The roles of cytochrome P450 3A4 and lA2 in the 3-hydroxylation of quinine in vivo

Mirghani, Rajaa A.; Hellgren, Urban; Westerberg, Per; Ericsson, Örjan; Bertilsson, Leif; Gustafsson, Lars L.

doi:10.1016/s0009-9236(99)70008-1

Cited by 41 publications

(37 citation statements)

References 30 publications

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“…This results mainly from a malaria-induced reduction in hepatic mixedfunction oxidase activity (principally CYP3A4). The other enzyme subfamilies that may be involved in Q metabolism are CYP1A2 and CYP2A19, but their significance in vivo has not been confirmed (7).…”

Section: Discussionmentioning

confidence: 99%

Adverse Effect of Rifampin on Quinine Efficacy in Uncomplicated Falciparum Malaria

Pukrittayakamee¹,

Prakongpan

Wanwimolruk

et al. 2003

Antimicrob Agents Chemother

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The effects of adding rifampin to quinine were assessed in adults with uncomplicated falciparum malaria. Patients were randomized to receive oral quinine either alone (n ‫؍‬ 30) or in combination with rifampin (n ‫؍‬ 29). Although parasite clearance times were shorter in the quinine-rifampin-treated patients (mean ؎ standard deviation, 70 ؎ 21 versus 82 ؎ 18 h; P ‫؍‬ 0.023), recrudescence rates were five times higher (n ‫؍‬ 15 of 23; 65%) than those obtained with quinine alone (n ‫؍‬ 3 of 25; 12%), P < 0.001. Patients receiving rifampin had significantly greater conversion of quinine to 3-hydroxyquinine and consequently considerably lower concentrations of quinine in their plasma after the second day of treatment (median area under the plasma drug concentration-time curve from day zero to day 7 ‫؍‬ 11.7 versus 47.5 g/ml ⅐ day, P < 0.001). Rifampin significantly increases the metabolic clearance of quinine and thereby reduces cure rates. Rifampin should not be combined with quinine for the treatment of malaria, and the doses of quinine should probably be increased in patients who are already receiving rifampin treatment.

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Section: Discussionmentioning

confidence: 99%

Adverse Effect of Rifampin on Quinine Efficacy in Uncomplicated Falciparum Malaria

Pukrittayakamee¹,

Prakongpan

Wanwimolruk

et al. 2003

Antimicrob Agents Chemother

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“…We finally settled on the use of oral quinine tablets followed by a simple high-performance liquid chromatography method for the quantification of the ratio in plasma. Enzyme activity for CYP3A4 in vivo was determined by administration of a 250-mg quinine tablet to the patients 24 to 48 h before the start of chemotherapy followed by blood sampling 16 h later (Mirghani et al, 1999(Mirghani et al, , 2001). The CYP3A4 activity was expressed as the metabolic ratio of at ASPET Journals on May 9, 2018 dmd.aspetjournals.org quinine (concentration of quinine/concentration of hydroxylquinine) and was in the range of 2.2 to 41.3 (median 10.0), where a low value indicates a high metabolic ratio.…”

Section: Methodsmentioning

confidence: 99%

Influence of Cremophor EL and Genetic Polymorphisms on the Pharmacokinetics of Paclitaxel and Its Metabolites Using a Mechanism-Based Model

Fransson¹,

Gréen²,

Litton³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6␣-hydroxypaclitaxel and p-3-hydroxypaclitaxel, and its secondary metabolite, 6␣-p-3-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer.Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6␣-hydroxypaclitaxel and p-3-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6␣-p-3-dihydroxypaclitaxel. Clearance of 6␣-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p < 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n ‫؍‬ 3) or G/G (n ‫؍‬ 5) showed a 30% increase, whereas individuals with polymorphism T/T (n ‫؍‬ 8) showed a 27% decrease relative to those with the polymorphism G/T (n ‫؍‬ 17). The correlation of G2677T/A with 6␣-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.

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“…Twelve were in chronic phase and two had reached blast crisis. To assess the in vivo CYP3A activity at inclusion, the patients were given a 250 mg quinine tablet (Kinin NM Pharma); 16 h later a blood sample was collected and the plasma concentration of quinine and 3-hydroxyquinine was measured using HPLC as previously described [10,11].…”

Section: Patient Samplesmentioning

confidence: 99%

CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity

Gréen

Skoglund

Rommel

et al. 2010

Eur J Clin Pharmacol

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Purpose: Imatinib is currently used for the treatment of chronic myeloid leukemia (CML) patients. The main metabolite CGP74588 has similar potency to that of imatinib and is a product of CYP3A4 and CYP3A5 metabolism. However, the clinical significance of the metabolism on therapeutic response and pharmacokinetics is still unclear. We designed this study to investigate the role of the CYP3A activity in the response to imatinib therapy.Methods: Fourteen CML patients were phenotyped for in vivo CYP3A activity using quinine as a probe drug. The plasma concentration ratio of quinine and its CYP3A metabolite was used for assessing CYP3A activity. The patients were divided into complete molecular responders with undetectable levels of BCR-ABL transcripts after 12 months of therapy and into partial molecular responders who had failed to achieve a complete molecular response.Results: Patients that achieved complete molecular response showed significantly (MannWhitney U-test, p = 0.013) higher in vivo CYP3A activity (median quinine metabolic ratio = 10.1) than patients achieving partial molecular response (median = 15.9).Conclusions: These results indicate a clinical significance of the CYP3A activity and its metabolic products in CML patients treated with imatinib.

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The roles of cytochrome P450 3A4 and lA2 in the 3-hydroxylation of quinine in vivo

Abstract: Cytochrome P450 3A4 is important for the 3-hydroxylation of quinine in vivo. On the other hand, CYP1A2 had no significant effect on this metabolic pathway.

Cited by 41 publications

References 30 publications

Adverse Effect of Rifampin on Quinine Efficacy in Uncomplicated Falciparum Malaria

Adverse Effect of Rifampin on Quinine Efficacy in Uncomplicated Falciparum Malaria

Influence of Cremophor EL and Genetic Polymorphisms on the Pharmacokinetics of Paclitaxel and Its Metabolites Using a Mechanism-Based Model

CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity

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