Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4?
Article first published online: 17 DEC 2002
British Journal of Clinical Pharmacology
Volume 54, Issue 6, pages 643–651, December 2002
How to Cite
Wanwimolruk, S., Paine, M. F., Pusek, S. N. and Watkins, P. B. (2002), Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4?. British Journal of Clinical Pharmacology, 54: 643–651. doi: 10.1046/j.1365-2125.2002.01687.x
- Issue published online: 17 DEC 2002
- Article first published online: 17 DEC 2002
- Accepted 12 July 2002.
- in vivo;
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.