Sensitive analysis of blood for amodiaquine and three metabolites by high-performance liquid chromatography with electrochemical detection

Mount, Dwight L.; Patchen, Leslie C.; Nguyen-Dinh, Phuc; Barber, Ann; Schwartz, Ira K.; Churchill, Frederick C.

doi:10.1016/s0378-4347(00)83483-0

Cited by 44 publications

(40 citation statements)

References 9 publications

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“…Amodiaquine N-deethylation is a frequently used in vitro marker reaction for CYP2C8 because of its high affinity (K m typically around 2 mM) and high turnover rate (Table 4). N-desethylamodiaquine, Role of CYP2C8 in Drug Metabolism and Interactions which is the main metabolite of amodiaquine, is assumed to be the main entity responsible for the pharmacological response to amodiaquine (Churchill et al, 1985;Mount et al, 1986).…”

Section: A Drugsmentioning

confidence: 99%

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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Section: A Drugsmentioning

confidence: 99%

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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“…The main metabolite of AQ is N-desethylamodiaquine (DEAQ) with other minor metabolites being 2-hydroxyl-DEAQ and N-bisdesethylAQ (bis-DEAQ) (Churchill et al, 1985Mount et al, 1986). Whereas the formation of DEAQ is rapid, its elimination is very slow with a terminal half-life of over 100 h (Winstanley et al, 1987;Laurent et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Amodiaquine Clearance and Its Metabolism toN-Desethylamodiaquine Is Mediated by CYP2C8: A New High Affinity and Turnover Enzyme-Specific Probe Substrate

Li¹,

Björkman²,

Andersson³

et al. 2002

J Pharmacol Exp Ther

252

183

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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) we 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 M and 2.6 pmol/ min/pmol of CYP2C8 for recombinant CYP2C8, and 2.4 M 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 ϭ 0.98 and 0.95) with 6␣-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 M 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 (AQ) is a 4-aminoquinoline derivative that has been widely used for treatment of malaria over the past 50 years. It is intrinsically more active than the other 4-aminoquinoline, chloroquine, against Plasmodium falciparum parasites, which are moderately chloroquine resistant. The drug is therefore increasingly being considered as a replacement for chloroquine as a first line drug in Africa because of widespread chloroquine resistance. Because of major side effects, mainly agranulocytosis, observed during prophylactic use of the drug, AQ is now only recommended for treatment of malaria, for which no serious cases of toxicity have been reported (Laurent et al., 1993).Upon oral administration, AQ is rapidly absorbed and extensively metabolized such that very little of the parent drug is detected in the plasma. The main metabolite of AQ is N-desethylamodiaquine (DEAQ) with other minor metabolites being 2-hydroxyl-DEAQ and N-bisdesethylAQ (bis-DEAQ) (Churchill et al., 1985Mount et al., 1986). Whereas the formation of DEAQ is rapid, its elimination is very slow with a terminal half-life of over 100 h (Winstanley et al., 1987;Laurent et al., 1993). AQ and DEAQ both have antimalarial activity, but AQ is 3 times more active (Churchill et al., 1985). However, since AQ is rapidly cleared and the formed DEAQ attains high plasma concentrations for a long time, AQ is considered a prodrug,...

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“…El metabolismo de la amodiaquina en humanos depende de la enzima CYP2C8 y da lugar a la formación de otros metabolitos menores y poco activos, tales como la bidesetilamodiaquina y la hidroxidesetilamodiaquina (32). Además, la enzima CYP2C8 muestra gran variación entre los individuos en el metabolismo de sustratos (36) y presenta diferentes variantes genéticas (37,38).…”

Section: Discussionunclassified

Susceptibilidad in vitro de aislamientos colombianos de Plasmodium falciparum a diferentes antipalúdicos

Blair¹,

Arango²,

Fonseca³

2008

biomedica

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Introducción. Los estudios de susceptibilidad in vitro de Plasmodium falciparum a los medicamentos antipalúdicos son herramientas importantes para vigilar la utilidad de esos medicamentos; tales estudios son escasos en Colombia. Objetivo. Evaluar la susceptibilidad in vitro de aislamientos colombianos de P. falciparum a cloroquina, amodiaquina, mefloquina, quinina y artesunato. Materiales y métodos. Se obtuvieron aislamientos clínicos de P. falciparum en varias regiones colombianas. De cada antipalúdico se probaron siete diluciones dobles seriadas, por duplicado, con la técnica HRP-2 y las cepas FCB2 (resistente a cloroquina) y NF54 (sensible a cloroquina) como controles. Se utilizaron las concentraciones inhibitorias 50 (CI 50 ) mayor de 100, 80, 64, 500 y 10,5 nM como puntos de corte para clasificar la resistencia a cloroquina, amodiaquina, mefloquina, quinina y artesunato, respectivamente. Resultados. Se evaluaron 25 aislamientos: 72% de Urabá, 8% de Bajo Cauca y 20% de la Costa Pacífica. Las CI 50 promedio de cloroquina, amodiaquina, mefloquina, quinina y artesunato fueron 422,9; 131,4; 56,3; 269,7 y 1,88 nM, respectivamente, y la proporción de aislamientos resistentes fue, en el mismo orden, 76%, 16%, 32%, 24% y 4%. Conclusiones. La baja sensibilidad a la cloroquina concuerda con otros estudios in vitro y con la baja eficacia terapéutica in vivo. Aunque 96% de los aislamientos fueron sensibles a artesunato, éste y otros estudios han observado aislamientos con disminución de la sensibilidad a las artemisininas (CI 50 >10,5 nM), lo que sugiere que el uso indiscriminado de estos medicamentos pone en riesgo su efectividad y podría dejarnos sin opciones para el tratamiento del paludismo por P. falciparum.Palabras clave: malaria/terapia, Plasmodium falciparum, antipalúdicos, resistencia a las drogas, Colombia

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Sensitive analysis of blood for amodiaquine and three metabolites by high-performance liquid chromatography with electrochemical detection

Cited by 44 publications

References 9 publications

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Amodiaquine Clearance and Its Metabolism toN-Desethylamodiaquine Is Mediated by CYP2C8: A New High Affinity and Turnover Enzyme-Specific Probe Substrate

Susceptibilidad in vitro de aislamientos colombianos de Plasmodium falciparum a diferentes antipalúdicos

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