Disposition Of Quinine Research Articles

Physiologically-Based Pharmacokinetic Modeling for Optimal Dosage Prediction of QuinineCoadministered With Ritonavir-Boosted Lopinavir.

The coformulated lopinavir/ritonavir significantly reduces quinine concentration in healthy volunteers due to potential drug-drug interactions (DDIs). However, DDI information in malaria and HIV coinfected patients are lacking. The objective of the study was to apply physiologically-based pharmacokinetic (PBPK) modeling to predict optimal dosage regimens of quinine when coadministered with lopinavir/ritonavir in malaria and HIV coinfected patients with different conditions. The developed model was validated against literature. Model verification was evaluated using the accepted method. The verified PBPK models successfully predicted unbound quinine disposition when coadministered with lopinavir/ritonavir in coinfected patients with different conditions. Suitable dose adjustments to counteract with the DDIs have identified in patients with various situations (i.e., a 7-day course at 1,800mg t.i.d. in patients with malaria with HIV infection, 648mg b.i.d. in chronic renal failure, 648mg t.i.d. in hepatic insufficiency except for severe hepatic insufficiency (324mg b.i.d.), and 648mg t.i.d. in CYP3A4 polymorphism).

Pharmacokinetic Parameters of Quinine in Healthy Subjects and in Patients with Uncomplicated Malaria in Nigeria: Analysis of Data using a Population Approach

The varied disposition of the antimalarial quinine partly explains its poor tolerance and toxicity in humans. Using a population approach, the disposition of quinine in healthy subjects and patients with acute uncomplicated symptomatic malaria from Nigeria was re-examined with a view to providing population-specific attributes. Concentration versus time profiles of quinine over 48 hours in healthy individuals, and over 7 days in malaria-infected patients, were stratified to reflect: concentration versus time data during the first 48 hours of quinine administration for healthy subjects and infected patients, concentration versus time data after 48 hours in infected patients, and all concentration versus time data available for healthy subjects and infected patients. Pharmacokinetic parameters were then estimated with a stochastic approximation expectation maximization algorithm. All datasets were fitted by a 1-compartment model with covariate contributions from body weight and infection status. The absorption rate constant, and volume of distribution and clearance were 1.72 h-1, 86.8 to 157.4 L, and 6.6 to 9.6 L/h, respectively. Infected patients experienced a 38% decrease in volume of distribution and a 31% decrease in clearance in the first 48 hours relative to healthy individuals. The contraction in volume of distribution and clearance diminished significantly after 48 hours of chronic quinine dosing in infected patients. The study findings suggest that clinical interventions aimed at enhancing the safety and tolerance of quinine might be achieved by a rational decrease in dose size and/or dosing interval, post-48 hours of chronic quinine administration, in malaria-infected patients.

The Effect of Malaria Infection on the Disposition of Quinine and Quinidine in the Rat Isolated Perfused Liver Preparation

The effect of malaria on the disposition of quinine and quinidine was studied in livers isolated from young rats infected with merozoites of Plasmodium berghei, a rodent malaria model, and non-infected controls. Following bolus administration of quinine (1 mg) or quinidine (1 mg) to the 100 mL recycling perfusion circuit, perfusate was sampled (0-4 h) and plasma assayed for quinine and quinidine by HPLC. Higher quinine (AUC:6470 +/- 1101 vs 3822 +/- 347 ng h mL-1, P less than 0.001) and quinidine (AUC: 6642 +/- 1304 vs 4808 +/- 872 ng h mL-1, P less than 0.05) concentrations were observed during malaria infection (MI). MI resulted in decreased quinine clearance (CL) (0.33 +/- 0.08 vs 0.64 +/- 0.09 mL min-1 g-1, P less than 0.001) and volume of distribution (Vd) (53.0 +/- 13.3 vs 81.2 +/- 23.7 mL g-1, P less than 0.05) but no significant change in elimination half-life (t1/2) (1.93 +/- 0.6 vs 1.37 +/- 0.25 h, P greater than 0.05). With quinidine, however, MI resulted in decreased CL (0.38 +/- 0.16 vs 0.64 +/- 0.09, P less than 0.05) with no change in Vd and a significant increase in t1/2 (1.62 +/- 0.42 vs 0.88 +/- 0.22, P less than 0.01). In summary, the hepatic disposition of quinine and quinidine is altered in the malaria-infected rat.

