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Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial.

BACKGROUND: Many countries in Africa are considering a change to combination treatment for falciparum malaria because of the increase in drug resistance. However, there are few effectiveness data for these combinations. Our aim was to study the effectiveness of three drug combinations that have proven efficacious in east Africa compared with amodiaquine monotherapy. METHODS: We undertook a randomised trial of antimalarial drug combinations for children (aged 4-59 months) with uncomplicated malaria in Muheza, Tanzania, an area with a high prevalence of resistance to sulfadoxine-pyrimethamine and chloroquine. Children were randomly allocated 3 days of amodiaquine (n=270), amodiaquine +sulfadoxine-pyrimethamine (n=507), or amodiaquine+artesunate (n=515), or a 3-day six-dose regimen of artemether-lumefantrine (n=519). Drugs were taken orally, at home, unobserved by medical staff. The primary endpoint was parasitological failure by day 14 assessed blind to treatment allocation. Secondary endpoints included day 28 follow-up and gametocyte carriage. Analysis was by intention to treat. FINDINGS: Of 3158 children screened, 1811 were randomly assigned treatment and 1717 (95%) reached the 14-day follow-up. The amodiaquine group was stopped early by the data and safety monitoring board. By day 14, the parasitological failure rates were 103 of 248 (42%) for amodiaquine, 97 of 476 (20%) for amodiaquine+sulfadoxine-pyrimethamine, 54 of 491 (11%) for amodiaquine+artesunate, and seven of 502 (1%) for artemether-lumefantrine. By day 28, the parasitological failure rates were 182 of 239 (76%), 282 of 476 (61%), 193 of 472 (40%), and 103 of 485 (21%), respectively. The difference between individual treatment groups and the next best treatment combination was significant (p<0.001) in every case. Recrudescence rates by day 28, after correction by genotyping, were 48.4%, 34.5%, 11.2%, and 2.8%, respectively. INTERPRETATION: The study shows how few the options are for treating malaria where there is already a high level of resistance to sulfadoxine-pyrimethamine and amodiaquine. The WHO-packaged six-dose regimen of artemether-lumefantrine is effective taken unsupervised, although cost is a major limitation.

Amodiaquine↗
PubMed2000

Amodiaquine for treating malaria.

BACKGROUND: Amodiaquine has been widely used to treat malaria. Due to reports of fatal adverse drug reactions, discontinuation or modification of its use has been suggested. OBJECTIVES: The objective of this review was to assess the effects of amodiaquine for treating malaria. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register and Medline. We also contacted researchers in the field and drug companies. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing amodiaquine with other treatment for uncomplicated malarial infections in adults and children. DATA COLLECTION AND ANALYSIS: Both reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Forty trials were included. Allocation was adequately concealed in three trials. Amodiaquine was more effective than chloroquine for parasite clearance. The combined results of parasite clearance at seven days from 24 trials was 83% for amodiaquine and 56% for chloroquine (odds ratio 4.29, 95% confidence interval 3.51 to 5.24). The odds ratio for parasite clearance at 14 days was 6.00, 95% confidence interval 4.38 to 8.21. Amodiaquine and sulfadoxine/pyrimethamine showed similar results for parasite clearance on day seven, but sulfadoxine/pyrimethamine appeared to be more effective on day 14 and 28. No significant difference for adverse events was observed between amodiaquine and chloroquine and sulfadoxine/pyrimethamine. Reported adverse effects were minor or moderate, not life threatening. REVIEWER'S CONCLUSIONS: There is some evidence to support the continued use of amodiaquine in the treatment of uncomplicated malaria, although drug resistance should be considered. Monitoring for toxicity should also continue.

Amodiaquine↗
PubMed2000

Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine for treating uncomplicated malaria.

