In vitro studies using human liver microsomes and recombinant P450 enzymes have shown that quinine is metabolized mainly by CYP3A4. Depending on the in vitro experimental conditions, other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 were shown to have some role in the metabolism of quinine.
Quinine is metabolized almost exclusively via hepatic oxidative cytochrome P450 (CYP) pathways, resulting in four primary metabolites, 3-hydroxyquinine, 2'-quinone, O-desmethylquinine, and 10,11-dihydroxydihydroquinine. Six secondary metabolites result from further biotransformation of the primary metabolites. The major metabolite, 3-hydroxyquinine, is less active than the parent drug.
IDENTIFICATION AND USE: Quinine is a bulky, white, amorphous powder or crystalline alkaloid, used as medication: non-narcotic analgesics; antimalarial; central muscle relaxants. It is also used as flavor in carbonated beverages. HUMAN EXPOSURE AND TOXICITY: Serious hypersensitivity reactions, including anaphylactic shock, anaphylactoid reactions, urticaria, serious skin rashes, angioedema, facial edema, bronchospasm, and pruritus, have been reported with quinine. In addition, thrombocytopenia, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), immune thrombocytopenic purpura, blackwater fever, disseminated intravascular coagulation, leukopenia, neutropenia, granulomatous hepatitis, and acute interstitial nephritis have been reported and may also be due to hypersensitivity reactions to the drug. Potentially fatal cardiac arrhythmias, including torsades de pointes and ventricular fibrillation, have been reported rarely during quinine therapy. At least 1 case of fatal ventricular arrhythmia has been reported in a geriatric patient with preexisting prolonged QT interval treated with IV quinine sulfate for Plasmodium falciparum malaria. Visual impairment can range from blurred vision and defective color perception, to visual field constriction and permanent blindness. Cinchonism occurs in virtually all patients with quinine overdose. There have been a large number of case reports of malformations following quinine ingestion in human pregnancy. Many of these pregnancies involved large doses of quinine used as an abortifacient. The most frequently reported abnormality following quinine exposure during early pregnancy is hypoplasia of the auditory nerve with resultant deafness. Other major malformations involving most organ systems have been reported also. However, the Perinatal Collaborative Study reported no association between first trimester exposure to quinine and birth defects. In general, there has been no proven association between quinine at doses used for malarial prophylaxis and an increased risk of malformations. Third trimester exposure to quinine does not appear to adversely affect uterine contractility. However, an increase in insulin secretion associated with hypoglycemia has been reported. Therefore, monitoring of blood or serum glucose levels during quinine therapy is advisable. Although the United States Food and Drug Administration banned its use for nocturnal leg cramps due to lack of safety and efficacy, quinine is widely available in beverages including tonic water and bitter lemon. Numerous anecdotal reports suggest that products containing quinine may produce neurological complications, including confusion, altered mental status, seizures, and coma, particularly in older women. ANIMAL STUDIES: Rabbits given 20 to 100 mg quinine hydrochloride/kg intravenously or intramuscularly 3 times a week for 10 weeks have been reported to show no ophthalmoscopic or histologic abnormalities in the fundus or optic nerve, and /another study/ similarly found no abnormality in most rabbits injected intraperitoneally with 10 mg/kg/day for 21 to 27 days showed degeneration of rods and cones and vacuoles in the retinal ganglion cells. In animal developmental studies conducted in multiple animal species, pregnant animals received quinine by the subcutaneous or intramuscular route at dose levels similar to the maximum recommended human dose based on body surface area (BSA) comparisons. There were increases in fetal death in utero in rabbits at maternal doses = 100 mg/kg/day and in dogs at = 15 mg/kg/day cochlea at maternal doses of 200 mg/kg corresponding to a dose level of approximately 1.4 times the MRHD based on BSA comparison. There were no teratogenic findings in rats at maternal doses up to 300 mg/kg/day and in monkeys at doses up to 200 mg/kg/day corresponding to doses approximately 1 and 2 times the MRHD respectively based on BSA comparisons. Quinine produces testicular toxicity in mice at a single intraperitoneal dose of 300 mg/kg, and in rats at an intramuscular dose of 10 mg/kg/day, 5 days/week, for 8 weeks. The findings include atrophy or degeneration of the seminiferous tubules, decreased sperm count and motility, and decreased testosterone levels in the serum and testes. Genotoxicity studies of quinine were positive in the Ames bacterial mutation assay with metabolic activation and in the sister chromatid exchange assay in mice. The sex-linked recessive lethal test performed in Drosophila, the in vivo mouse micronucleus assay, and the chromosomal aberration assay in mice and Chinese hamsters were negative.
