Metabolism and elimination of quinine in healthy volunteers.
OBJECTIVE
The aims were to investigate: (1) The renal elimination of quinine and its metabolites 3-hydoxyquinine, 2'-quininone, (10R) and (10S)-11-dihydroxydihydroquinine and (2) the relative importance of CYP3A4, CYP1A2 and CYP2C19 for the formation of 2'-quininone, (10R) and (10S)-11-dihydroxydihydroquinine in vivo.


METHODS
In a randomised three-way crossover study, nine healthy Swedish subjects received a single oral dose of quinine hydrochloride (500 mg), on three different occasions: (A) alone, (B) concomitantly with ketoconazole (100 mg twice daily for 3 days) and (C) concomitantly with fluvoxamine (25 mg twice daily for 2 days). Blood and urine samples were collected before quinine intake and up to 96 h thereafter. All samples were analysed by means of high-performance liquid chromatography.


RESULTS
Co-administration with ketoconazole significantly increased the area under the plasma concentration versus time curve (AUC) of 2'-quininone, (10S)-11-dihydroxydihydroquinine, and (10R)-11-dihydroxydihydroquinine, the geometric mean ratios (90% CI) of the AUC were 1.9 (1.8, 2.0), 1.3 (1.1, 1.7) and 1.6 (1.4, 1.8), respectively. Co-administration with fluvoxamine had no significant effect on the mean AUC of any of the metabolites. A mean of 56% of the administered oral quinine dose was recovered in urine after hydrolysis with beta-glucuronidase relative to the 40% recovered before hydrolysis.


CONCLUSIONS
Quinine is eliminated in urine mainly as unchanged drug and as 3-hydroxyquinine. The major metabolite of quinine is 3-hydroxyquinine formed by CYP3A4. There is no evidence for the involvement of CYP3A4, 1A2 or 2C19 in the formation of 2'-quininone, (10S)-11-dihydroxydihydroquinine and (10R)-11-dihydroxydihydroquinine in vivo. Glucuronidation is an important pathway for the renal elimination of quinine, mainly as direct conjugation of the drug.
Mirghani
Rajaa A
RA
Department of Laboratory Medicine and Technology, C1-68 Huddinge University Hospital, 141 86 Stockholm, Sweden. rajaa.a.mirghani@labmed.ki.se
Hellgren
Urban
U
Bertilsson
Leif
L
Gustafsson
Lars L
LL
Ericsson
Orjan
O
D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D016227:Benzoquinones / Q000097:blood / Q000378:metabolism / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011802:Quinidine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D011803:Quinine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D011809:Quinones / Q000097:blood / Q000378:metabolism / Q000652:urine; D013997:Time Factors
C429827:10,11-dihydroxydihydroquinine; D000962:Antimalarials; D016227:Benzoquinones; D065607:Cytochrome P-450 Enzyme Inhibitors; D011809:Quinones; C013569:3-hydroxyquinidine; C070445:quininone; C004532:quinone; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D016666:Fluvoxamine; D007654:Ketoconazole