Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4?
OBJECTIVE
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.
Wanwimolruk
Sompon
S
College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA.
Paine
Mary F
MF
Pusek
Susan N
SN
Watkins
Paul B
PB
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001944:Breath Tests / Q000379:methods; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015335:Molecular Probes; D010051:Ovarian Neoplasms / Q000378:metabolism; D011802:Quinidine / Q000031:analogs & derivatives* / Q000097:blood; D011803:Quinine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014217:Troleandomycin / Q000008:administration & dosage
D000962:Antimalarials; D015335:Molecular Probes; C013569:3-hydroxyquinidine; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D014217:Troleandomycin; D011802:Quinidine