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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Sirolimus Oral Absorption in Rats Is Increased by Ketoconazole but Is Not Affected by d-α-Tocopheryl Poly(Ethylene Glycol 1000) Succinate

Vincent J. Wacher, Jeffrey A. Silverman, Susan Wong, Paulina Tran-Tau, Amy O. Chan, Anne Chai, Xiang-Qing Yu, Daniel O'Mahony and Zeibun Ramtoola
Journal of Pharmacology and Experimental Therapeutics October 2002, 303 (1) 308-313; DOI: https://doi.org/10.1124/jpet.102.036541
Vincent J. Wacher
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Jeffrey A. Silverman
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Susan Wong
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Paulina Tran-Tau
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Amy O. Chan
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Anne Chai
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Xiang-Qing Yu
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Daniel O'Mahony
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Zeibun Ramtoola
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Abstract

The contributions of cytochrome P450 3A (CYP3A) and P-glycoprotein to sirolimus oral bioavailability in rats were evaluated by coadministration of sirolimus (Rapamune) with the CYP3A inhibitor ketoconazole or the P-glycoprotein inhibitord-α-tocopheryl poly(ethylene glycol 1000) succinate (TPGS). Groups of six male Sprague-Dawley rats (250–300 g) were administered Rapamune (1 mg/kg) by oral gavage, alone and with ketoconazole (30 mg/kg) or TPGS (50 mg/kg). Sirolimus levels were measured in whole blood over a 6-h time course. SirolimusCmax (6.6 ± 1.6 versus 26 ± 7 ng/ml) and area under the concentration versus time curve from 0 to 6 h (AUC0–6) (22 ± 7 versus 105 ± 27 ng · h/ml) were increased 3- to 5-fold by ketoconazole. MedianTmax (1.5–2 h) was unchanged. TPGS had no effect on sirolimus absorption. The interaction of sirolimus with P-glycoprotein was also evaluated in vitro using HCT-8 and Caco-2 cell monolayers. Consistent with published reports, sirolimus was a good inhibitor of P-glycoprotein, inhibiting polarized basolateral-to-apical flux of rhodamine 123 with an IC50 of 0.625 to 1.25 μM (cyclosporine caused >80% inhibition at 5 μM). Sirolimus did not demonstrate significant polarized flux in either direction using the same monolayers (basolateral-to-apical flux was <2 times the apical-to-basolateral). Moreover, sirolimus flux was not impacted by cyclosporine, suggesting that it does not undergo P-glycoprotein-mediated transport in this system. The lack of significant sirolimus transport by P-glycoprotein may, in part, explain the lack of a TPGS effect on sirolimus absorption in rats.

Footnotes

  • ↵1 Current address: Sunesis Corporation, 341 Oyster Point Boulevard, South San Francisco, CA 94080.

  • This work was funded by Avlan Pharmaceuticals Ltd. (Flatts, Smith, Bermuda), a joint venture of AvMax Inc. and Elan Pharmaceutical Technologies.

  • DOI: 10.1124/jpet.102.036541

  • Abbreviations:
    CYP3A
    cytochrome P450 3A
    P-gp
    P-glycoprotein
    MRP
    multidrug resistance-related protein
    TPGS
    d-α-tocopheryl poly(ethylene glycol 1000) succinate
    HPLC-MS
    high-pressure liquid chromatography-mass spectroscopy
    QC
    quality control
    AUC
    area under the concentration versus time curve
    P450
    cytochrome P450
    R123
    rhodamine 123
    M1–3
    unidentified sirolimus metabolites
    TBS
    Tween-phosphate-buffered saline
    39-ODM
    39-O-desmethylsirolimus
    CDNB
    1-chloro-2,4-dinitrobenzene
    • Received March 25, 2002.
    • Accepted June 21, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 1
1 Oct 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Sirolimus Oral Absorption in Rats Is Increased by Ketoconazole but Is Not Affected by d-α-Tocopheryl Poly(Ethylene Glycol 1000) Succinate

Vincent J. Wacher, Jeffrey A. Silverman, Susan Wong, Paulina Tran-Tau, Amy O. Chan, Anne Chai, Xiang-Qing Yu, Daniel O'Mahony and Zeibun Ramtoola
Journal of Pharmacology and Experimental Therapeutics October 1, 2002, 303 (1) 308-313; DOI: https://doi.org/10.1124/jpet.102.036541

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Sirolimus Oral Absorption in Rats Is Increased by Ketoconazole but Is Not Affected by d-α-Tocopheryl Poly(Ethylene Glycol 1000) Succinate

Vincent J. Wacher, Jeffrey A. Silverman, Susan Wong, Paulina Tran-Tau, Amy O. Chan, Anne Chai, Xiang-Qing Yu, Daniel O'Mahony and Zeibun Ramtoola
Journal of Pharmacology and Experimental Therapeutics October 1, 2002, 303 (1) 308-313; DOI: https://doi.org/10.1124/jpet.102.036541
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