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OtherDRUG METABOLISM AND DISPOSITION

Metabolism and Transport of the Macrolide Immunosuppressant Sirolimus in the Small Intestine

Alfonso Lampen, Yuanchao Zhang, Ina Hackbarth, Leslie Z. Benet, Karl-Fr. Sewing and Uwe Christians
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1104-1112;
Alfonso Lampen
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Yuanchao Zhang
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Ina Hackbarth
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Leslie Z. Benet
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Karl-Fr. Sewing
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Uwe Christians
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Abstract

Small intestinal metabolism and transport of sirolimus, a macrolide immunosuppressant with a low and highly variable oral bioavailability, were investigated using small intestinal microsomes and intestinal mucosa in the Ussing chamber. After incubation of sirolimus with human and pig small intestinal microsomes, five metabolites were detected using high performance liquid chromatography/electrospray-mass spectrometry: hydroxy, dihydroxy, trihydroxy, desmethyl and didesmethyl sirolimus. The same metabolites were generated by human liver microsomes and pig small intestinal mucosa in the Ussing chamber. Anti-CYP3A antibodies, as well as the specific CYP3A inhibitors troleandomycin and erythromycin, inhibited small intestinal metabolism of sirolimus, confirming that, as in the liver, CYP3A enzymes are responsible for sirolimus metabolism in the small intestine. Of 32 drugs tested, only known CYP3A substrates inhibited sirolimus intestinal metabolism with inhibitor constants (Ki) equal to those in human liver microsomes. The formation of hydroxy sirolimus by small intestinal microsomes isolated from 14 different patients ranged from 28 to 220 pmol·min−1·mg−1microsomal protein. In the Ussing chamber, >99% of the sirolimus metabolites reentered the mucosa chamber against a sirolimus gradient, indicating active countertransport. Intestinal drug metabolism and countertransport into the gut lumen, drug interactions with CYP3A substrates and inhibitors in the small intestine and an 8-fold interindividual variability of the intestinal metabolite formation rate significantly contribute to the low and highly variable bioavailability of sirolimus.

Footnotes

  • Send reprint requests to: Uwe Christians, MD., Ph.D., Department of Biopharmaceutical Sciences, School of Pharmacy, University of California at San Francisco, 513 Parnassus Ave., Room S-834, San Francisco, CA 94143-0446. E-mail:uwec{at}itsa.ucsf.edu

  • ↵1 This study was supported by the Deutsche Forschungsgemeinschaft, Grants SFB265/A7 and SFB280/A8 and “Heisenberg” Grant Ch95/6–1.

  • Abbreviations:
    CYP
    cytochrome P450
    ESI
    electrospray ionization
    MDR
    multidrug resistance
    HPLC
    high performance liquid chromatography
    MS
    mass spectrometry
    • Received September 29, 1997.
    • Accepted February 24, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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OtherDRUG METABOLISM AND DISPOSITION

Metabolism and Transport of the Macrolide Immunosuppressant Sirolimus in the Small Intestine

Alfonso Lampen, Yuanchao Zhang, Ina Hackbarth, Leslie Z. Benet, Karl-Fr. Sewing and Uwe Christians
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1104-1112;

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OtherDRUG METABOLISM AND DISPOSITION

Metabolism and Transport of the Macrolide Immunosuppressant Sirolimus in the Small Intestine

Alfonso Lampen, Yuanchao Zhang, Ina Hackbarth, Leslie Z. Benet, Karl-Fr. Sewing and Uwe Christians
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1104-1112;
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