Chloroquine pharmacokinetics

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. 

Chloroquine can cause seizures in patients with epilepsy. The mechanism is uncertain, but it may include reductions in inhibitory neurotransmitters and pharmacokinetic interactions that alter anticonvulsant concentrations. Tonic-clonic convulsions were reported in four patients in whom chloroquine was part of a prophylactic regimen. Antiepileptic treatment was required to control the seizures. None had further seizures after withdrawal of the antimalarial drugs (9). 

The most common dermatological adverse event associated with chloroquine is skin discomfort (often called pruritus). It is much more common in people with darker skins and has been ascribed to chloroquine binding to increased melanin concentrations in the skin. In a pharmacokinetic study, the ratio of AUCo 48 for chloroquine and its major metabolite desethylchloroquine was significantly higher in the plasma and urine of 18 patients with chloroquine-induced pruritus than in that of 18 patients without (25). These results imply... 

There have been three reports of chloroquine overdose, two from Oman (40) and one from the Netherlands (41). The two reports from Oman were similar to previously published reports of chloroquine overdose associated with cardiac dysfunction, confusion, and coma both patients had standard treatment with activated charcoal, diazepam infusions, and positive inotropic drugs, and both survived. The single case report from the Netherlands gave pharmacokinetic measurements performed before, during, and after hemoperfusion. This showed that hemoperfusion extracted very little chloroquine and was unlikely to be of any use in chloroquine overdose, as would be expected from the high protein binding and large volume of distribution of chloroquine. 

Onyeji CO, Ogunbona FA. Pharmacokinetic aspects of chloroquine-induced pruritus influence of dose and evidence for varied extent of metabolism of the drug. Eur J Pharm Sci 2001 13(2) 195-201. 

Okonkwo CA, Coker HA, Agomo PU, Ogunbanwo JA, Mafe AG, Agomo CO, Afolabi BM. Effect of chlorpheniramine on the pharmacokinetics of and response to chloroquine of Nigerian children with falciparum malaria. Trans R Soc Trop Med Hyg 1999 93(3) 306-ll. 

Ducharme J, Farinotti R. Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clin Pharmacokinet 1996 31(4) 257-74. 

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

Ferroquine possesses planar chirality due to the non-symmetrical 1,2-substitution of the ferrocene entity, and the pure enantiomers (+)35 and (—)35 were obtained by enzymatic resolution using the Candida rugosa lipase as a biocatalyst. The enantiomeric purity levels exceed 98%. However, the two optical isomers display identical activity in vitro at the nanomolecular level. In vivo, however, either of the enantiomers alone is less active than the racemic mixture against both chloroquine-sensitive and chloroquine-resistant strains. In addition, (4-)35 displays better curative effects than (—)35, suggesting different pharmacokinetic properties. The reasons for the enhanced behavior of racemic ferroquine have not yet been elucidated. It is still not clear whether 35 is oxidized by the parasite to give the ferricinium ion, thus initiating Fenton-type reactivity. Such a hypothesis is reasonable, given that reactive oxidative species can escalate in cancer cells due to the malfunction of mitochondria. ... 

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

C. Pharmacokinetics. Chloroquine and related dmgs are highly tissue-bound (volume of distribution [Vd] = 150-250 L/kg) and are eliminated veiy slowly from the body. The tenninal half-life of chloroquine is 2 months. Primaquine is extensively metabolized with a half-life of 3-8 hours to an active metabolite that is eliminated much more slowly (half-life 22-30 hours) and can accumulate with chronic dosing. (See also Table 11-59.)... 

A column liquid chromatographic method for the simultaneous determination of chloroquine, amodiaquine and their monodesethyl metabolites in human plasma, red blood cells, whole blood and urine has been developed (41). The drugs and internal standards are extracted as bases with dichloromethane and then re-extracted into an acidic aqueous phase. Separation is achieved using a reversed-phase column and a mobile phase of phosphate buffer (pH 3.0) methyl cyanide (88 12). The absorbance of the drugs is monitored at 340 nm with a sensitivity limit of 10 pmol/ml. The mean overall recovery from each biological fluid is more than 75%. This method can be applied to therapeutic, pharmacokinetic, and epidemological studies. 