BACKGROUND: Amodiaquine and chloroquine give fast relief from malaria symptoms, particularly fever. When used alone in areas where there is some parasite resistance they do not completely clear parasites from the blood in all cases, and so not all patients are cured of infection. The major disadvantage of using sulfadoxine-pyrimethamine alone is that it takes a relatively long time to relieve fever. OBJECTIVES: To assess the effectiveness of chloroquine or amodiaquine given with sulfadoxine-pyrimethamine to treat uncomplicated falciparum malaria. SEARCH STRATEGY: The Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, Science Citation Index, African Index Medicus and LILACS were searched. Experts in the field and drug companies were contacted. SELECTION CRITERIA: Randomised and quasi-randomised trials of chloroquine or amodiaquine given with sulfadoxine-pyrimethamine compared with either drug alone in adults or children with confirmed uncomplicated falciparum malaria. DATA COLLECTION AND ANALYSIS: Two people independently applied the inclusion criteria. Data were extracted by the reviewer and checked independently by another person. MAIN RESULTS: Five trials were included. Fever clearance time was reduced by combination therapy compared with sulfadoxine-pyrimethamine alone. Parasite clearance at day seven follow-up was not significantly different for chloroquine or amodiaquine treatment with or without sulfadoxine-pyrimethamine. Parasite clearance at day 28 was better with combination therapy compared with chloroquine or amodiaquine alone (odds ratio 14.28, 95% confidence interval 6.76 to 30.19), but not significantly better than sulfadoxine-pyrimethamine alone (odds ratio 3.17, 95% confidence interval 0.96 to 10.43). There was no evidence from the included trials of serious side effects with combination treatment. REVIEWER'S CONCLUSIONS: In areas where chloroquine or amodiaquine are still effective, despite some degree of resistance, using these drugs in combination with sulfadoxine-pyrimethamine, rather than sulfadoxine-pyrimethamine alone, may make people feel better faster and improve sustained parasites clearance.

Adult↗
PubMed2002

Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomised, multicentre trial.

BACKGROUND: Increasing drug resistance limits the choice of efficacious chemotherapy against Plasmodium falciparum malaria in Africa. Amodiaquine still retains efficacy against P falciparum in many African countries. We assessed the safety, treatment efficacy, and effect on gametocyte carriage of adding artesunate to amodiaquine in three randomised trials in Kenya, Sénégal, and Gabon. METHODS: We enrolled 941 children (400 in Kenya, 321 in Sénégal, and 220 in Gabon) who were 10 years or older and who had uncomplicated P falciparum malaria. Patients were randomly assigned amodiaquine (10 mg/kg per day for 3 days) plus artesunate (4 mg/kg per day for 3 days) or amodiaquine (as above) and placebo (for 3 days). The primary endpoints were parasitological cure rates at days 14 and 28. Analysis was by intention to treat and by an evaluability method. FINDINGS: Both regimens were well tolerated. Six patients in the amodiaquine-artesunate group and five in the amodiaquine group developed early, drug-induced vomiting, necessitating alternative treatment. By intention-to-treat analysis, the day-14 cure rates for amodiaquine-artesunate versus amodiaquine were: 175/192 (91%) versus 140/188 (74%) in Kenya (D=16.7% [95% CI 9.3-24.1], p<0.0001), 148/160 (93%) versus 147/157 (94%) in Sénégal (-1.1% [-6.7 to 4.5], p=0.7), and 92/94 (98%) versus 86/96 (90%) in Gabon (8.3% [1.5-15.1], p=0.02). The corresponding rates for day 28 were: 123/180 (68%) versus 75/183 (41%) in Kenya (27.3% [17.5-37.2], p<0.0001), 130/159 (82%) versus 123/156 (79%) in Sénégal (2.9% [-5.9 to 11.7], p=0.5), and 80/94 (85%) versus 70/98 (71%) in Gabon (13.7% [2.2-25.2], p=0.02). Similar rates were obtained by evaluability analysis. INTERPRETATION: The combination of artesunate and amodiaquine improved treatment efficacy in Gabon and Kenya, and was equivalent in Sénégal. Amodiaquine-artesunate is a potential combination for use in Africa. Further investigations to assess the potential effect on the evolution of drug resistance, disease transmission, and safety of amodiaquine-artesunate are warranted.

