Amodiaquine

/HUMAN EXPOSURE STUDIES/ The cytotoxicity of amodiaquine (AQ), amodiaquine quinoneimine (AQQI) and desethylamodiaquine (AQm) has been assessed in comparison with that of chloroquine (CQ) using mononuclear leucocytes (MNL) and granulocyte/monocyte colony forming units (GM-CFU) from hematologically normal subjects. Toxicity toward MNL was assessed after 2 hr and 16 hr incubations with each compound. After 2 hr, AQ, AQm and AQQI but not CQ (within the concentration range 1 to 100 umol/L) produced a significant decrease in cell viability. After 16 hr, all four compounds significantly increased cell death. After both 2 hr and 16 hr incubations CQ was the least toxic and AQQI the most toxic of the four compounds towards MNL. Toxicity to GM-CFU was assessed by the inhibition of colony formation in vitro. After 10 to 14 days incubation, there was significant concentration-dependent inhibition of colony formation by AQ, AQm, AQQI and CQ (within the range 0.1 to 10.0 umol/L). There were no significant differences between the ability of the four compounds to inhibit colony formation but toxicity towards GM-CFU was observed at drug concentrations at least 10-fold lower than those that were toxic to MNL. These data show that the four compounds are equally toxic in vitro toward GM-CFU, although some differences in their toxicity toward MNL were seen.

/SIGNS AND SYMPTOMS/ The adverse effects of amodiaquine are similar to those of chloroquine. Amodiaquine is associated with less pruritus and is more palatable than chloroquine, but is associated with a much higher risk of agranulocytosis and, to a lesser degree, of hepatitis when used for prophylaxis. The risk of a serious adverse reaction with prophylactic use (which is no longer recommended) appears to be between 1 in 1,000 and 1 in 5,000. It is not clear whether the risks are lower when amodiaquine is used to treat malaria. Following overdose cardiotoxicity appears to be less frequent than with chloroquine. Large doses of amodiaquine have been reported to cause syncope, spasticity, convulsions and involuntary movements.

/SIGNS AND SYMPTOMS/ Oral administration of a single dose of amodiaquine may be followed by abdominal discomfort, nausea, vomiting, headache, dizziness, blurring of vision, mental and physical weakness, and fatigue. These symptoms are usually mild and transient.

/SIGNS AND SYMPTOMS/ Because the 4-aminoquinoline derivatives are rapidly and completely absorbed from the GI tract, symptoms of acute toxicity may occur within 30 minutes following ingestion of the drugs and death has occurred within 2 hours. ... Symptoms of overdosage of 4-aminoquinoline derivatives include headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, and seizures followed by sudden and early respiratory and cardiac arrest. Hypotension, if not treated, may progress rapidly to shock. Electrocardiograms (ECG) may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, and progressive bradycardia leading to ventricular fibrillation and/or arrest.

For more Human Toxicity Excerpts (Complete) data for AMODIAQUINE (11 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

amodiaquine

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

/GENOTOXICITY/ Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquine, were assessed in the Ames mutagenicity assay (in strains TA97a, TA100, TA102 and TA104) and in vivo sister chromatid exchange (SCE) and chromosome aberration (CA) assays in bone marrow cells of mice. ... The results of the bacterial mutagenicity assays showed a very weak mutagenic effect of all three drugs in Salmonella strains TA97a and TA100 both with and without S9 mix and in TA104 only with S9 mix. The results of the in vivo SCE and CA assays indicate that these three drugs are genotoxic in bone marrow cells of mice.

/IMMUNOTOXICITY/ Amodiaquine is an antimalarial drug that has been associated with adverse reactions which may be immune mediated. Specific IgG anti-amodiaquine antibodies were detected after administration of the drug to rats (269 mumols/kg for 4 days), using an enzyme-linked immunosorbent assay employing amodiaquine conjugated to metallothionein as an antigen. A positive immune response was observed regardless of the route of administration, but the magnitude of the response in terms of antibody titre was in the order intraperitoneal administration greater than intramuscular administration greater than oral administration. Hapten inhibition experiments with structurally related drugs defined the specificity of the antibody which appears to recognize a conjugate of amodiaquine quinone imine and cysteine residues present in protein. Amodiaquine was converted to a protein-reactive species by activated human polymorphonuclear leukocytes in vitro, and this may provide a mechanism for immunogen formation in vivo. A humoral immune response was observed with doses of amodiaquine that did not produce either direct hepatotoxicity or leukopenia.

A mild degree of itching with or without a rash can follow the use of amodiaquine in all races. However, in Africans, a more severe itching has been reported. The itching has a curious biting or pricking character, and affects all parts of the body including the scalp, the palms of the hands, and the soles of the feet. It is often unassociated with urticaria or any other kind of rash. It begins within a few hours of taking the drug and often continues for between 48 and 72 hours. It is usually severe enough to make sleep impossible for as long as it lasts. The itching occurs in all age groups but it is unusual for it to be experienced on the first exposure to the drug.

While data specific to amodiaquine were not located(SRC, 2006), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils(1).