Stereoselectivity has been reported in the pharmacokinetic properties of some of the chiral antimalarial drugs (chloroquine, hydroxychloroquine, halofantrine, and mefloquine Tables 1 and 3). Each of these drugs possesses low hepatic extraction ratios, large Vd and ranging from one day to months. Plasma protein binding has been reported to range from about 50% (chloroquine and hydroxychloroquine. Table 3) to over 99% (halofantrine [19]). Chloroquine and its hydroxylated congener. 

Augustijns, P. Verbeke, N. Stereoselective pharmacokinetic properties of chloroquine and de-ethyl-chloroquine in humans. Clin. Pharmacokinet. 1993, 24, 259-269. 

Although modest pharmacokinetic effects occur when paracetamol and chloroquine are given together this is not thought to be clinically significant. 

Raina RK, Bano G, Amla V, Kapoor V, Gupta KL. The effect of aspirin, paracetamol and analgin on pharmacokinetics of chloroquine. Indian J Physiol Pharmacol (1993) 37,229-31. 

The modest pharmacokinetic interactions between chloroquine and magnesium trisilicate or kaolin are established, but their clinical importance does not seem to have been assessed. One way to minimise any interaction is to separate the dosages of the antimalarials and magnesium trisilicate or kaolin as much as possible (at least 2 to 3 hours) to reduce admixture in the gut. There do not appear to be any studies to see if other antacids behave similarly. 

No pharmacokinetic interaction was seen in 6 healthy subjects given single doses of chloroquine 300 mg and imipramine 50 mg. See also Drugs that prolong the QT interval + Other drugs that prolong the QT interval , p.257. 

Masimirembwa CM, Naik YS, Hasler JA. The effect of chloroquine on tiie pharmacokinetics and metabolism of praziquantel in rats and in humans. Biopharm Drug Dispos ( 994) 15,33-43. 

A study in which healthy subjects were given azithromycin 1 g daily for 3 days either alone or with chloroquine base 600 mg daily on days 1 and 2, and 300 mg on day 3, found no pharmacokinetic interaction. ... 

Cook JA, Randinitis EJ, Bramson CR, Wesche DL. Lack of a pharmacokinetic interaction between azithromycin and chloroquine. AmJTrop MedHyg (2006) 74, 407-12. 

Back DJ, Breckenridge AM, Grimmer SF Orme ML E, PurbaHS. Pharmacokinetics of oral contraceptive steroids following the administration of the antimalarial drugs primaquine and chloroquine. Contraception (1984) 30,289-95. 

Studies in which chloroquine was given to patients taking penicillamine found that it was more effective, less effective, or indistinguishable from penicillamine alone. However in some instances penicillamine toxicity was reported to be increased. A pharmacokinetic study in patients with rheumatoid arthritis taking penicillamine 250 mg daily found that a single 250-mg dose of chloroquine phosphate increased the AUC by 34%, and raised the peak plasma levels by about 55%. It therefore seems possible that any increased toxicity is simply a reflection of increased plasma pen-... 

It is worth noting that the two optical isomers of ferroquine exist due to the planar chirality of the unsymmetrically 1,2-substituted ferrocene moiety. Both enantiomers were prepared by enzymatic resolution of an ester intermediate in >98% optical purity. Both isomers display similar activity in vitro " Although both enantiomers are less active than the racemate in vivo the (+)-enantiomer displays better curative effects than the optical antipode. This different behavior indicates different pharmacokinetics of the two enantiomers. Ferrocene derivatives of other antimalarial drugs like artemisinine, quinine, and mefloquine have also been tested, as well as various other chloroquine-derived organometallics. Moss and coworkers synthesized and tested chloroquine and ferroquine derivatives with other organometallic groups. 

Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus 1996 5(suppl 1) S11-S15. 

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