Amodiaquine↗
PubMed2003

Comparison of the in-vitro activity of amodiaquine and its main metabolite, monodesethyl-amodiaquine, in Plasmodium falciparum.

After its rehabilitation for therapeutic use in uncomplicated falciparum malaria, there is renewed interest in amodiaquine. After oral administration, the drug undergoes rapid metabolism to monodesethyl-amodiaquine, and in patients with normal hepatic function the parent drug usually becomes undetectable within a few hours. The main antimalarial activity is therefore mainly due to the metabolite. In a comparative study in northwestern Thailand, 21 fresh isolates of Plasmodium falciparum were tested, in parallel, for their in-vitro sensitivity to both compounds, using the WHO micro-test Mark II, measuring the inhibition of schizont maturation. The geometric mean cut-off concentrations of schizont maturation were 1826 nM (related to blood) for amodiaquine, and 1654 nM for monodesethyl-amodiaquine. The log-probit regressions for both compounds showed good fits to the data points. The EC50 values were 331 nM and 291 nM, and the EC90 values 1337 nM and 993 nM for amodiaquine and monodesethyl-amodiaquine, respectively. Differences between regression slopes and effective concentrations were well below statistical significance. Both compounds showed highly significant activity correlation. These findings suggest that the sensitivity of Plasmodium falciparum to amodiaquine closely reflects its sensitivity to monodesethyl-amodiaquine.

Adolescent↗
PubMed1985

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

Existing analytical methods for assaying the 4-aminoquinoline antimalarial amodiaquine in body fluids are nonspecific and obscure the fact that little or no amodiaquine is present in the blood of dosed persons. We have isolated four metabolites of amodiaquine. The two major metabolites have been identified; one is desethylamodiaquine, and the other has been tentatively identified on the basis of proton nuclear magnetic resonance spectroscopy as 2-hydroxydesethylamodiaquine. We developed a reverse-phase high-performance liquid chromatographic (HPLC) method that separates the two major metabolites from each other and from amodiaquine, allowing separate quantification. The impact of these findings on in vitro sensitivity testing and blood analysis of persons dosed with amodiaquine is discussed.

Amodiaquine↗
PubMed2002

Therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine and the sulfadoxine-pyrimethamine-amodiaquine combination against uncomplicated Plasmodium falciparum malaria in young children in Cameroon.

OBJECTIVE: To evaluate the therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine, and the sulfadoxine-pyrimethamine-amodiaquine combination for the treatment of uncomplicated Plasmodium falciparum malaria in young children in Cameroon. METHODS: In a randomized study we evaluated the effectiveness and tolerance of (i) sulfadoxine-pyrimethamine (SP) (25 mg/kg body weight of sulfadoxine and 1.25 mg/kg of pyrimethamine in a single oral dose), (ii) amodiaquine (AQ) (30 mg/kg body weight in three divided daily doses), and (iii) the sulfadoxine-pyrimethamine-amodiaquine combination (SP+AQ) (same doses as in the other two treatment groups, given simultaneously on day 0) in young children in southern Cameroon. The parasitological and clinical responses were studied until day 28 in accordance with the modified 1996 WHO protocol for the evaluation of the therapeutic efficacy of antimalarial drugs. FINDINGS: Of 191 enrolled patients, 6 and 8 were excluded or lost to follow-up before day 14 and between day 14 and day 28, respectively. For the AQ-treated patients, parasitological and clinical evaluation on day 14 showed late treatment failure in 2 of 61 (3.3%) and adequate clinical response with parasitological failure in one (1.6%). There was an adequate clinical response in all patients treated with SP or SP+AQ. Therapeutic failure rates on day 28 were 13.6%, 10.2% and 0% in the SP, AQ, and SP+AQ groups, respectively. Anaemia improved in all three regimens. AQ produced faster fever clearance but was associated with more transient minor side-effects than SP. SP+AQ reduced the risk of recrudescence between day 14 and day 28 but increased the incidence of minor side-effects. CONCLUSION: SP+AQ can be recommended as a temporary means of slowing the spread of multidrug resistance in Plasmodium falciparum in Africa while the introduction of other combinations, including artemisinin derivatives, is awaited.

