Pharmacokinetics of quinine and its metabolites in pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria.

OBJECTIVES: The study was conducted in New Halfa teaching hospital, eastern Sudan to investigate the pharmacokinetics of quinine in pregnant Sudanese women. METHODS: Sixteen (eight pregnant and eight non-pregnant) Sudanese women infected with Plasmodium falciparum malaria were given a single dose of quinine hydrochloride (10 mg/kg body weight) as intravenous infusion over 2 h. The women were treated with intramuscular artemether. Plasma was collected before quinine administration and up to 72 h thereafter. These were analysed for quinine and its metabolites, 3-hydroxyquinine, (10R)-10,11-dihydroxyquinine and (10S)-10,11-dihydroxyquinine using high-performance liquid chromatography. RESULTS: The two groups were well matched in their basic characteristics. There was no significant difference in the mean maximum plasma concentration attained (C(max)), the mean time at which C(max) was attained, the elimination half-life (t(1/2)) and the total area under the plasma concentration vs. time curve (AUC) of quinine and its metabolites between the pregnant in non-pregnant women. CONCLUSION: There was no significant difference in quinine metabolism between pregnant and non-pregnant women and there is no need to adjust quinine dose when treating pregnant women.

Cyclophosphamide induces mRNA, protein and enzyme activity of cytochrome P450 in rat.

The effects of cyclophosphamide (CPA) on CYP enzymes in vivo and its auto induction in rat were investigated in Wistar/Fu male rats at a single dose (40 or 200 mg kg(-1)) or as repeated dose of 200 mg kg(-1) CPA. After a single dose of CPA, mRNAs of CYPs 2B1, 2B2, 3A2, 2C11 were significantly induced up to 220-, 6.7-, 5.0- and 5.8-fold at the low dose CPA, and 4800-, 52-, 22- and 2.5-fold at the high dose. CYP2B1/2 and CYP3A proteins were increased by 4- and 2-fold (low dose) and by 28- and 1.7-fold (high dose). CYP2C11 protein levels were not altered. Microsomal activities of CYP2B, CYP3A and 2C11 were increased by 2-, 1.8- and 1.3-fold at low dose CPA, and 3.2-, 1.7- and 1.6-fold at high dose. A significant (p<0.05) decrease in CPA concentration and a significant (p<0.05) increase in 4-OH-CPA levels were observed with repeated administration of CPA. Acute induction effect on CYP2B1, 2B2, 2C11 and 3A2 and a substantial up regulation of CYP2B1 mRNA were observed after a single dose of CPA, auto induction was observed by repeated administration.

Simultaneous determination of quinine and four metabolites in plasma and urine by high-performance liquid chromatography.

The determination of quinine, (3S)-3-hydroxyquinine, 2'-quininone and (10R)- and (10S)-10,11-dihydroxydihydroquinine in plasma and urine samples is described. This is the first time the R and S configurations have been correctly assigned to the two metabolites of 10,11-dihydroxyquinine. One hundred microliter-plasma samples were protein precipitated with 200 microl cold methanol. Urine samples were 10-100 x diluted and then directly injected into the HPLC. A reversed-phase liquid chromatography system with fluorescence detection and a Zorbax Eclipse XDB phenyl column and gradient elution was used. The within and between assay coefficients of variation of the method for quinine and its metabolites in plasma and urine was less than 13%. The lower limit of quantitation was in the range of 0.024-0.081 microM.

The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in vivo.

OBJECTIVE: To investigate the roles of CYP3A4 and CYP1A2 in the 3-hydroxylation of quinine in vivo. METHODS: In a randomized, three-way crossover study, nine healthy Swedish volunteers received single oral doses of quinine hydrochloride (500 mg), quinine hydrochloride (500 mg) plus ketoconazole (100 mg twice daily for 3 days), and quinine hydrochloride (500 mg) plus fluvoxamine (25 mg twice daily for 2 days) on three different occasions. Blood and urine samples were collected before quinine intake and up to 96 hours thereafter. Plasma and urine samples were analyzed for both quinine and its main metabolite 3-hydroxyquinine with HPLC methods. RESULTS: Coadministration with ketoconazole (which inhibits CYP3A4) decreased the mean apparent oral clearance of quinine significantly (P < .001) by 31% (from 8.7 to 6.0 L/h), whereas coadministration with fluvoxamine (which inhibits CYP1A2 and to some extent CYP2C19) had no significant effect (P > .05) on the mean apparent oral clearance of quinine. Coadministration with ketoconazole also decreased the mean area under the plasma concentration versus time curve (AUC) of 3-hydroxyquinine (from 28.4 to 19.7 micromol x h x L(-1); P < .001), whereas coadministration with fluvoxamine increased 3-hydroxyquinine AUC significantly (from 28.4 to 30.2 micromol x h x L(-1); P < .05). CONCLUSION: 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.

High-performance liquid chromatographic method for the determination of the major quinine metabolite, 3-hydroxyquinine, in plasma and urine.

The determination of 3-hydroxyquinine in urine and plasma samples is described. Extraction was performed using a mixture of toluene-butanol (75:25, v/v), followed by back-extraction into the mobile phase, which consisted of 0.1 M phosphate buffer, acetonitrile, tetrahydrofuran and triethylamine. A reversed-phase liquid chromatography system with fluorescence detection and a CT-sil C18 column were used. The within-assay coefficient of variation of the method was 2% at the higher concentration values in plasma, 2.95 microM, 4% at 227 nM and 9% at the lower limit of quantitation, 4.5 nM. In urine, the coefficient of variation was 11% at the lower concentration, 227 nM and was 3% at 56.8 microM. The between-assay coefficient of variation was 4% at the low concentration (5.1 nM) in plasma, 2% at 276.8 nM and 3% at 1.97 microM. In urine, the between assay coefficient of variation was 4% at 204.6 nM, 3% at 5.12 microM and 2% at 56.8 microM.