The Influence of α1-Acid Glycoprotein on Quinine and Quinidine Disposition in the Rat Isolated Perfused Liver Preparation

We have studied the effect of 0.5 and 2.0 g L-1 of alpha 1-acid glycoprotein (AAG) on the disposition of quinine and quinidine in the rat isolated perfused liver preparation. The higher concentration of AAG (2.0 g L-1) resulted in a significant decrease in clearance [quinine study (control: 9.6 +/- 2.9 vs test: 3.1 +/- 1.2 mL min-1); quinidine study (control: 9.8 +/- 2.4 vs test: 3.5 +/- 1.1 mL min-1]) and volume of distribution [quinine study (control: 1198 +/- 416 vs test: 466 +/- 95 mL); quinidine study (control: 1352 +/- 459 vs test: 317 +/- 24 mL]) but not the elimination half-life compared with control. At the lower concentration (0.5 g L-1) of AAG there was no significant difference in clearance, volume of distribution and elimination half-life for either drug compared with control. By increasing the concentration of AAG from 0.5 to 2.0 g L-1 both the hepatic extraction ratio and the fraction of drug unbound when compared with controls significantly decreased by about 66 and 60% for quinine, and by 65 and 58% for its diastereoisomer quinidine, respectively. The consequence of these changes is a substantial increase in the total quinine (or quinidine) concentrations without any change in the free quinine (or quinidine) concentrations. However, at 0.5 g L-1 AAG compared with control, no significant difference was observed in fraction of drug unbound, extraction ratio, total drug concentration or free drug concentration for either drug. In summary, changing concentrations of AAG, an important binding protein for quinine and quinidine, can affect the hepatic disposition of both drugs.

The Disposition of Quinine in the Rat Isolated Perfused Liver: Effect of Dose Size

We have investigated the pharmacokinetics of both free and total quinine in the rat isolated perfused liver at three doses, 6.25, 12.5 and 25 mg. The plasma concentrations of free and total quinine decayed biexponentially over 4 h. However, on increasing dose, the terminal half-life of free and total quinine showed marked increases ranging from 12.4 +/- 3.7 min at 6.25 mg to 176.0 +/- 153 min at 25 mg (total quinine). Quinine clearance was reduced approximately by half as the dose was doubled. At 10 min post dosage, quinine extraction at the 6.25 mg dose (56 +/- 16.3%) was more than twice that of the highest dose (25 mg, 25.0 +/- 6.5%). Free quinine at the 6.25 mg dose was cleared at approximately 100% of perfusate flow, whereas at 25 mg, clearance was less than one fifth of that value. Unchanged quinine elimination in bile was low, with less than 1% of the parent drug being detected at the 12.5 and 25 mg doses. Relatively little parent drug was recovered from the liver at 4 h. At the 25 mg dose, less than or equal to 6% was recovered as parent drug. HPLC analysis revealed some polar metabolites of quinine in the bile and in the liver homogenates. Dose dependent kinetics of quinine were demonstrated in this study, as hepatic extraction of quinine decreased with increasing dose and input concentration.

Disposition of quinine and its major metabolite, 3-hydroxyquinine in patients with liver diseases

Quinine, extensively metabolized by CYP 3A4, has 3-hydroxyquinine as the major metabolite which also contributes to its antimalarial activity. This study assessed the impact of various liver diseases on the disposition of quinine and 3-hydroxyquinine. Ten adult patients with liver diseases ranging from cirrhosis, primary liver carcinoma, hepatitis, ascites, and amoebic liver disease as well as six healthy subjects received single oral dose of 600 mg quinine sulphate tablets. Venous blood and urine were collected over 48 h. Quinine and 3-hydroxyquinine were determined from the matrices by a validated high performance liquid chromatography (HPLC) method. Wide inter-individual variations were observed in the subjects especially those with liver diseases. Cmax (4.47 vs 2.41mcg/ml) and AUC (73 vs 51mcg.h/ml) values were significantly increased in liver disease patients. Clearance was reduced by 30% from 3.27 to 2.31 (p = 0.009). Metabolic ratio of quinine/3-hydroxyquinine in plasma decreased from 5.5 to 1.42 over 4 to 48 h. Cumulative amount of quinine and 3-hydroxyquinine produced in urine were 38 mg (8%) and 32 mg (7%) respectively. Compromised metabolism of quinine in liver disease patients suggests the necessity of reviewing the dosage of quinine in liver disease patients who come up with malaria, a situation that further reduces liver function.