Treatment of overdosage of 4-aminoquinoline derivatives must be prompt, since acute toxicity with the drugs can progress rapidly, possibly leading to cardiovascular collapse and respiratory and cardiac arrest. ECG should be monitored. Because of the importance of supporting respiration, early endotracheal intubation and mechanical ventilation may be necessary. Early gastric lavage may provide some benefit in reducing absorption of the drugs, but generally should be preceded by measures to correct severe cardiovascular disturbances, if present, and by respiratory support that includes endotracheal intubation with cuff inflated and in place to prevent aspiration (since seizures may occur). IV diazepam may control seizures and other manifestations of cerebral stimulation and, possibly, may prevent or minimize other toxic effects (eg, cardiotoxicity, including ECG abnormalities and conduction disturbances) of 4-aminoquinoline derivatives. However, additional study and experience are necessary to further establish the effects of diazepam on noncerebral manifestations of toxicity with these drugs. If seizures are caused by anoxia, anoxia should be corrected with oxygen and respiratory support. Equipment and facilities for cardioversion and for insertion of a transvenous pacemaker should be readily available. Administration of IV fluids and placement of the patient in Trendelenburg's position may be useful in managing hypotension, but more aggressive therapy, including administration of vasopressors (eg, epinephrine, isoproterenol, dopamine), may be necessary, particularly if shock appears to be impending.

Administration of activated charcoal by stomach tube, after lavage and within 30 minutes after ingestion of 4-aminoquinoline derivatives, may inhibit further intestinal absorption of the drugs; the dose of activated charcoal should be at least 5 times the estimated dose of /4-aminoquinoline derivative/ ingested. Peritoneal dialysis, hemodialysis, and hemoperfusion do not appear to be useful in the management of overdosage with 4-aminoquinoline derivatives. Patients who survive the acute phase of overdosage and are asymptomatic should be closely observed for at least 48-96 hours after ingestion...

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

5.2 ± 1.7 (range 0.4 to 5.5) minutes

Amodiaquine 600 mg was given by mouth, the apparent terminal half-life of amodiaquine was 5.2 + 1.7 (range 0.4 to 5.5) minutes and the geometric mean of the estimated elimination phase half-lives was 2.1 (range 0.5 to 5.7) hours.

Hepatic biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation.

... Amodiaquine hydrochloride ... undergoes rapid and extensive metabolism to desethylamodiaquine which concentrates in blood cells. It is likely that desethylamodiaquine, not amodiaquine, is responsible for most of the observed antimalarial activity, and that the toxic effects of amodiaquine after oral administration may in part be due to desethylamodiaquine.

When amodiaquine is given orally relatively little of the parent compound is present in the blood. Hepatic biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation.

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 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. After intraportal 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. 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. 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. 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. 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 (AQ) metabolism to N-desethylamodiaquine (DEAQ) is the principal route of disposition in humans. Using human liver microsomes and two sets of recombinant human cytochrome P450 isoforms (from lymphoblastoids and yeast) /the authors/ performed studies to identify the CYP isoform(s) involved in the metabolism of AQ. CYP2C8 was the main hepatic isoform that cleared AQ and catalyzed the formation of DEAQ. The extrahepatic P450s, 1A1 and 1B1, also cleared AQ and catalyzed the formation of an unknown metabolite M2. The K(m) and V(max) values for AQ N-desethylation were 1.2 microM and 2.6 pmol/min/pmol of CYP2C8 for recombinant CYP2C8, and 2.4 microM and 1462 pmol/min/mg of protein for human liver microsomes (HLMs), respectively. Relative contribution of CYP2C8 in the formation of DEAQ was estimated at 100% using the relative activity factor method. Correlation analyses between AQ metabolism and the activities of eight hepatic P450s were made on 10 different HLM samples. Both the formation of DEAQ and the clearance of AQ showed excellent correlations (r(2) = 0.98 and 0.95) with 6alpha-hydroxylation of paclitaxel, a marker substrate for CYP2C8. The inhibition of DEAQ formation by quercetin was competitive with K(i) values of 1.96 for CYP2C8 and 1.56 microM for HLMs. Docking of AQ into the active site homology models of the CYP2C isoforms showed favorable interactions with CYP2C8, which supported the likelihood of an N-desethylation reaction. These data show that CYP2C8 is the main hepatic isoform responsible for the metabolism of AQ. The specificity, high affinity, and high turnover make AQ desethylation an excellent marker reaction for CYP2C8 activity.

Rapidly absorbed following oral administration.

Amodiaquine hydrochloride is readily absorbed from the gastrointestinal tract. It is rapidly converted in the liver to the active metabolite desethylamodiaquine, which contributes nearly all of the antimalarial effect (10). There are insufficient data on the terminal plasma elimination half-life of desethylamodiaquine. Both amodiaquine and desethylamodiaquine have been detected in the urine several months after administration.

After oral administration amodiaquine hydrochloride is rapidly absorbed...

After oral administration of amodiaquine (600 mg) to 7 healthy adult males ... The peak concentration of amodiaquine was 32 +/- 3 ng/mL at 0.5 +/- 0.03 hr. The peak concentrations of amodiaquine in whole blood and packed cells were 60 +/- 10 and 42 +/- 6 ng/mL respectively, reached at 0.5+/- 0.1hr in both. Thereafter the concentration of amodiaquine declined rapidly, and was detectable for no more than 8 hr.

Mean peak plasma concentration of the metabolite (desethylamodiaquine) was 181 +/- 26 ng/mL. Times to peak for whole blood and packed cells were 2.2 +/- 0.5 and 3.6 +/- 1.1 hr respectively

For more Absorption, Distribution and Excretion (Complete) data for AMODIAQUINE (10 total), please visit the HSDB record page.