. S. Lee, H.-E. Jeong, J.-H. Shon, J.-Y. Ryu, Y. E. Sunwoo, K.-H. Liu, W. Kang, Y.-J. Park, C.-M. Shin, et al. The CYP3A4*18 Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals Drug Metab. Dispos., November 1, 2007; 35(11): 2095 - 2101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Rodriguez-Antona, S. Leskela, M. Zajac, M. Cuadros, J. Alves, M. V. Moneo, C. Martin, J. C. Cigudosa, A. Carnero, M. Robledo, et al. Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas Blood, November 1, 2007; 110(9): 3345 - 3351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Jones, S. Ekins, L. Li, and S. D. Hall Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b5) Drug Metab. Dispos., September 1, 2007; 35(9): 1466 - 1475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Court A Pharmacogenomics Primer J. Clin. Pharmacol., September 1, 2007; 47(9): 1087 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ma, S. L. Polsky-Fisher, S. Vickers, D. Cui, and A. D. Rodrigues Cytochrome P450 3A-Dependent Metabolism of a Potent and Selective {gamma}-Aminobutyric AcidA{alpha}2/3 Receptor Agonist in Vitro: Involvement of Cytochrome P450 3A5 Displaying Biphasic Kinetics Drug Metab. Dispos., August 1, 2007; 35(8): 1301 - 1307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zhao, C. A. Lee, and K. L. Kunze Sequential Metabolism Is Responsible for Diltiazem-Induced Time-Dependent Loss of CYP3A Drug Metab. Dispos., May 1, 2007; 35(5): 704 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Dennison, D. R. Jones, J. L. Renbarger, and S. D. Hall Effect of CYP3A5 Expression on Vincristine Metabolism with Human Liver Microsomes J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 553 - 563. [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. Torimoto, I. Ishii, K.-I. Toyama, M. Hata, K. Tanaka, H. Shimomura, H. Nakamura, N. Ariyoshi, S. Ohmori, and M. Kitada Helices F-G Are Important for the Substrate Specificities of CYP3A7 Drug Metab. Dispos., March 1, 2007; 35(3): 484 - 492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Lee, I. P. van der Heiden, J. A. Goldstein, and R. H. N. van Schaik A New CYP3A5 Variant, CYP3A5*11, Is Shown to Be Defective in Nifedipine Metabolism in a Recombinant cDNA Expression System Drug Metab. Dispos., January 1, 2007; 35(1): 67 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-A. Kim, P.-W. Park, O.-J. Lee, D.-K. Kang, and J.-Y. Park Effect of Polymorphic CYP3A5 Genotype on the Single-Dose Simvastatin Pharmacokinetics in Healthy Subjects J. Clin. Pharmacol., January 1, 2007; 47(1): 87 - 93. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Carr, R. Norcross, Y. Fang, P. Lu, A. D. Rodrigues, M. Shou, T. Rushmore, and C. Booth-Genthe Characterization of the Rhesus Monkey CYP3A64 Enzyme: Species Comparisons of CYP3A Substrate Specificity and Kinetics Using Baculovirus-Expressed Recombinant Enzymes Drug Metab. Dispos., October 1, 2006; 34(10): 1703 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Dennison, P. Kulanthaivel, R. J. Barbuch, J. L. Renbarger, W. J. Ehlhardt, and S. D. Hall SELECTIVE METABOLISM OF VINCRISTINE IN VITRO BY CYP3A5 Drug Metab. Dispos., August 1, 2006; 34(8): 1317 - 1327. [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]
|
|
|
|
|
|
S.-J. Lee, W. J. Jusko, C. G. Salaita, K. A. Calis, M. W. Jann, V. E. Spratlin, J. A. Goldstein, and Y. Y. Hon Reduced Methylprednisolone Clearance Causing Prolonged Pharmacodynamics in a Healthy Subject Was Not Associated With CYP3A5*3 Allele or a Change in Diet Composition. J. Clin. Pharmacol., May 1, 2006; 46(5): 515 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Kharasch, A. Walker, C. Hoffer, and P. Sheffels Sensitivity of Intravenous and Oral Alfentanil and Pupillary Miosis as Minimally Invasive and Noninvasive Probes for Hepatic and First-Pass CYP3A Activity J. Clin. Pharmacol., October 1, 2005; 45(10): 1187 - 1197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Leeder, R. Gaedigk, K. A. Marcucci, A. Gaedigk, C. A. Vyhlidal, B. P. Schindel, and R. E. Pearce Variability of CYP3A7 Expression in Human Fetal Liver J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 626 - 635. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S.-J. Lee, D. A. Bell, S. J. Coulter, B. Ghanayem, and J. A. Goldstein Recombinant CYP3A4*17 Is Defective in Metabolizing the Hypertensive Drug Nifedipine, and the CYP3A4*17 Allele May Occur on the Same Chromosome as CYP3A5*3, Representing a New Putative Defective CYP3A Haplotype J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 302 - 309. [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. Phillips, S. R. Hood, G. G. Gibson, and N. J. Plant IMPACT OF TRANSCRIPTION FACTOR PROFILE AND CHROMATIN CONFORMATION ON HUMAN HEPATOCYTE CYP3A GENE EXPRESSION Drug Metab. Dispos., February 1, 2005; 33(2): 233 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Baker, R. H. N. van Schaik, L. P. Rivory, A. J. ten Tije, K. Dinh, W. J. Graveland, P. W. Schenk, K. A. Charles, S. J. Clarke, M. A. Carducci, et al. Factors Affecting Cytochrome P-450 3A Activity in Cancer Patients Clin. Cancer Res., December 15, 2004; 10(24): 8341 - 8350. [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]