Genetic Variations in ABCB1 and CYP3A5 as well as Sex Influence Quinine Disposition Among Ugandans

Quinine is one of the most effective antimalarial drugs, although its clinical use is limited as a result of its narrow safety margin. Quinine is a substrate of the polymorphic p-glycoprotein and CYP3A4/3A5. This study aimed to examine the effects of genetic variations in ABCB1 and CYP3A5 genes, sex, demographic, and biochemical variables (serum albumin, creatinine, alanine aminotransferase and albumin) on quinine disposition among Ugandans. Quinine (600 mg) was orally administered to 140 healthy volunteers. Quinine and its metabolite 3-hydroxyquinine concentrations were determined from 16-hour postdose plasma by high-performance liquid chromatography. CYP3A5 activity was measured using quinine/3-hydroxyquinine ratio (metabolic ratio). Genotyping for a total of 20 single nucleotide polymorphisms in ABCB1 (n = 13) and CYP3A5 (n = 7) was done using Taqman and minisequencing on microarray. There were 20.5- and 13-fold variations in body weight-adjusted plasma quinine concentrations (mean +/- standard deviation, 5.26 +/- 2.5 mumol/L; range, 0.88-18.10 mumol/L) and quinine-to-3-hydroxyquinine metabolic ratio (mean +/- standard deviation, 7.68 +/- 3.3 mumol/L; range, 1.66-22.3 mumol/L), respectively. Weight-adjusted plasma quinine concentration was significantly influenced by sex and ABCB1 haplotype. There was a significant sex difference in quinine metabolic ratio, women being faster metabolizers than men (P = 0.01). CYP3A5 genotype/haplotype significantly (P = 0.03) influenced quinine disposition with a clear CYP3A5*1 gene dose effect. The result confirms that quinine disposition is influenced mainly by sex as well as by ABCB1 and CYP3A5 genotypes. Despite being fast metabolizers, women display higher quinine bioavailability than men in Uganda. This may have clinical significance in determining an individual's susceptibility to quinine-associated adverse reactions such as cinchonism.

Effects of concurrent administration of nevirapine on the disposition of quinine in healthy volunteers

AbstractObjectivesNevirapine and quinine are likely to be administered concurrently in the treatment of patients with HIV and malaria. Both drugs are metabolised to a significant extent by cytochrome P450 (CYP)3A4 and nevirapine is also an inducer of this enzyme. This study therefore evaluated the effect of nevirapine on the pharmacokinetics of quinine.MethodsQuinine (600 mg single dose) was administered either alone or with the 17th dose of nevirapine (200 mg every 12 h for 12 days) to 14 healthy volunteers in a crossover fashion. Blood samples collected at predetermined time intervals were analysed for quinine and its major metabolite, 3-hydroxquinine, using a validated HPLC method.Key findingsAdministration of quinine plus nevirapine resulted in significant decreases (P < 0.01) in the total area under the concentration–time curve (AUCT), maximum plasma concentration (Cmax) and terminal elimination half-life (T1/2β) of quinine compared with values with quinine dosing alone (AUC: 53.29 ± 4.01 vs 35.48 ± 2.01 h mg/l; Cmax: 2.83 ± 0.16 vs 1.81 ± 0.06 mg/l; T1/2β: 11.35 ± 0.72 vs 8.54 ± 0.76 h), while the oral plasma clearance markedly increased (11.32 ± 0.84 vs 16.97 ± 0.98 l/h). In the presence of nevirapine there was a pronounced increase in the ratio of AUC(metabolite)/AUC (unchanged drug) and highly significant increases in Cmax and AUC of the metabolite (P < 0.01).ConclusionsNevirapine significantly alters the pharmacokinetics of quinine. An increase in the dose of quinine may be necessary when the drug is co-administered with nevirapine.