Administration, Oral↗
PubMed1983

[Amodiaquine-induced agranulocytosis in malaria prevention: demonstration of an amodiaquine-induced cytotoxic antibody against granulocytes].

A patient is presented who developed agranulocytosis while taking amodiaquine for suppressive therapy of malaria. An amodiaquine-dependent granulocytotoxic antibody could be demonstrated in the patient's serum on day 1 after stopping amodiaquine medication. Granulocyte transfusion was ineffective on days 6 and 7, possibly due to the slow elimination of the drug.

Adolescent↗
PubMed2005

Efficacy of combination therapy with artesunate plus amodiaquine compared to monotherapy with chloroquine, amodiaquine or sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum in Afghanistan.

INTRODUCTION: In South and Central Asia resistance to chloroquine (CQ) has reached unmanageable levels, and resistance to sulfadoxine-pyrimethamine (SP) is emerging. Amodiaquine (AQ) is widely used in the region, and elsewhere shows only partial resistance to CQ. In Afghanistan, one option for slowing the spread of resistance and improving treatment outcomes is the use of artemisinin combination therapy (ACT). METHODS: The efficacy of CQ, AQ, SP and amodiaquine plus artesunate (AQ/AS) in the treatment of uncomplicated falciparum malaria was investigated using standard World Health Organization (WHO) procedures. Malaria patients were randomized to four treatment groups: 268 were enrolled and 240 completed the trial. RESULTS: There was a high level of cross-resistance between CQ and AQ resistance: adequate clinical and parasitological response by day 42 was 11% after CQ treatment and 9% after AQ treatment. The trend of treatment failure between AQ and CQ was almost identical. Cure rates were considerably improved by the addition of artesunate to AQ or by use of SP; adequate clinical and parasitological response being 72% for AQ/AS and 92% for SP. The combination of AS/AQ substantially reduced the odds of treatment failure relative to AQ monotherapy by day 42 [odds ratio (OR) = 0.03, 95% confidence interval (CI) 0.01-0.1] in addition to reducing the proportion of patients with gametocytes throughout the 42-day period. Gametocyte carriage rate was only marginally higher in the SP than in the CQ- and AQ-treated groups. CONCLUSION: The therapeutic and parasitological cure rates with AS/AQ were inadequate, and the criteria for deploying ACT - namely to prevent further selection of drug resistance from a position of low frequency - was not met in the region. An alternative drug combination to AQ/AS is required for Afghanistan.

Adolescent↗
PubMed2005

Antimalarial efficacy of chloroquine, amodiaquine, sulfadoxine-pyrimethamine, and the combinations of amodiaquine + artesunate and sulfadoxine-pyrimethamine + artesunate in Huambo and Bie provinces, central Angola.

We studied three antimalarial treatments in Caala and Kuito, Angola, in 2002 and 2003. We tested chloroquine (CQ), amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP) in Caala, and AQ, SP and the combinations AQ+artesunate (AQ+AS) and SP+artesunate (SP+AS) in Kuito. A total of 619 children (240 in Caala, 379 in Kuito) with uncomplicated Plasmodium falciparum malaria were followed-up for 28 days, with PCR genotyping to distinguish recrudescence from reinfection. PCR-corrected failure proportions at day 28 were very high in the CQ group (83.5%, 95% CI 74.1-90.5), high in the SP groups (Caala: 25.3%, 95% CI 16.7-35.8; Kuito: 38.8%, 95% CI 28.4-50.0), around 20% in the AQ groups (Caala: 17.3%, 95% CI 10.0-27.2; Kuito: 21.6%, 95% CI 14.3-30.6) and very low in the artemisinin-based combination groups (1.2%, 95% CI 0.0-6.4 for each combination AQ+AS and SP+AS). These results show that CQ and SP are no longer efficacious in Caala and Kuito and that the moderate efficacy of AQ is likely to be compromised in the short term if used as monotherapy. We recommend the use of AQ with AS, though this combination might not have a long useful therapeutic life because of AQ resistance.

