TY - JOUR
T1 - Gene, ethnic and gender influences predisposition of adverse drug reactions to artesunate among Malaysians
AU - Yusof, Wardah
AU - Hua, Gan Siew
N1 - Funding Information:
This work was supported by World Health Organization (WHO) (grant number 305/PPSP/6150066/E108) and Universiti Sains Malaysia (USM) under the Research University Grant (grant number 1001/PPSP/815022) as well as USM Fellowship Programme.
PY - 2012/4
Y1 - 2012/4
N2 - Context: Artesunate (AS) and amodiaquine (AQ) are two prodrugs widely used as antimalarial agents and are metabolized by the CYP P450 2A6 (CYP 2A6) and CYP P450 2C8 (CYP 2C8) enzymes, respectively. Objective: In this study, we aim to investigate the association of both genes on AS and AQ's tolerabilities in the hope of identifying a pharmacogenetic approach that could be useful in prediction and prevention of adverse drug reactions (ADRs) among Malaysian population. Materials and methods: In this randomized crossover study, loose and AS/AQ formulations were administered to normal healthy volunteers (n=24) over two study phases. The drugs' tolerabilities (incidence of facial flushing, giddiness, headache, nausea, abdominal discomfort, progression of liver enzymes and neutrophil counts) were compared between the two treatment arms. Volunteers were also genotyped for the CYP2C8 and CYP2A6 variants. Results: The frequency of the CYP2A6*1B, CYP2A6*4, CYP2A6*8 and CYP2A6*9 alleles were 54.2%, 16.7%, 4.2% and 10.4%, respectively. No mutations for CYP2C8 gene were, however, detected. Most (96%) of the subjects were of the Malay ethnicity. Subjects having the CYP2A6*1B variants responsible for ultra rapid metabolism of AS suffered a significantly higher incidence of ADRs. Discussion: Our study is the first to report that CYP2A6 genotyping influences AS's ADR. Gender also plays a role where females reported more incidences of nausea (p<0.05). Conclusion: It is concluded that genetic polymorphisms of CYP2A6 as well as gender influence the side effect profiles of subjects receiving AS among this Malaysian population.
AB - Context: Artesunate (AS) and amodiaquine (AQ) are two prodrugs widely used as antimalarial agents and are metabolized by the CYP P450 2A6 (CYP 2A6) and CYP P450 2C8 (CYP 2C8) enzymes, respectively. Objective: In this study, we aim to investigate the association of both genes on AS and AQ's tolerabilities in the hope of identifying a pharmacogenetic approach that could be useful in prediction and prevention of adverse drug reactions (ADRs) among Malaysian population. Materials and methods: In this randomized crossover study, loose and AS/AQ formulations were administered to normal healthy volunteers (n=24) over two study phases. The drugs' tolerabilities (incidence of facial flushing, giddiness, headache, nausea, abdominal discomfort, progression of liver enzymes and neutrophil counts) were compared between the two treatment arms. Volunteers were also genotyped for the CYP2C8 and CYP2A6 variants. Results: The frequency of the CYP2A6*1B, CYP2A6*4, CYP2A6*8 and CYP2A6*9 alleles were 54.2%, 16.7%, 4.2% and 10.4%, respectively. No mutations for CYP2C8 gene were, however, detected. Most (96%) of the subjects were of the Malay ethnicity. Subjects having the CYP2A6*1B variants responsible for ultra rapid metabolism of AS suffered a significantly higher incidence of ADRs. Discussion: Our study is the first to report that CYP2A6 genotyping influences AS's ADR. Gender also plays a role where females reported more incidences of nausea (p<0.05). Conclusion: It is concluded that genetic polymorphisms of CYP2A6 as well as gender influence the side effect profiles of subjects receiving AS among this Malaysian population.
KW - Adverse drug reactions
KW - Amodiaquine
KW - Artesunate
KW - CYP2A6
KW - CYP2C8
UR - http://www.scopus.com/inward/record.url?scp=84856892102&partnerID=8YFLogxK
U2 - 10.3109/15376516.2011.623331
DO - 10.3109/15376516.2011.623331
M3 - Article
C2 - 22003869
AN - SCOPUS:84856892102
VL - 22
SP - 184
EP - 192
JO - Toxicology Mechanisms and Methods
JF - Toxicology Mechanisms and Methods
SN - 1537-6516
IS - 3
ER -