Amodiaquine as a prodrug: Importance of metabolite(s) in the antimalarial effect of amodiaquine in humans

Churchill, Frederick C.; Patchen, Leslie C.; Campbell, Carlos C.; Schwartz, Ira K.; Nguyen-Dinh, Phuc; Dickinson, Charlotte M.

doi:10.1016/0024-3205(85)90285-1

Cited by 97 publications

(89 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When amodiaquine is given orally, relatively small amounts of the parent drug are present in blood (23). Hepatic biotransformation to monodesethyl amodiaquine is the main route of amodiaquine clearance, and this metabolite is the effective form of the drug (5,14). Only a small amount of bidesethyl amodiaquine was detected in the blood and in urine (4,14), and this amodiaquine metabolite was actually the primary amine derivative obtained by chemical reactions on the double bonds of the pyrrolidyl cycle of amopyroquin.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria

Verdier

Pussard

Clavier

et al. 1989

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The disposition of amopyroquin was investigated in 10 healthy volunteers after a single 2-mg/kg (body weight) intramuscular dose of amopyroquin base. The major form of the drug in plasma and in whole blood was nonmetabolized amopyroquin, and only very low levels of its primary amine derivative were detected. After a rapid absorption phase (15 min), levels in plasma declined, following a tri-exponential model with a terminal elimination half-life of 129.6 + 92.5 h. The apparent volume of distribution (V/F) and the systemic clearance (CL/F) were 238 + 75 liters/kg and 2,063 ± 1,159 ml/min, respectively. The renal clearance, calculated by using urine excreted during the first 48 h, was 119 + 99 ml/min and represented about 6% of the systemic clearance. About 1.2 and 0.2% of the amopyroquin dose was excreted in the urine during the first 48 h as nonmetabolized amopyroquin and its primary amine metabolite, respectively. Twenty-two Plasmodium falciparum malaria patients were studied after treatment with one of the following regimens of intramuscularly injected amopyroquin base: 3 mg/kg (body weight), 6 mg/kg, or 6 mg/kg followed by 3 mg/kg 24 h later. Parasitemia was cleared at day 7 in one of six, four of seven, and seven of nine patients, respectively. On the basis of this study, a regimen of 12 mg/kg (body weight) administered in two or three injections is suggested.The 4-amino quinoline amopyroquin was proposed for antimalarial therapy nearly 30 years ago. It has been effective in the treatment of acute Plasmodium falciparum and Plasmodium vivax malaria (10,11,17). Moreover, amopyroquin seems more active in vitro than the other 4-amino quinolines (chloroquine or monodesethyl amodiaquine) against resistant strains of P. falciparum (15).Amopyroquin is metabolized more extensively in rats than in rabbits to three metabolites, one of which is probably the primary amine derivative (15). In rats, amopyroquin is widely distributed in tissues and in plasma the drug concentrations are decreased, with a terminal half-life of 14 h (15,18). But during the 8 h after a single 60-or 120-mg/kg (body weight) dose of amopyroquin given intraperitoneally, this half-life has been estimated as 2 h (6). In rabbits, a similar bioavailability, about 70%, was observed after oral and intramuscular (i.m.) administration, and terminal elimination half-lives were 18, 24, and 26 h for intravenous (i.v.), i.m., and oral routes, respectively (15). No study has described the metabolism and the pharmacokinetic behavior of amopyroquin in humans.The aims of the present study were as follows: (i) to investigate the metabolism and the pharmacokinetic parameters of amopyroquin in healthy subjects after i.m. administration of amopyroquin base at 2 mg/kg (body weight) and (ii) to compare the following three i.m. therapeutic regimens in P. falciparum malaria patients on the basis of drug concentrations in the blood and in vivo efficacy: 3 mg/kg (body weight) (group 1), 6 mg/kg (group 2), and 6 mg/kg followed by 3 mg/kg 24 h later (group 3). * Corresponding...

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria

Verdier

Pussard

Clavier

et al. 1989

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…In South America, where in vitro IC 50 levels indicate only moderate levels of resistance to CQ but high levels of resistance to monodesethylamodiaquine (MDAQ) (15), the principal active metabolite of AQ (16), drug-resistant P. falciparum strains have stably saturated large regions of the continent for half a century even where use of these drugs was discontinued. Such dominance in South America contrasts dramatically with changes that have been observed after discontinued drug pressure in certain countries of Africa and Southeast Asia.…”

mentioning

confidence: 99%

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

Sá

Twu

Hayton

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

242

230

View full text Add to dashboard Cite

Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum originated from at least six foci in South America, Asia, and Oceania. Malaria parasites from these locations exhibit contrasting resistance phenotypes that are distinguished by point mutations and microsatellite polymorphisms in and near the CQR transporter gene, pfcrt, and the multidrug resistance transporter gene, pfmdr1. Amodiaquine (AQ), a 4-aminoquinoline related to CQ, is recommended and often used successfully against CQ-resistant P. falciparum in Africa, but it is largely ineffective across large regions of South America. The relationship of different pfcrt and pfmdr1 combinations to these drug-resistant phenotypes has been unclear. In two P. falciparum genetic crosses, particular pfcrt and pfmdr1 alleles from South America interact to yield greater levels of resistance to monodesethylamodiaquine (MDAQ; the active metabolite of AQ) than to CQ, whereas a pfcrt allele from Southeast Asia and Africa is linked to greater CQ than MDAQ resistance with all partner pfmdr1 alleles. These results, together with (i) available haplotype data from other parasites; (ii) evidence for an emerging focus of AQ resistance in Tanzania; and (iii) the persistence of 4-aminoquinoline-resistant parasites in South America, where CQ and AQ use is largely discontinued, suggest that different histories of drug use on the two continents have driven the selection of distinct suites of pfcrt and pfmdr1 mutations. Increasing use of AQ in Africa poses the threat of a selective sweep of highly AQ-resistant, CQ-resistant parasites with pfcrt and pfmdr1 mutations that are as advantaged and persistent as in South America.

show abstract

“…The in vitro effects of AQ on adult S. mansoni worms demonstrated in the present study may not entirely reflect the in vivo effects of AQ. In fact, after oral administration, AQ is rapidly and predominantly metabolised to DEAQ (Churchill et al 1985, Winstanley et al 1987. Although both AQ and DEAQ exhibit antimalarial activity, the activity of DEAQ is approximately 3.5 times lower than that of AQ (Churchill et al 1985, Childs et al 1989.…”

Section: Discussionmentioning

confidence: 99%

In vitro effects of amodiaquine on paired Schistosoma mansoni adult worms at concentrations of less than 5 µg/mL

Kato

Miura

Mitsui

2013

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

show abstract

Amodiaquine as a prodrug: Importance of metabolite(s) in the antimalarial effect of amodiaquine in humans

Cited by 97 publications

References 7 publications

Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria

Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

In vitro effects of amodiaquine on paired Schistosoma mansoni adult worms at concentrations of less than 5 µg/mL

Contact Info

Product

Resources

About