|
|
|
|
|
|
W. Huang, Y. S. Lin, D. J. McConn II, J. C. Calamia, R. A. Totah, N. Isoherranen, M. Glodowski, and K. E. Thummel EVIDENCE OF SIGNIFICANT CONTRIBUTION FROM CYP3A5 TO HEPATIC DRUG METABOLISM Drug Metab. Dispos., December 1, 2004; 32(12): 1434 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Williams, R. Hyland, B. C. Jones, D. A. Smith, S. Hurst, T. C. Goosen, V. Peterkin, J. R. Koup, and S. E. Ball DRUG-DRUG INTERACTIONS FOR UDP-GLUCURONOSYLTRANSFERASE SUBSTRATES: A PHARMACOKINETIC EXPLANATION FOR TYPICALLY OBSERVED LOW EXPOSURE (AUCI/AUC) RATIOS Drug Metab. Dispos., November 1, 2004; 32(11): 1201 - 1208. [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]
|
|
|
|
|
|
K. Kim, J. A. Johnson, and H. Derendorf Differences in Drug Pharmacokinetics Between East Asians and Caucasians and the Role of Genetic Polymorphisms J. Clin. Pharmacol., October 1, 2004; 44(10): 1083 - 1105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Desta, B. A. Ward, N. V. Soukhova, and D. A. Flockhart Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6 J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1062 - 1075. [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]
|
|
|
|
 |
|
 H. Schrem, J. Klempnauer, and J. Borlak Liver-Enriched Transcription Factors in Liver Function and Development. Part II: the C/EBPs and D Site-Binding Protein in Cell Cycle Control, Carcinogenesis, Circadian Gene Regulation, Liver Regeneration, Apoptosis, and Liver-Specific Gene Regulation Pharmacol. Rev., June 1, 2004; 56(2): 291 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Mills, K. A. Rose, N. Sadagopan, J. Sahi, and S. M. F. de Morais Induction of Drug Metabolism Enzymes and MDR1 Using a Novel Human Hepatocyte Cell Line J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 303 - 309. [Abstract] [Full Text]
|
|
|
|
|
|
K. C. Patki, L. L. von Moltke, J. S. Harmatz, L. M. Hesse, M. H. Court, and D. J. Greenblatt Effect of Age on in Vitro Triazolam Biotransformation in Male Human Liver Microsomes J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 874 - 879. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Shen, J. F. Fitzloff, and C. S. Cook DIFFERENTIAL ENANTIOSELECTIVITY AND PRODUCT-DEPENDENT ACTIVATION AND INHIBITION IN METABOLISM OF VERAPAMIL BY HUMAN CYP3AS Drug Metab. Dispos., February 1, 2004; 32(2): 186 - 196. [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]
|
|
|
|
|
|
J. C. Stevens, R. N. Hines, C. Gu, S. B. Koukouritaki, J. R. Manro, P. J. Tandler, and M. J. Zaya Developmental Expression of the Major Human Hepatic CYP3A Enzymes J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 573 - 582. [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]
|
|
|
|
|
|
A. Westlind-Johnsson, S. Malmebo, A. Johansson, C. Otter, T. B. Andersson, I. Johansson, R. J. Edwards, A. R. Boobis, and M. Ingelman-Sundberg COMPARATIVE ANALYSIS OF CYP3A EXPRESSION IN HUMAN LIVER SUGGESTS ONLY A MINOR ROLE FOR CYP3A5 IN DRUG METABOLISM Drug Metab. Dispos., June 1, 2003; 31(6): 755 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Granvil, A.-M. Yu, G. Elizondo, T. E. Akiyama, C. Cheung, L. Feigenbaum, K. W. Krausz, and F. J. Gonzalez Expression of the Human CYP3A4 Gene in the Small Intestine of Transgenic Mice: In Vitro Metabolism and Pharmacokinetics of Midazolam Drug Metab. Dispos., May 1, 2003; 31(5): 548 - 558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nakamura, N. Torimoto, I. Ishii, N. Ariyoshi, H. Nakasa, S. Ohmori, and M. Kitada CYP3A4 and CYP3A7-Mediated Carbamazepine 10,11-Epoxidation Are Activated by Differential Endogenous Steroids Drug Metab. Dispos., April 1, 2003; 31(4): 432 - 438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Cook, L. M. Berry, D. H. Kim, E. G. Burton, J. D. Hribar, and L. Zhang Involvement of CYP3A in the Metabolism of Eplerenone in Humans and Dogs: Differential Metabolism by CYP3A4 and CYP3A5 Drug Metab. Dispos., December 1, 2002; 30(12): 1344 - 1351. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
