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

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

Life Sciences

Volume 36, Issue 1, 7 January 1985, Pages 53-62

https://doi.org/10.1016/0024-3205(85)90285-1 Get rights and content

Abstract

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 desethyl-amodiaquine, 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.

References (11)

B. Brodie et al.
J. Biol. Chem.
(1947)
L. Patchen et al.
J. Chromatogr.
(1983)
W. Wernsdorfer
WHO Chronicle
(1983)
K. Rieckmann
J. Am. Med. Assoc.
(1971)
C. Campbell et al.
Amer. J. Trop. Med. Hyg.
(1983)

There are more references available in the full text version of this article.

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Apoptosis contributes to the cytotoxicity induced by amodiaquine and its major metabolite N-desethylamodiaquine in hepatic cells
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After oral administration, ADQ is rapidly absorbed and extensively metabolized to its major metabolite N-desethylamodiaquine (NADQ) (Laurent et al., 1993). Other minor metabolites include N-bisdesethylamodiaquine and 2-hydroxydesethylamodiaquine (Churchill et al., 1985; Mount et al., 1986). Both ADQ and NADQ have antimalarial activity, with the activity of ADQ being about three-fold more potent than that of NADQ.
Amodiaquine (ADQ), an antimalarial drug used in endemic areas, has been reported to be associated with liver toxicity; however, the mechanism underlying its hepatoxicity remains unclear. In this study, we examined the cytotoxicity of ADQ and its major metabolite N-desethylamodiaquine (NADQ) and the effect of cytochrome P450 (CYP)-mediated metabolism on ADQ-induced cytotoxicity. After a 48-h treatment, ADQ and NADQ caused cytotoxicity and induced apoptosis in HepG2 cells; NADQ was slightly more toxic than ADQ. ADQ treatment decreased the levels of anti-apoptotic Bcl-2 family proteins, which was accompanied by an increase in the levels of pro-apoptotic Bcl-2 family proteins, indicating that ADQ-induced apoptosis was mediated by the Bcl-2 family. NADQ treatment markedly increased the phosphorylation of JNK, extracellular signal-regulated kinase (ERK1/2), and p38, indicating that NADQ-induced apoptosis was mediated by MAPK signaling pathways. Metabolic studies using microsomes obtained from HepG2 cell lines overexpressing human CYPs demonstrated that CYP1A1, 2C8, and 3A4 were the major enzymes that metabolized ADQ to NADQ and that CYP1A2, 1B1, 2C19, and 3A5 also metabolized ADQ, but to a lesser extent. The cytotoxicity of ADQ was increased in CYP2C8 and 3A4 overexpressing HepG2 cells compared to HepG2/CYP vector cells, confirming that NADQ was more toxic than ADQ. Moreover, treatment of CYP2C8 and 3A4 overexpressing HepG2 cells with ADQ increased the phosphorylation of JNK, ERK1/2, and p38, but not the expression of Bcl-2 family proteins. Our findings indicate that ADQ and its major metabolite NADQ induce apoptosis, which is mediated by members of the Bcl-2 family and the activation of MAPK signaling pathways, respectively.
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Citation Excerpt :
AQ is a 4-aminoquinoline metabolized by hepatic cytochrome P450 2C8 (CYP2C8) to desethylamodiaquine (DEAQ) its active metabolite, which is subsequently eliminated via extra-hepatic biotransformation by CYP1A1 and CYP1B1.9 DEAQ is primarily responsible for the pharmacological activity of AQ (parent drug), due to its long elimination half-life.10 The pharmacokinetics (PK) of AQ when used in combination with artesunate (AS), has been described in healthy volunteers,11,12 children,13–15 and adults,16 with UM.
There is limited information on the safety or efficacy of currently recommended antimalarial drugs in patients with sickle cell disease (SCD), a population predisposed to worse outcomes if affected by acute malaria. Artesunate-amodiaquine (ASAQ) is the first-line treatment for uncomplicated malaria (UM) in many malaria-endemic countries and is also used for treatment of UM in SCD patients. There is, however, no information to date, on the pharmacokinetics (PK) of amodiaquine or artesunate or the metabolites of these drugs in SCD patients.
This study sought to determine the PK of desethylamodiaquine (DEAQ), the main active metabolite of amodiaquine, among paediatric SCD patients with UM treated with artesunate-amodiaquine (ASAQ).
Plasma concentration-time data (median DEAQ levels) of SCD children (n = 16) was initially compared with those of concurrently recruited non-SCD paediatric patients with acute UM (n = 13). A population PK modelling approach was then used to analyze plasma DEAQ concentrations obtained between 64 and 169 hours after oral administration of ASAQ in paediatric SCD patients with acute UM (n = 16). To improve PK modeling, DEAQ concentration-time data (n = 21) from SCD was merged with DEAQ concentration-time data (n = 169) of a historical paediatric population treated with ASAQ (n = 103) from the same study setting.
The median DEAQ concentrations on days 3 and 7 were comparatively lower in the SCD patients compared to the non-SCD patients. A two-compartment model best described the plasma DEAQ concentration-time data of the merged data (current SCD data and historical data). The estimated population clearance of DEAQ was higher in the SCD patients (67 L/h, 21% relative standard error (RSE) compared with the non-SCD population (15.5 L/h, 32% RSE). The central volume of distribution was larger in the SCD patients compared with the non-SCD patients (4400 L, 43% RSE vs. 368 L, 34% RSE).
The data shows a tendency towards lower DEAQ concentration in SCD patients and the exploratory population PK estimates suggest altered DEAQ disposition in SCD patients with acute UM. These findings, which if confirmed, may reflect pathophysiological changes associated with SCD on DEAQ disposition, have implications for therapeutic response to amodiaquine in SCD patients. The limited number of recruited SCD patients and sparse sampling approach however, limits extrapolation of the data, and calls for further studies in a larger population.
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Citation Excerpt :
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The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate release (IR) multisource solid dosage forms containing amodiaquine hydrochloride (ADQ) as the single active pharmaceutical ingredient (API). Both biopharmaceutical and clinical data of ADQ were assessed. Solubility studies revealed that ADQ meets the “highly soluble” criteria according to World Health Organization (WHO) and European Medicines Agency (EMA) but fails to comply with the United States Food and Drug Administration (US FDA) specifications. Although metabolism hints at high permeability, available permeability data are too scanty to classify ADQ inequivocably as a Class I drug substance. According to WHO and EMA guidances, ADQ would be conservatively categorized as a Class III drug, whereas according to the US FDA specifications, it would fall into Class IV. ADQ has a wide therapeutic index. Furthermore, no cases of bioinequivalent products have been reported in the open literature. As risks associated with biowaiving appear minimal and requirements for “highly soluble” API are met in the WHO and EMA jurisdictions, the biowaiver procedure can be recommended for bioequivalence (BE) testing of multisource IR products containing ADQ as the only API, provided the test product contains excipients used in ADQ products approved in International Conference of Harmonisation and associated countries, and in similar amounts. Furthermore, both comparator and test should conform to “very rapidly dissolving” product criteria (≥85% dissolution of the API in 15 min at pH 1.2, 4.5, and 6.8) and the labeling should specify that the product not be coadministered with high‐fat meals. If the comparator and/or test product fails to meet these criteria, BE needs to be established by pharmacokinetic studies in humans. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4390–4401, 2012
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Amodiaquine as a prodrug: Importance of metabolite(s) in the antimalarial effect of amodiaquine in humans

Abstract

J. Biol. Chem.

J. Chromatogr.

WHO Chronicle

J. Am. Med. Assoc.

Amer. J. Trop. Med. Hyg.