Amodiaquine↗
PubMed2004

Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria.

We investigated the safety and efficacy of amodiaquine alone (AQ) and combined with artesunate (AQ + AS) in 308 Rwandan children 6-59 months old with uncomplicated Plasmodium falciparum malaria attending three sentinel sites. The two treatment regimes were well tolerated and no serious adverse events were recorded. After excluding new infections, children treated with AQ + AS had fewer clinical failures at day 28 after treatment than those treated with AQ alone: OR = 0.20 [95% CI: 0.06-0.57 (P = 0.001)]. Total (parasitological and clinical) failure was also significantly less frequent in the AQ + AS group: OR = 0.34 [95% CI: 0.17-0.67 (P = 0.001)]. When adjusting for study site, the hazard ratio for treatment failure was 0.37 [95% CI: 0.20-0.68 (P = 0.001)]. Combining AQ with AS increases the efficacy of the treatment but the apparent increase of AQ resistance observed in just a 1-year period is worrying and casts doubts on the suitability of implementing AQ + AS as first-line treatment in Rwanda. Alternative treatments should be identified and tested.

Amodiaquine↗
PubMed2005

Efficacy of chloroquine, amodiaquine, sulfadoxine-pyrimethamine, chloroquine-sulfadoxine-pyrimethamine combination, and amodiaquine-sulfadoxine-pyrimethamine combination in Central African children with noncomplicated malaria.

This paper reports a two-phase study in Bangui, Central African Republic (CAR): first, we assessed the clinical efficacy to chloroquine (CQ), sulfadoxine-pyrimethamine (SP), and amodiaquine (AQ), then we tested the efficacy of two combinations: CQ + SP and AQ + SP. We used the standard 14-day WHO 2001 protocol to compare therapeutic responses in children under 5 years of age with acute uncomplicated Plasmodium falciparum malaria in Bangui between February 2002 and March 2004. The overall treatment failure rates with CQ, AQ, SP, CQ + SP, and AQ + SP were 40.9%, 20.0%, 22.8%, 7.2%, and 0%. These findings suggest that the Ministry of Health should recommend an interim policy with AQ + SP combination as the first-line antimalarial drug in Bangui until best alternative treatments like artemisinin-based combination therapies (ACTs) become available at low prices in the CAR.

Amodiaquine↗
PubMed1996

Systematic review of amodiaquine treatment in uncomplicated malaria.

BACKGROUND: Opinion and policy over the use of amodiaquine for treating malaria vary. Amodiaquine is more palatable than chloroquine and may be more effective but serious adverse events have been reported in travellers taking it as prophylaxis. It is not recommended as first-line treatment. In the light of the global debate over the use of this drug, we conducted a systematic review of the effectiveness and tolerability of amodiaquine in the treatment of uncomplicated falciparum malaria. METHODS: This is a systematic review of published and unpublished randomised or pseudorandomised trials of amodiaquine. Observational reports were also systematically identified and reviewed to access evidence of serious adverse events. FINDINGS: 40 trials met the inclusion criteria. Symptomatic patients were enrolled in 24 studies in comparisons of amodiaquine (n = 1071) with chloroquine (n = 1097). Amodiaquine was significantly more effective than chloroquine, with odds ratios and 99% confidence intervals (OR [99% CI]) of 4.29 (3.30-5.58) on day 7 and 6.00 (3.97-9.06) on day 14. Time to parasite clearance was significantly shorter with amodiaquine and fever clearance times were marginally faster. Eight studies compared amodiaquine with chloroquine in asymptomatic parasitaemia, with effects on parasitological outcomes similar to those for symptomatic malaria. At twelve sites, 692 amodiaquine and 679 sulfadoxine/pyrimethamine (S/P) recipients were enrolled. The two drugs did not differ significantly on day 7 (OR 0.74 [0.48-1.15]) but the odds ratios favoured S/P on day 14 (OR 0.51 [0.28-0.93]) and on day 28 (OR 0.30 [0.16-0.55]). The time to parasitological clearance was similar in the two groups; fever clearance times were significantly shorter with amodiaquine. Tolerability was assessed for both comparative and non-comparative trials. The rates of adverse events in controlled trials were 10.7%, 8.8%, and 14.3% with amodiaquine, chloroquine, and S/P, respectively. No life-threatening adverse events and no significant shifts in laboratory indices were reported. INTERPRETATION: This systematic review of published and unpublished trials supports the use of amodiaquine in the treatment of uncomplicated malaria. However, there is partial cross-resistance between chloroquine and amodiaquine, and monitoring of the effectiveness of this drug and surveillance for evidence of toxicity must continue.

