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Journal of Pharmacology and Experimental Therapeutics

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OtherDRUG METABOLISM AND DISPOSITION

Characterization of Interintestinal and Intraintestinal Variations in Human CYP3A-Dependent Metabolism

Mary F. Paine, Mehraneh Khalighi, Jeannine M. Fisher, Danny D. Shen, Kent L. Kunze, Christopher L. Marsh, James D. Perkins and Kenneth E. Thummel
Journal of Pharmacology and Experimental Therapeutics December 1997, 283 (3) 1552-1562;
Mary F. Paine
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Mehraneh Khalighi
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Jeannine M. Fisher
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Danny D. Shen
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Kent L. Kunze
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Christopher L. Marsh
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James D. Perkins
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Kenneth E. Thummel
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Abstract

Cytochrome P450 3A (CYP3A) metabolizes a diverse array of clinically important drugs. For some of these (e.g., cyclosporine, verapamil, midazolam), CYP3A in the intestinal mucosa contributes to their extensive and variable first-pass extraction. To further characterize this phenomenon, we measured CYP3A content and catalytic activity toward the probe substrate midazolam in mucosa isolated from duodenal, jejunal and ileal sections of 20 human donor intestines. For comparison, the same measurements were performed for 20 human donor livers, eight of which were obtained from the same donors as eight of the intestines. Excellent correlations existed between homogenate and microsomal CYP3A content for the three intestinal regions. Median microsomal CYP3A content was greatest in the duodenum and lowest in the ileum (31 vs. 17 pmol/mg of protein). With respect to midazolam 1′-hydroxylation kinetics, the medianKm for each intestinal region was similar to the median hepatic Km , ∼4 μM. In contrast, the median Vmax decreased from liver to duodenum to jejunum to ileum (850 vs. 644 vs. 426vs. 68 pmol/min/mg). Intrinsic clearance (Vmax/Km ) followed a similar trend for the intestinal regions; median duodenal intrinsic clearance was comparable to hepatic intrinsic clearance (157 and 200 μl/min/mg, respectively). Vmax correlated with CYP3A content for all tissues except the ileum. Duodenal and jejunalVmax and CYP3A content varied by >30-fold among donors. Microsomes prepared from every other 1-foot section of six intestines were also analyzed for CYP3A as well as for two coenzymes. In general, CYP3A activity, CYP3A content and CYP reductase activity rose slightly from duodenum to middle jejunum and then declined to distal jejunum and ileum. Cytochrome b5 content and cytochrome b5 reductase activity varied little throughout the intestinal tract. Regional intrinsic midazolam 1′-hydroxylation clearance was greatest for the jejunum, followed by the duodenum and ileum (144, 50 and 19 ml/min, respectively). Collectively, these results demonstrate that the upper small intestine serves as the major site for intestinal CYP3A-mediated first-pass metabolism and provides a rationale for interindividual differences in oral bioavailability for some CYP3A substrates.

Footnotes

  • Send reprint requests to: Kenneth E. Thummel, Ph.D., Department of Pharmaceutics, Box 357610, University of Washington, Seattle, WA 98195.

  • ↵1 This work was supported in part by National Institutes of Health Grants GM48349, GM32165 and ES07033 and a fellowship from the American Foundation for Pharmaceutical Education.

  • Abbreviations:
    CYP
    cytochrome P450
    MDZ
    midazolam
    1′-OH MDZ
    1′-hydroxymidazolam
    4-OH MDZ
    4-hydroxymidazolam
    S9
    supernatant fraction at 9000 × g
    SDS
    sodium dodecyl sulfate
    PAGE
    polyacrylamide gel electrophoresis
    TEMED
    N,N,N′,N′-tetra-methyl-ethylenediamine
    BCIP-NBT
    5-bromo-4-chloro-3-indoyl phosphate and nitroblue tetrazolium
    IOD
    integrated optical density
    PMSF
    phenylmethylsulfonyl fluoride
    EDTA
    ethylenediamine tetraacetic acid
    ANOVA
    analysis of variance
    • Received April 28, 1997.
    • Accepted August 27, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 3
1 Dec 1997
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OtherDRUG METABOLISM AND DISPOSITION

Characterization of Interintestinal and Intraintestinal Variations in Human CYP3A-Dependent Metabolism

Mary F. Paine, Mehraneh Khalighi, Jeannine M. Fisher, Danny D. Shen, Kent L. Kunze, Christopher L. Marsh, James D. Perkins and Kenneth E. Thummel
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1552-1562;

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OtherDRUG METABOLISM AND DISPOSITION

Characterization of Interintestinal and Intraintestinal Variations in Human CYP3A-Dependent Metabolism

Mary F. Paine, Mehraneh Khalighi, Jeannine M. Fisher, Danny D. Shen, Kent L. Kunze, Christopher L. Marsh, James D. Perkins and Kenneth E. Thummel
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1552-1562;
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