Quinine pharmacokinetics

Quinine is readily absorbed when given orally or intramuscularly. Oral absorption occurs mainly from the upper small intestine and exceeds 80%, even in patients with marked diarrhea. After an oral dose, plasma levels of quinine reach a maximum in 3—8 hours and after distributing into an apparent volume of -1.5 L/kg, decline with a t of -II hours after termination of therapy. Quinine pharmacokinetics may change according to the severity of malarial infection. Values for both the apparent volume of distribution and the systemic clearance of quinine decrease, the latter more than the former, so that the average elimination t increases from 11 to 18 hours. After standard therapeutic doses, peak plasma levels of quinine may reach 15—20 mg/L in severely ill patients without causing major toxicity (see below) in contrast, levels >10 mg/L produce severe... 

Ho PC, Chalcroft SC, Coville PF, Wanwimolruk S, Grapefruit juice has no effect on quinine pharmacokinetics. EurJ Clin Pharmacol (1999) 55, 393-8. 

Smokers cleared quinine from the body much more quickly than non-smokers in a single-dose study in healthy subjects. However, quinine metabolism is reduced in patients with falciparum malaria, which may negate this effect. Quinine pharmacokinetics and efficacy were unchanged by smoking in one study. 

In a study in 13 patients with acute falciparum malaria, the addition of intravenous doxycycline to treatment with intravenous quinine did not affect quinine pharmacokinetics, when compared with 13 patients taking... 

Pukrittayakamee S, Pitisuttithum P, Zhang H, Jantra A, Wanwimolruk S, White NJ. Effects of cigarette smoking on quinine pharmacokinetics in malaria. EurJ Clin Pharmacol (2002) 58, 315-19. 

Mecfianism of Action A quinolone-methanol compound structurally similar to quinine that destroys the asexual blood forms of malarial pafhogens, Plasmodium falciparum, P. vivax, P. malariae, P. ovale. Therapeutic Effect Inhibifs parasite growth. Pharmacokinetics Well absorbed from fhe gasfroinfesfinal (GI) tract. Protein binding 98%. Widely distributed, including cerebrospinal fluid (CSF). Metabolized in liver. Primarily excreted in urine. Half-life 21-22 days. 

Interactions with drugs have also been demonstrated for flavonoids from citrus. Naringin and naringenin were shown to interact with simvastatin and saquinavir in in vitro experiments (41,42) and caused alterations in the pharmacokinetics of quinine in rats (44). Moreover, naringenin and naringin were found to inhibit the OATP-B-mediated uptake of estrone-3-sulfate into human embryonic kidney cells (23). 

Quinine is derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America. The alkaloid quinine was purified from the bark in 1820, and it has been used in the treatment and prevention of malaria since that time. Quinidine, the dextrorotatory stereoisomer of quinine, is at least as effective as parenteral quinine in the treatment of severe falciparum malaria. After oral administration, quinine is rapidly absorbed, reaches peak plasma levels in 1-3 hours, and is widely distributed in body tissues. The use of a loading dose in severe malaria allows the achievement of peak levels within a few hours. The pharmacokinetics of quinine varies among populations. Individuals with malaria develop higher plasma levels of the drug than healthy controls, but toxicity is not increased, apparently because of increased protein binding. The half-life of quinine also is longer in those with severe malaria (18 hours) than in healthy controls (11 hours). Quinidine has a shorter half-life than quinine, mostly as a result of decreased protein binding. Quinine is primarily metabolized in the liver and excreted in the urine. 

Pharmacokinetics When a chloroquine-resistant organism is encountered, therapy usually consists of a combination of quinine, pyrimethamine, and a sulfonamide. All are administered orally. [Note fansidar, a combination of pyrimethamine and sulfa-doxime is used.] Taken orally, quinine is well distributed throughout the body and can reach the fetus across the placenta. Alkalinization of the urine decreases its excretion. 

Newton P, Keeratithakul D, Teja-Isavadharm P, Pukrittayakamee S, Kyle D, White N. Pharmacokinetics of quinine and 3-hydroxyquinine in severe falciparum malaria with acute renal failure. Trans R Soc Trop Med Hyg 1999 93(l) 69-72. 

The pharmacokinetic interaction of quinidine with digoxin also occurs with quinine (280,281) and hydroxychloroquine (282). However, the effects of these drugs are smaller than those with quinidine. Quinine reduces the extrarenal clearance of digoxin, perhaps by altering its biliary secretion (283). 

The pharmacokinetic interaction of quinidine with digoxin also occurs with quinine and hydroxychloroquine (49). 

Quinine given orally is well absorbed the half-life is 11 hours. Clearance is predominantly by hepatic metabolism urinary clearance accounts for only 20%. Information on pharmacokinetics in healthy volunteers can be misleading, since plasma quinine concentrations are higher in the presence of malaria infection than in healthy subjects given the same dose (SEDA-13, 814). The dosage regimen therefore needs to be adapted to the severity of the illness and amended as improvement occurs. 

A population pharmacokinetic study of intramuscular quinine (loading dose 20 mg/kg salt diluted 1 1 in water) in 120 Ghanaian children with severe malaria showed predictable profiles, which were within the target range for quinine (15-20 pg/ml) and independent of clinical and laboratory variables (1). Adverse events included skin induration or abscesses at the injection site (12%), all of which resolved without surgical intervention, and hypoglycemia (10%), a special risk in children who were hypoglycemic at presentation. 

A pharmacokinetic study in adults with renal insufficiency showed that concentrations of the main metabolite, hydroxy quinine, rose to 45% of the concentrations of the parent compound, and may contribute up to 25% of the cardiac effects of quinine (31). 

