Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man.
OBJECTIVE
To investigate the usefulness of the 3-hydroxylation of quinine as a biomarker reaction for the activity of CYP3A4 in man and to study the interindividual variation in the metabolic ratio (MR), i.e. quinine/3-hydroxyquinine.


METHODS
Data from a previous study (A) was used for determination of the MR of quinine in plasma and urine at different time points. In study B, 24 healthy Swedish subjects received 250 mg quinine hydrochloride first alone and later together with four other CYP probe drugs [losartan (CYP2C9), omeprazole (CYP2C19), debrisoquine (CYP2D6) and caffeine (CYP1A2)] administered on the same day. Plasma and urine samples were collected before quinine intake and 16 h thereafter and analysed for quinine and 3-hydroxyquinine using high-performance liquid chromatography. Plasma and/or urine were collected for the other probes at different time points. MRs of all the probes were determined and correlations to quinine MR were studied.


RESULTS
In study A, the MR in plasma was stable over 96 h. The ratio increased from 5.8 to 12.2 (P=0.006) during co-administration with ketoconazole, whereas no significant difference (P=0.76) was observed during co-administration with fluvoxamine (from 5.8 to 6.0). In study B, there was no significant difference (P=0.36) between the mean MRs when quinine was given alone (4.7) or together with the four other drugs (4.5). There was a significant correlation between the MR of quinine and omeprazole sulphone formation (r=0.52, P<0.01), but not to the MRs of the other probes. There was a fivefold interindividual variability in the MR.


CONCLUSIONS
The MR of quinine in plasma or urine may serve as a stable measure of the activity of CYP3A4 in man. These results together with in vitro data show that quinine is also a specific CYP3A4 probe.
Division of Clinical Pharmacology, Department of Medical Laboratory Sciences and Technology, Karolinska Institutet and Hospital Pharmacy, C1-68 Huddinge University Hospital, 141 86 Stockholm, Sweden. rajaa.a.mirghani@labtek.ki.se
Rajaa A
RA
Mirghani
Orjan
O
Ericsson
Gunnel
G
Tybring
Lars L
LL
Gustafsson
Leif
L
Bertilsson
D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011802:Quinidine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011803:Quinine / Q000097:blood / Q000378:metabolism* / Q000652:urine
D015415:Biomarkers; D007527:Isoenzymes; C013569:3-hydroxyquinidine; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D016666:Fluvoxamine; D007654:Ketoconazole