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Research ArticleArticle

Complex Drug Interactions of the HIV Protease Inhibitors 3: Effect of Simultaneous or Staggered Dosing of Digoxin and Ritonavir, Nelfinavir, Rifampin, or Bupropion

Brian J. Kirby, Ann C. Collier, Evan D. Kharasch, Dale Whittington, Kenneth E. Thummel and Jashvant D. Unadkat
Drug Metabolism and Disposition March 2012, 40 (3) 610-616; DOI: https://doi.org/10.1124/dmd.111.042705
Brian J. Kirby
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Ann C. Collier
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Evan D. Kharasch
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Dale Whittington
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Kenneth E. Thummel
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Jashvant D. Unadkat
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Abstract

As part of a larger clinical drug-drug interaction (DDI) study aimed at in vitro to in vivo prediction of HIV protease inhibitor metabolic and transporter-based DDIs, we measured the inductive (staggered administration) and inductive plus inhibitory (simultaneously administered) effect of multiple dose ritonavir (RTV), nelfinavir (NFV), or rifampin (RIF) on the pharmacokinetics of the P-glycoprotein probe, digoxin (DIG), when administered simultaneously or staggered with the protease inhibitors or RIF. In both cases, NFV did not significantly affect DIG disposition. RTV decreased DIG renal clearance (Clrenal) when administered simultaneously or staggered but significantly increased DIG area under the curve from time zero to 24 h (AUC0–24 h) only when administered simultaneously. RIF decreased DIG AUC0–24 h only when RIF and DIG administration was staggered. When RIF and DIG were administered simultaneously, DIG maximal observed plasma concentration and area under the curve from time zero to 4 h were significantly increased, and DIG Clrenal was decreased. An unexpected and potentially clinically significant DDI was observed between DIG and the CYP2B6 probe, bupropion, which decreased DIG AUC0–24 h 1.6-fold and increased Clrenal 1.8-fold. Because this was an unexpected DDI and our studies were not specifically designed to quantify this interaction, further studies are required to confirm the interaction and understand the mechanistic basis of the DDI. In summary, RTV or NFV do not induce P-glycoprotein activity measured with DIG, and RIF does so only under staggered administration.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM032165]; the National Institutes of Health National Institute on Drug Abuse [Grants K24-DA00417, R01-DA14211]; and the National Institutes of Health National Center for Research Resources [Grant M01-RR00037]. A portion of this work was conducted through the Clinical Research Center Facility at the University of Washington. B.J.K. was supported in part by an ARCS fellowship, a National Institutes of Health National Institute of General Medical Sciences Pharmacological Sciences training grant [Grant GM07550], and a Simcyp-sponsored fellowship.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.042705.

  • ABBREVIATIONS:

    PI
    protease inhibitor
    DDI
    drug-drug interaction
    P450
    cytochrome P450
    P-gp
    P-glycoprotein
    RTV
    ritonavir
    RIF
    rifampin
    NFV
    nelfinavir
    DIG
    digoxin
    BUP
    bupropion
    Cmax
    maximal observed plasma concentration
    Tmax
    time of maximal observed plasma concentration
    Clrenal
    renal clearance
    OATP
    organic anion-transporting polypeptide
    AUC0-t
    area under the plasma concentration-time curve
    AUC0–24 h
    area under the curve from time zero to 24 h
    AUC0–4 h
    area under the curve from time zero to 4 h
    AUC0–3 h
    area under the curve from time zero to 3 h
    AUC0–72 h
    area under the curve from time zero to 72 h
    AUC
    area under the plasma concentration-time curve
    BUP/Met
    bupropion and/or its metabolites.

  • Received September 10, 2011.
  • Accepted December 5, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

RITONAVIR, NELFINAVIR, OR RIFAMPIN EFFECT ON P-GLYCOPROTEIN

Brian J. Kirby, Ann C. Collier, Evan D. Kharasch, Dale Whittington, Kenneth E. Thummel and Jashvant D. Unadkat
Drug Metabolism and Disposition March 1, 2012, 40 (3) 610-616; DOI: https://doi.org/10.1124/dmd.111.042705

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Research ArticleArticle

RITONAVIR, NELFINAVIR, OR RIFAMPIN EFFECT ON P-GLYCOPROTEIN

Brian J. Kirby, Ann C. Collier, Evan D. Kharasch, Dale Whittington, Kenneth E. Thummel and Jashvant D. Unadkat
Drug Metabolism and Disposition March 1, 2012, 40 (3) 610-616; DOI: https://doi.org/10.1124/dmd.111.042705
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