Effects of concurrent administration of nevirapine on the disposition of quinine in healthy volunteers

Nevirapine and quinine are likely to be administered concurrently in the treatment of patients with HIV and malaria. Both drugs are metabolised to a significant extent by cytochrome P450 (CYP)3A4 and nevirapine is also an inducer of this enzyme. This study therefore evaluated the effect of nevirapine on the pharmacokinetics of quinine. Quinine (600 mg single dose) was administered either alone or with the 17th dose of nevirapine (200 mg every 12 h for 12 days) to 14 healthy volunteers in a crossover fashion. Blood samples collected at predetermined time intervals were analysed for quinine and its major metabolite, 3-hydroxquinine, using a validated HPLC method. Administration of quinine plus nevirapine resulted in significant decreases (P < 0.01) in the total area under the concentration-time curve (AUC(T)), maximum plasma concentration (C(max)) and terminal elimination half-life (T((1/2)beta)) of quinine compared with values with quinine dosing alone (AUC: 53.29 +/- 4.01 vs 35.48 +/- 2.01 h mg/l; C(max): 2.83 +/- 0.16 vs 1.81 +/- 0.06 mg/l; T((1/2)beta): 11.35 +/- 0.72 vs 8.54 +/- 0.76 h), while the oral plasma clearance markedly increased (11.32 +/- 0.84 vs 16.97 +/- 0.98 l/h). In the presence of nevirapine there was a pronounced increase in the ratio of AUC(metabolite)/AUC (unchanged drug) and highly significant increases in C(max) and AUC of the metabolite (P < 0.01). Nevirapine significantly alters the pharmacokinetics of quinine. An increase in the dose of quinine may be necessary when the drug is co-administered with nevirapine.

Irreversible CYP3A Inhibition Accompanied by Plasma Protein–Binding Displacement: A Comparative Analysis in Subjects With Normal and Impaired Liver Function

In this study, quinine was used as a probe substrate and erythromycin as a prototypical irreversible inhibitor of CYP3A to ascertain whether, like reversible CYP inhibition, the magnitude of irreversible inhibition is also strictly dependent on the status of liver function. The effect of erythromycin on oral quinine disposition was studied in 10 healthy subjects and in 20 patients with cirrhosis of the liver who had varying degrees of liver dysfunction. This effect was shown to be the result of two types of interaction: (i) irreversible inhibition of CYP3A-mediated quinine metabolism, the extent of which proved to be independent of liver function, and (ii) displacement of quinine from plasma protein-binding sites, the magnitude of the displacement increasing dramatically as liver function worsened. Such an interaction causes limited increases in the total concentration of the displaced drug but disproportionate increases in its free concentration; the latter increases are magnified by liver dysfunction, thereby requiring that the monitoring of free drug concentrations be made mandatory.

Increased uptake of quinine into the brain by inhibition of P-glycoprotein

The impact of P-glycoprotein (P-gp) on the distribution of quinine between brain and plasma was studied experimentally in mice. Administration of quinine (20 mg/kg, i.v.) to mdrla knockout mice resulted in enhanced brain concentrations of quinine as compared to the wild-type mice (7.9 ± 1.4 μg/g versus 1.6 ± 0.8 μg/g, respectively). Quinine concentrations and quinine-to-3-hydroxyquinine ratio in plasma were similar in normal and P-gp-deficient mice. The effect of intravenously administered drugs before quinine (20 mg/kg, i.v.) was evaluated on brain uptake and biotransformation of quinine in mice. Cyclosporine A (50 mg/kg), erythromycine (40 mg/kg), verapamil (5 mg/kg) or mefloquine (20 mg/kg) increased the brain-to-plasma quinine concentration ratio (by factors of 3.8-, 1.8-, 1.9- and 2.5-fold, respectively) and the quinine-to-3-hydroxyquinine ratio in plasma (by factors 2.1-, 3.7-, 1.8- and 2.0-fold, respectively). After cinchonine (40 mg/kg) and halofantrine (40 mg/kg) pre-treatment, the brain-to-plasma ratio for quinine increased by factor of 2.3 and 1.8, respectively without changes of quinine or metabolite concentrations in plasma. Doxycycline (20 mg/kg), artesunate (50 mg/kg) or artemether (50 mg/kg) did not alter quinine disposition. These results confirm in vivo that quinine is a substrate for mdr1a P-gp. Drug associations led not only to metabolic interactions but also increased quinine uptake by tissues protected by P-gp. Such interactions may have implications for the improvement of chemotherapy but should be also taken into account for potential enhancement of adverse effects.

