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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics and Interactions of a Novel Antagonist of Chemokine Receptor 5 (CCR5) with Ritonavir in Rats and Monkeys: Role of CYP3A and P-Glycoprotein

Sanjeev Kumar, Gloria Y. Kwei, Grace K. Poon, Susan A. Iliff, Yanfeng Wang, Qing Chen, Ronald B. Franklin, Varsha Didolkar, Regina W. Wang, Masayo Yamazaki, Shuet-Hing Lee Chiu, Jiunn H. Lin, Paul G. Pearson and Thomas A. Baillie
Journal of Pharmacology and Experimental Therapeutics March 2003, 304 (3) 1161-1171; DOI: https://doi.org/10.1124/jpet.102.045096
Sanjeev Kumar
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Gloria Y. Kwei
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Grace K. Poon
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Susan A. Iliff
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Yanfeng Wang
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Qing Chen
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Ronald B. Franklin
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Varsha Didolkar
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Regina W. Wang
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Masayo Yamazaki
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Shuet-Hing Lee Chiu
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Jiunn H. Lin
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Paul G. Pearson
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Thomas A. Baillie
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Abstract

The mechanisms of pharmacokinetic interactions of a novel anti-human immunodeficiency virus (anti-HIV-1) antagonist of chemokine receptor 5 (CCR5) [2-(R)-[N-methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)amino]-3-methylbutanoic acid (MRK-1)] with ritonavir were evaluated in rats and monkeys. MRK-1 was a good substrate for the human (MDR1) and mouse (Mdr1a) multidrug resistance protein transporters and was metabolized by CYP3A isozymes in rat, monkey, and human liver microsomes. Both the in vitro MDR1-mediated transport and oxidative metabolism of MRK-1 were inhibited by ritonavir. Although the systemic pharmacokinetics of MRK-1 in rats and monkeys were linear, the oral bioavailability increased with an increase in dose from 2 to 10 mg/kg. The area under the plasma concentration-time curve (AUC) of MRK-1 was increased 4- to 6-fold when a 2 or 10 mg/kg dose was orally coadministered with 10 mg/kg ritonavir. Further pharmacokinetic studies in rats indicated that P-glycoprotein (P-gp) inhibition by ritonavir increased the intestinal absorption of 2 mg/kg MRK-1 maximally by ∼30 to 40%, and a major component of the interaction likely resulted from its reduced systemic clearance via the inhibition of CYP3A isozymes. Oral coadministration of quinidine (10 and 30 mg/kg) increased both the extent and the first-order rate of absorption of MRK-1 (2 mg/kg) by ∼40 to 50% and ∼100 to 300%, respectively, in rats, thus further substantiating the role of P-gp in modulating the intestinal absorption of MRK-1 in this species. At the 10 mg/kg MRK-1 dose, however, the entire increase in its AUC upon coadministration with ritonavir or quinidine could be attributed to a reduced systemic clearance, and no effects on intestinal absorption were apparent. In contrast to rats, the effects of P-gp in determining the intestinal absorption of MRK-1 appeared less significant in rhesus monkeys at either dose.

Footnotes

  • DOI: 10.1124/jpet.102.045096

  • Abbreviations:
    CCR5
    chemokine receptor 5
    HIV-1
    human immunodeficiency virus
    AUC
    area under the plasma concentration-time curve
    MDR
    multidrug resistance
    PEG
    polyethylene glycol
    EtOH
    ethanol
    MRK-1
    2-(R)-[N-methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1-yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)amino]-3-methylbutanoic acid
    CLblood
    systemic blood clearance
    CLint
    intrinsic clearance
    Cmax
    maximal plasma concentration
    CLp
    systemic plasma clearance
    P450
    cytochrome P450
    Ka
    first-order absorption rate constant
    Kel
    first-order elimination rate constant
    MS
    mass-spectrometry
    LC-MS/MS
    liquid chromatography tandem mass spectrometry
    P-gp
    P-glycoprotein
    Tmax
    time to reach maximal plasma concentration
    • Received October 9, 2002.
    • Accepted November 5, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 3
1 Mar 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics and Interactions of a Novel Antagonist of Chemokine Receptor 5 (CCR5) with Ritonavir in Rats and Monkeys: Role of CYP3A and P-Glycoprotein

Sanjeev Kumar, Gloria Y. Kwei, Grace K. Poon, Susan A. Iliff, Yanfeng Wang, Qing Chen, Ronald B. Franklin, Varsha Didolkar, Regina W. Wang, Masayo Yamazaki, Shuet-Hing Lee Chiu, Jiunn H. Lin, Paul G. Pearson and Thomas A. Baillie
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 1161-1171; DOI: https://doi.org/10.1124/jpet.102.045096

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics and Interactions of a Novel Antagonist of Chemokine Receptor 5 (CCR5) with Ritonavir in Rats and Monkeys: Role of CYP3A and P-Glycoprotein

Sanjeev Kumar, Gloria Y. Kwei, Grace K. Poon, Susan A. Iliff, Yanfeng Wang, Qing Chen, Ronald B. Franklin, Varsha Didolkar, Regina W. Wang, Masayo Yamazaki, Shuet-Hing Lee Chiu, Jiunn H. Lin, Paul G. Pearson and Thomas A. Baillie
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 1161-1171; DOI: https://doi.org/10.1124/jpet.102.045096
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