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.
Amodiaquine has been linked to serum aminotransferase elevations in a small proportion of patients (1%). More importantly, there have been multiple reports of idiosyncratic acute liver injury due to amodiaquine. The onset of injury is usually within 1 to 4 months and is often associated with agranulocytosis. The pattern of serum enzyme elevations is most frequently hepatocellular, and symptoms resembling acute viral hepatitis are typical. Features of hypersensitivity are uncommon, as are autoantibodies. The hepatitis can be severe, and several fatal instances or cases requiring emergency liver transplantation have been reported. The frequency of serious hepatic injury is estimated to be ~1:15,000. Because of the risks of agranulocytosis and liver injury, amodiaquine is no longer recommended for use as prophylaxis against malaria and is used largely for therapy in endemic areas outside of the United States. General recommendations on the therapy of malaria including specific details on diagnosis, management, drug dosage and safety are available at the CDC website: http://www.cdc.gov/malaria/.
Since magnesium trisilicate and kaolin are known to decrease the gastrointestinal absorption of chloroquine when administered simultaneously, it is likely that this also follows for amodiaquine.
Concomitant administration of chloroquine at recommended doses for malaria suppression of chemoprophylaxis during pre-exposure prophylaxis of rabies with intra-dermally administered rabies vaccine may interfere with the antibody response to the vaccine. However, the clinical significance of this interaction remains to be clearly established but should be considered and may have relevance in the case of amodiaquine.
Concomitant use with other antimalarials should be avoided and regular laboratory investigations should be performed to assure that blood values and liver function tests remain within normal limits.
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.
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 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