The use of quinine to treat cerebral malaria, and to a lesser extent severe malaria, has always been considered more risky than treatment of common cases of malaria. The changes in the pharmacokinetics of quinine caused by the malaria provide an explanation the standard dose of 10 mg/kg is usually well tolerated in patients with uncomplicated malaria but causes markedly higher plasma serum concentrations in patients with cerebral malaria. Total quinine clearance and total apparent volume of distribution are significantly lower in severe malaria, and after recovery, the pharmacokinetics return to normal. Probably the first loading dose should be as generally advised, but with a reduction in subsequent doses until the general condition has improved. Monitoring of plasma or red cell concentrations of quinine would of course be ideal, but this luxury is rarely available (SEDA-13, 816). 

Krishna S, Nagaraja NV, Planche T, Agbenyega T, Bedo-Addo G, Among D, Owusu-Ofori A, Shroads AL, Henderson G, Hutson A, Derendorf H, Stacpoole PW. Population pharmacokinetics of intramuscular quinine in children with severe malaria. Antimicrob Agents Chemother 2001 45(6) 1803-9. 

Amabeoku GJ, Chikuni O, Akino C, Mutetwa S. Pharmacokinetic interaction of single doses of quinine and carbamazepine, phenobarbitone and phenytoin in healthy volunteers. East Afr Med J 1993 70(2) 90-3. 

Zhao XJ, Ishizaki T. A further interaction study of quinine with chnically important drugs by human liver microsomes determinations of inhibition constant (Ki) and type of inhibition. Eur J Drug Metab Pharmacokinet 1999 24(3) 272-8. 

Krishna S, White NJ. Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clinical Pharmacokinetics, 1996,30 263-299. 

A novel structural type (5) was reported to have potent activity against resistant malaria strains. Minor modifications, including removal of the N-OH substituent eliminated activity.Limited clinical pharmacology, biochemistry and mode of action studies are available in the entire parasitology area. Two recent papers report the pharmacokinetics of amodiaquine, chlorguanide, chloraquine, pyrimethamine, quinine and sulfadoxine. 

Jernigan, Hatch, and Wilson (1988) studied the pharmacokinetics of tobramycin after intramuscular administration in cats. Bioavailability was estimated at 102.5% with maximal concentrations occurring within about an hour. Hence, tobramycin absorption appears rapid and complete. There are few papers modeling the intramuscular absorption of drugs. Swabb et al. (1983) modeled the intramuscular administration of aztreonam, another antibiotic, in humans and found that a simple first-order absorption was adequate to explain the rapid (time to maximal concentrations was 0.88 h) and complete (101% bioavailability) absorption. Similarly, Krishna et al. (2001) also found that first-order absorption was sufficient to model the pharmacokinetics of quinine after intramuscular administration. In both cases, the drugs were formulated in water. 

Krishna, S., Nagaraja, N.V., Planche, T., Agbenyega, T., Bedo-Addo, G., Ansong, A., Owusu-Ofori, A., Shroads, A.L., Henderson, G., Hutson, A., Derendorf, H., and Stacpoole, P.W. Population pharmacokinetics of intramuscular quinine in children with severe malaria. Antimicrobial Agents and Chemotherapy 2001 45 1803-1809. 

Band, C.J. Band, P.R. Deschamps, M. Besner, J.-G. Goldman, A.J. Human pharmacokinetic study of immediate-release (codeine phosphate) and sustained-release (codeine contin) codeine. J.Clin. Pharmacol., 1994, 34, 938-943 [electrochemical detection SPE plasma ethylmorphine (IS)] Papadoyannis, I. Zotou, A. Samanidou, V. Theodoridis, G. Zougrou, F. Comparative study of different solid-phase extraction cartric es in the simultaneous RP-HPLC analysis of morphine and codeine in biological fluids. J.Liq.Chromatogn, 1993,16, 3017—3040 [simultaneous caffeine, morphine, quinine, strychnine SPE urine plasma LOD 10-20 ng/mL]... 

The use of drugs for prophylaxis or therapy is dictated by their pharmacokinetics and safety. Thus, quinine and primaquine, which have short half-hves and common toxicities, are reserved for... 

Describe the pharmacodynamic and pharmacokinetic properties of the major antimalarial drugs (chloroquine, mefloquine, quinine, primaquine, and the antifolate agents). 

Classification and pharmacokinetics Quinine is the principal alkaloid derived from the bark of the cinchona tree. Quinine is rapidly absorbed orally and is metabolized before renal excretion. Intravenous administration of quinine is possible in severe infections. 

Classiflcation and pharmacokinetics Mefloquine is a synthetic 4-quinoline derivative chemically related to quinine. Because of local irritation, mefloquine can only be given orally, though it is subject to variable absorption. Its mechanism of action is not known. 

No clinically significant pharmacokinetic interaction appears to occur between quinine and co-artemether. Quinine-induced QTc prolongation may be enhanced by artemether. 

A study in animals found that ketoconazole roughly doubled the AUC of halofantrine and inhibited its metabolism to the equipotent metabolite, desbutylhalofantrine. In in vitro studies, ketoconazole markedly inhibited the metabolism of halofantrine by CYP3A4. It has been suggested that the rise in halofantrine levels could reasonably be expected to increase toxicity. Other CYP3A4 inhibitors, diltiazem and erythromycin, also inhibited the metabolism of halofantrine in vitro, and might therefore do so clinically. The manufacturer recommended caution with the concurrent use of potent CYP3A4 inhibitors. Further study is needed of these potential pharmacokinetic interactions. Mefloquine, quinine and quinidine may also inhibit the metabolism of halofantrine by CYP3A4, see (b) below. 

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