Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4?

Authors

  • Sompon Wanwimolruk,

    1. College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA, and the General Clinical Research Center, University of North Carolina, Chapel Hill, NC, USA
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  • Mary F. Paine,

    1. College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA, and the General Clinical Research Center, University of North Carolina, Chapel Hill, NC, USA
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  • Susan N. Pusek,

    1. College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA, and the General Clinical Research Center, University of North Carolina, Chapel Hill, NC, USA
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  • Paul B. Watkins

    Corresponding author
    1. College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA, and the General Clinical Research Center, University of North Carolina, Chapel Hill, NC, USA
    • Paul B. Watkins, MD, General Clinical Research Center, Rm. 3005 APCF, CB# 7600, UNC Hospitals, Chapel Hill, NC 27599–7600, USA. Tel.: + 1 919 966 1435; Fax: + 1 919 966 1576; E-mail: pbwatkins@med.unc.edu

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Abstract

Aims To evaluate the antimalarial agent quinine as a potential in vivo probe for hepatic cytochrome P450 (CYP) 3A4 activity.

Methods Ten healthy adult volunteers received, by randomized crossover design, either a single oral dose of quinine sulphate (600 mg) alone, or quinine sulphate (600 mg) plus the CYP3A4 inhibitor troleandomycin (TAO; 500 mg every 8 h). Plasma and urine samples were collected before quinine administration, and up to 48 h thereafter, then analysed by h.p.l.c. for both quinine and its CYP3A4-generated metabolite, 3-hydroxyquinine. During both phases, the erythromycin breath test (ERMBT) was administered at specific times to assess hepatic CYP3A4 activity.

Results Compared with control, TAO treatment significantly decreased the mean time-averaged ERMBT result by 77% (95% CI, 68, 85%), the mean apparent oral clearance of quinine (CL/F ) by 45% (95% CI, 39, 52%), and the mean apparent formation clearance of 3-hydroxyquinine (CL3-OH) by 81% (95% CI, 76, 87%). There was no correlation between the TAO-mediated percent decrease in the time-averaged ERMBT result and the percent decrease in CL/F or in CL3-OH. When TAO and control treatments were analysed separately, there were no significant correlations between the time-averaged ERMBT result and CL/F, CL3-OH, or single plasma quinine concentration at 12, 24, and 48 h.

Conclusions Quinine may be a useful probe to detect inhibition of liver CYP3A4 activity within an individual. Further studies are needed to determine whether it can provide a quantitative measure of CYP3A4 activity suitable for intersubject comparison.

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