Amodiaquine↗
PubMed2004

Liquid chromatographic determination of amodiaquine in human plasma.

A normal-phase high-performance liquid chromatographic method using dichloromethane- methanol-1M perchloric acid (100:10:0.9, v/v/v) at a flow rate of 1.0 ml min(-1) on a LiChrospher Si column with UV (254 nm) detection has been developed for the determination of amodiaquine and its metabolites desethyl amodiaquine and bisdesethyl amodiaquine in plasma. The limit of quantification was 5 ng ml(-1). Mean within-day and day-to-day coefficients of variation (CV) were 4.10 and 6.27% for amodiaquine, 3.43 and 4.80% for desethyl amodiaquine and 3.53 and 5.23% for bisdesethyl amodiaquine, respectively. Mean extraction recovery of amodiaquine, desethyl amodiaquine and bisdesethyl amodiaquine from plasma were 82.48, 74.50 and 69.65%, respectively. Chloroquine and its metabolite desethyl chloroquine, quinine, sulfadoxine and primaquine do not interfere in the detection of amodiaquine, desethyl amodiaquine and bisdesethyl amodiaquine in plasma.

Amodiaquine↗
PubMed1975

Amodiaquin accumulation by mouse erythrocytes infected with Plasmodium berghei.

[14C]amodiaquin accumulation by washed erythrocyte preparations was characterized to permit comparisons with chloroquine accumulation. Erythrocytes infected with Plasmodium berghei CS (chloroquine-susceptible) accumulate amodiaquin by a saturable process that has an apparent dissociation constant for amodiaquin of 7.6 X 10(-8) M and is competitively inhibited by chloroquine, quinine and quinacrine, as is the process of chloroquine accumulation. Within experimental error, the K1 of 8 X 10(-7) M estimated for chloroquine is the same regardless of whether the drug being accumulated is [14C]amodiaquin or [14C]chloroquine. Likewise, the K1 for amodiaquin is the same regardless of which drug is being accumulated. In addition, glucose stimulates and hydrogen ion, cold or interruption of glycolysis inhibits amodiaquin as well as chloroquine accumulation. These findings are evidence that a single process serves to accumulate both drugs. In the absence of substrate, erythrocytes infected with P. berghei CR (chloroquine-resistant) accumulate twice as much amodiaquin as chloroquine, and they accumulate more amodiaquin than do erythrocytes infected with P. berghei CS. These differences occur because P. berghei CR infects polychromatophilic erythrocytes possessing a high-affinity, substrate-independent process of accumulation to which amodiaquin has greater access than chloroquine. In the presence of glucose, amodiaquin accumulation by erythrocytes infected with P. berghei CR, when plotted as a function of amodiaquin concentration in the medium, describes a sigmoid curve.

Amodiaquine↗
PubMed2006

Amodiaquine, its desethylated metabolite, or both, inhibit the metabolism of debrisoquine (CYP2D6) and losartan (CYP2C9) in vivo.