There is little evidence that chronic quinine therapy is associated with elevations in serum enzymes, although it has not been carefully assessed. However, there have been several reports of acute hypersensitivity reactions to quinine that include hepatic involvement. The reactions usually arise after 1 to 2 weeks of therapy, but can appear within 24 hours of restarting quinine or with rechallenge. The clinical features are marked by fatigue, nausea, vomiting, diffuse muscle aches, arthralgias and high fever. Blood testing at an early stage shows increases in serum aminotransferase and alkaline phosphatase levels as well as mild jaundice, which can deepen for a few days even after stopping quinine. The pattern of serum enzymes elevations is typically cholestatic or mixed. Rash is uncommon and eosinophilia is not typical, despite the presence of other signs of hypersensitivity (fever, arthralgias). Autoantibodies are not typically found. Liver biopsies usually show mild injury and small epithelioid granulomas, as are typically found in many organs during systemic hypersensitivity reactions. A similar clinical signature of liver injury occurs with quinidine, an optical isomer of quinine that is used predominantly as an antiarrhythmic.
Cinchona alkaloids, including quinine, may depress the hepatic synthesis of vitamin K-dependent coagulation factors, and the resulting hypoprothrombinemic effect may enhance the action of warfarin and other oral anticoagulants. In patients receiving these anticoagulants and concomitant therapy with quinine, the prothrombin time (PT), partial thromboplastin time (PTT), or international normalized ratio (INR) should be closely monitored as indicated.
The pharmacokinetics of quinine was investigated in patients with acute Falciparum malaria treated with quinine alone or in the presence of doxycycline. Twenty six patients divided into two groups of equal number were enrolled in the study. In the absence of doxycycline, the volume of distribution of quinine (mean + or - standard deviation) was estimated to be 1.32 + or - 0.32 l/kg, and its clearance was 0.125 + or - 0.47 l/hr/kg, which was only in partial agreement with previously published data. No effect of doxycycline on the pharmacokinetics of quinine was observed.
Quinine is a substrate for and an inhibitor of P-glycoprotein, and has the potential to affect the transport of drugs that are P-glycoprotein substrates.
Following oral administration of a single 600-mg dose of quinine sulfate in healthy adults, the mean plasma clearance was 0.08-0.47 L/hour per kg (median: 0.17 L/hour per kg) and the mean plasma elimination half-life was 9.7-12.5 hours. Following oral administration of 10 mg/kg of quinine sulfate in patients with uncomplicated malaria, mean total clearance of quinine was decreased (approximately 0.09 L/hour per kg) during the acute phase of the infection and increased (approximately 0.16 L/hour per kg) during the recovery or convalescent phase.
Following oral administration of a single 600-mg dose of quinine sulfate in geriatric and younger adults, the mean clearance of the drug was decreased (0.06 versus 0.08 L/hour per kg) and the mean elimination half-life was significantly increased (18.4 versus 10.5 hours) in geriatric adults compared with younger adults. Although renal clearance of quinine was similar in geriatric and younger adults, geriatric adults excreted a larger proportion of the dose in urine as unchanged drug compared with younger adults (16.6 versus 11.2%). The steady-state pharmacokinetics after a quinine sulfate dosage of 648 mg 3 times daily for 7 days were similar in healthy geriatric adults 65-78 years of age and healthy younger adults 20-39 years of age; however, the mean elimination half-life was 24 hours in the geriatric individuals compared with 20 hours in the younger adults.
Following oral administration of a single dose of 10 mg/kg of quinine sulfate in healthy children or pediatric patients 1.5-12 years of age with uncomplicated Plasmodium falciparum malaria, the mean total clearance (0.06 versus 0.3 L/hour per kg) is reduced and the plasma elimination half-life increased (12.1 versus 3.21 hours) in pediatric patients with malaria as compared to that observed in healthy children.
In 15 patients with uncomplicated malaria who received a 10 mg/kg oral dose of quinine sulfate, the mean total clearance of quinine was slower (approximately 0.09 L/hr/kg) during the acute phase of the infection, and faster (approximately 0.16 L/hr/kg) during the recovery or convalescent phase.