Quinine disposition in globally malnourished children with cerebral malaria.

Both malnutrition and malaria affect drug disposition and are frequent among children in the tropics. We assessed their respective influence on quinine distribution. Forty children were divided into 4 groups: children with normal nutritional status without (group 1) or with (group 2) cerebral malaria, and malnourished children without (group 3) or with (group 4) cerebral malaria. All children received an infusion of 8 mg/kg of a combination solution of cinchona alkaloids that contained 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (corresponding to 4.7 mg/kg quinine base). The children with malaria then received repeated infusions every 8 hours for 3 days. Pharmacokinetic profiles of plasma and erythrocyte quinine were determined during the first 8 hours, together with quinine protein binding. Additional measurements of plasma quinine concentrations were used to simulate quinine concentrations profiles in children with malaria with and without malnutrition. Clinical recovery and parasitemia clearance times were determined in the children with malaria. Compared with control children, malaria and malnutrition increased plasma concentrations of quinine and reduced both the volume of distribution and the total plasma clearance. Simultaneously, alglycoprotein plasma concentrations and protein-bound fraction of the drug were increased. Erythrocyte quinine concentrations correlated strongly with free plasma quinine but not with the extent of parasitemia. Similar effective and nontoxic quinine concentration profiles were obtained in malaria with and without malnutrition. Severe global malnutrition and cerebral malaria have a similar effect on quinine pharmacokinetics in children. Moderate malnutrition does not potentiate cerebral malaria-mediated modifications of quinine disposition. These results suggest that current parenteral quinine regimens can be used, unmodified, to treat children with both malaria and malnutrition.

Dose linearity of quinine in healthy human subjects

The pharmacokinetics of quinine were assessed in seven healthy volunteers after administration of single oral doses of 250, 500, 750 and 1000 mg quinine in a randomized cross-over design. Serial blood samples were collected at predetermined times before and after the doses. Plasma quinine concentrations were assayed by a reversed-phase HPLC method with UV detection and the data were evaluated by non-compartmental methods to determine pharmacokinetic parameters. The mean elimination half-lives t 1 2 ) of quinine, which did not vary with the dose, were 10.1 ± 4.3, 12.3 ± 1.6, 9.0 ± 2.8 and 13.4 ± 7.0 h, respectively after the four doses. The peak plasma levels ( C max) and area under the plasma level versus time curve (AUC) data showed dose-proportional response. The time to peak plasma concentration ( t max), oral clearance ( CL F ) and apparent volume of distribution ( V d F ) were all similar regardless of the administered dose ( P > 0.05). There were minor side effects which increased with increase in dose but the effects were all reversible. These findings suggest that quinine disposition is linear over the dose range studied.

Disposition of quinine in rats with induced renal failure.

Aetiologically different models of experimental acute renal failure were induced in rats by the administration of glycerol, mercuric chloride and gentamicin, respectively, to different groups. Quinine levels in plasma and urine of the rats with induced renal failure were determined and pharmacokinetic parameters (elimination t1/2, CLp, V, CLR AUC0-infinity) of the drug were derived and compared with values obtained from control rats following intraperitoneal administration of a 10 mg/kg body-weight dose of quinine. Results showed that each of the three compounds caused an up to 25-fold increase in the plasma levels of the drug and a marked decrease in the levels of the metabolite 3-hydroxyquinine. All the pharmacokinetic parameters determined for the rats with renal impairment were markedly different when compared to control. The high plasma quinine levels observed in the rats with renal failure could be largely due to the marked decrease in V and reduced metabolism. Also, in the rats with renal impairment, no correlation was observed between the increased plasma urea levels and plasma quinine levels or disposition of the drug. The results of the study suggest that quinine should be used with caution in patients with renal impairment. The plasma urea levels, as a measure of renal function, might not provide a suitable index for determining quinine dosage.

