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Metabolism and elimination of quinine in healthy volunteers.
Eur J Clin Pharmacol. 2003 Sep; 59(5-6):423-7.EJ

Abstract

OBJECTIVES

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.

CONCLUSION

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.

Authors+Show Affiliations

Department of Laboratory Medicine and Technology, C1-68 Huddinge University Hospital, 141 86 Stockholm, Sweden. rajaa.a.mirghani@labmed.ki.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12920491

Citation

Mirghani, Rajaa A., et al. "Metabolism and Elimination of Quinine in Healthy Volunteers." European Journal of Clinical Pharmacology, vol. 59, no. 5-6, 2003, pp. 423-7.
Mirghani RA, Hellgren U, Bertilsson L, et al. Metabolism and elimination of quinine in healthy volunteers. Eur J Clin Pharmacol. 2003;59(5-6):423-7.
Mirghani, R. A., Hellgren, U., Bertilsson, L., Gustafsson, L. L., & Ericsson, O. (2003). Metabolism and elimination of quinine in healthy volunteers. European Journal of Clinical Pharmacology, 59(5-6), 423-7.
Mirghani RA, et al. Metabolism and Elimination of Quinine in Healthy Volunteers. Eur J Clin Pharmacol. 2003;59(5-6):423-7. PubMed PMID: 12920491.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolism and elimination of quinine in healthy volunteers. AU - Mirghani,Rajaa A, AU - Hellgren,Urban, AU - Bertilsson,Leif, AU - Gustafsson,Lars L, AU - Ericsson,Orjan, Y1 - 2003/08/12/ PY - 2002/12/16/received PY - 2003/06/16/accepted PY - 2003/8/16/pubmed PY - 2004/2/24/medline PY - 2003/8/16/entrez SP - 423 EP - 7 JF - European journal of clinical pharmacology JO - Eur J Clin Pharmacol VL - 59 IS - 5-6 N2 - OBJECTIVES: 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. CONCLUSION: 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. SN - 0031-6970 UR - https://www.unboundmedicine.com/medline/citation/12920491/Metabolism_and_elimination_of_quinine_in_healthy_volunteers_ L2 - https://dx.doi.org/10.1007/s00228-003-0637-8 DB - PRIME DP - Unbound Medicine ER -