OBJECTIVE: To study the extent of in vivo inhibition by the antimalarial drug amodiaquine, its active metabolite N-desethylamodiaquine, or both, of the metabolism of four probe drugs of the enzymes CYP2D6, CYP2C19, CYP2C9 and CYP1A2. METHODS: Twelve healthy Swedish volunteers received a cocktail of four probe drugs (debrisoquine, omeprazole, losartan and caffeine) to determine their baseline metabolic capacities. After a washout period, they received a 600 mg oral dose of amodiaquine hydrochloride; and 2-3 h later the cocktail was administered again. One week after the intake of amodiaquine, the subjects received the cocktail a third time. The levels of probe drugs and their metabolites as well as amodiaquine and its metabolite were determined by HPLC. RESULTS: Plasma levels of amodiaquine and N-desethylamodiaquine could be followed in all subjects for 6 h and 28 days, respectively. Among the 12 subjects, a 3-fold variation in amodiaquine AUC and a 2-fold variation in N-desethylamodiaquine AUC, were observed. The CYP2D6 and CYP2C9 activities of the subjects were measured by debrisoquine and losartan phenotyping tests, respectively. There were significant mean increases in debrisoquine metabolic ratio (MR) between baseline and the second cocktail [MR(2 h)-MR(baseline) 1.426 (95% confidence interval 1.159, 1.755), P=0.002; ANOVA, Fisher LSD test] and in mean losartan MR between baseline and the second cocktail [MR(2 h)-MR(baseline) 1.724 (95% confidence interval 1.076, 2.762), P=0.026; ANOVA, Fisher LSD test]. The effects on CYP2D6 and CYP2C9 activities subsided within a week after intake of amodiaquine as tested by the phenotyping cocktail. The changes in omeprazole MRs and caffeine MRs were not statistically significant between any of the study phases. CONCLUSION: A single dose of amodiaquine decreased CYP2D6 and CYP2C9 activities significantly compared to baseline values. Amodiaquine has the potential to cause drug-drug interactions and should be further investigated in malarial patients treated with drug combinations containing amodiaquine.

Administration, Oral↗
PubMed1995

Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine.

1. The hepatic metabolism of the antimalarial drug amodiaquine was investigated in order to gain further insight into the postulated metabolic causation of the hepatotoxicity, which restricts the use of the drug. After intraportal (i.p.) administration (54 mumol/kg) to the anaesthetized rat, the drug was excreted in bile (23 +/- 3% dose over 5 h; mean +/- SD, n = 6) primarily as thioether conjugates. 2. After i.p. administration, 20% of the dose was excreted into urine over 24 h as parent compound and products of N-dealkylation and oxidative deamination. Desethylamodiaquine accumulated in liver, but was not a substrate for bioactivation as measured by biliary elimination of a glutathione adduct. 3. Prior administration of ketoconazole, an inhibitor of P450, reduced biliary excretion by 50% and effected a corresponding decrease in the amount of drug irreversibly bound to liver proteins. This indicated a role for P450 in the bioactivation of amodiaquine to a reactive metabolite that conjugates with glutathione and protein. 4. De-ethylation and irreversible binding were observed in vitro using male rat liver microsomes, and were again inhibited by ketoconazole. However, no such binding was observed with human (six individuals) hepatic microsomes despite extensive turnover of amodiaquine to desethylamodiaquine. 5. Amodiaquine quinoneimine underwent rapid reduction in the presence of either human or rat liver microsomes. Therefore in vitro studies may underestimate the bioactivation of amodiaquine in vivo. These data indicate that the extent of protein adduct formation in the liver will depend on the relative rates of oxidation of amodiaquine and reduction of its quinoneimine. This in turn may be a predisposing factor in the idiosyncratic hepatotoxicity associated with amodiaquine. 6. Substitution of a fluorine for the phenolic hydroxyl group in amodiaquine blocked bioactivation of the drug in vivo. Insertion of an N-hydroxyethyl function enabled partial clearance of amodiaquine and its deshydroxyfluoro analogue via O-glucuronidation and altered the balance between phase I oxidation and direct phase II conjugation of amodiaquine.

Amodiaquine↗