Quinine disposition kinetics.

Intravenous quinine dihydrochloride (5 mg kg-1 over 5 min) was given to seven healthy male volunteers. There were minor subjective symptoms in all subjects but no significant changes in pulse or blood pressure. There was significant prolongation of the electrocardiographic QRS and rate corrected QT intervals which was greatest between 1 and 4 min after completion of the quinine infusion. Values then returned towards baseline. Plasma concentrations of quinine were measured spectrophotofluorimetrically after benzene extraction. Peak plasma concentrations (mean +/- 1 s.d.) after the infusion were 5.1 +/- 1.3 mg 1(-1). Pharmacokinetic analysis fitted a two compartment open model in each case; distribution half-time (t 1/2, lambda 1) was 1.89 +/- 0.54 min (mean +/- 1 s.d.), elimination half-time (t 1/2, z) 11.1 +/- 2.1 h, apparent volume of the central compartment (V1) 0.57 +/- 0.32 1 kg-1, total apparent volume of distribution 1.80 +/- 0.37 1 kg-1 and total clearance 1.92 +/- 0.45 ml min-1 kg-1.

Quinine disposition during malaria and during induced fever

In the report on quinine disposition during malaria and during induced fever, which appeared on page 459 of the April, 1976, issue of the Journal, we inadvertently failed to reference a paper by Elin, Vesell, and Wolff (Clin. Pharmacal. Ther. 17:447, 1975) who demonstrated retardation of antipyrine metabolism in etiocholanolone fever. Their data are in agreement with our conclusions concerning quinine metabolism during etiocholanolone fever. We hope this information will help to encourage additional studies of drug metabolism and the role of the liver during fever.

Quinine disposition during malaria and during induced fever.

Quinine disposition was studied in 5 subjects before and during an experimentally induced infection with a chloroquine-resistant strain of Plasmodium falciparum and in 2 individuals before and during artificially induced fever. Plasma quinine levels were determined by both a benzene extraction method (QB), which measures principally unmetabolized quinine, and a metaphosphoric acid precipitation method (QMPA), which measures quinine and quinine metabolites. The ratio QB/QMPA in plasma was used to estimate the extent of metabolism of quinine. In all individuals plasma levels of quinien and QB/QMPA ratios were increased during malaria, suggesting impaired hepatic metabolism of quinine. The changes observed during malaria were not due to altered renal excretion of quinine. In 2 subjects in whom fever was artificially induced there were similar changes in quinine metabolism. These observations suggest that quinine dosage should be modified during the initial period of treatment, when symptoms and fever are greatest, in acute falciparum malaria.

Quinine-induced alterations in drug disposition.

In normal volunteers, chronic quinine administration shortened plasma antipyrine half-life and significantly increased the intraindividual correlation between the disposition of quinine and antipyrine. Decreased plasma antipyrine half-life appears to be due to a quinine-induced enhancement of antipyrine metabolism. A dose-dependent prolongation of plasma quinine half-life was observed and attributed primarily to an increased apparent volume of distribution of quinine, although our data did not permit separation of an effect on quinine metabolism from an effect on quinine distribution between the peripheral and central compartments. Plasma protein binding of quinine was similar at both the low and high doses of quinine. Studies in dogs given quinine intravenously revealed a biphasic plasma decay curve compatible with a 2-compartment open model for quinine disposition. Dose dependence of plasma quinine half-life in the dog after intravenous quinine eliminated altered gastrointestinal absorption of quinine as a cause for the dose dependence of plasma quinine half-life. These studies illustrate the importance of such conditions as dose and time of administration in determining the type and magnitude of interaction observed between drugs.