Dataset Information

Characterization of human cytochrome P450 mediated bioactivation of amodiaquine and its major metabolite N-desethylamodiaquine.

ABSTRACT:

Aims

Oxidative bioactivation of amodiaquine (AQ) by cytochrome P450s to a reactive quinoneimine is considered as an important mechanism underlying its idiosyncratic hepatotoxicity. However, because internal exposure to its major metabolite N-desethylamodiaquine (DEAQ) is up to 240-fold higher than AQ, bioactivation of DEAQ might significantly contribute to covalent binding. The aim of the present study was to compare the kinetics of bioactivation of AQ and DEAQ by human liver microsomes (HLM) and to characterize the CYPs involved in bioactivation of AQ and DEAQ.

Methods

Glutathione was used to trap reactive metabolites formed in incubations of AQ and DEAQ with HLM and recombinant human cytochrome P450s (hCYPs). Kinetics of bioactivation of AQ and DEAQ in HLM and involvement of hCYPs were characterized by measuring corresponding glutathione conjugates (AQ-SG and DEAQ-SG) using a high-performance liquid chromatography method.

Results

Bioactivation of AQ and DEAQ in HLM both exhibited Michaelis-Menten kinetics. For AQ bioactivation, enzyme kinetical parameters were K_m , 11.5 ± 2.0 ?mol l^-1 , V_max , 59.2 ± 3.2 pmol min^-1 mg^-1 and CL_int , 5.15 ?l min^-1 mg^-1 . For DEAQ, parameters for bioactivation were K_m , 6.1 ± 1.3 ?mol l^-1 , V_max , 5.5 ± 0.4 pmol min^-1 mg^-1 and CL_int 0.90 ?l min^-1 mg^-1 . Recombinant hCYPs and inhibition studies with HLM showed involvement of CYP3A4, CYP2C8, CYP2C9 and CYP2D6 in bioactivation.

Conclusions

The major metabolite DEAQ is likely to be quantitatively more important than AQ with respect to hepatic exposure to reactive metabolites in vivo. High expression of CYP3A4, CYP2C8, CYP2C9, and CYP2D6 may be risk factors for hepatotoxicity caused by AQ-therapy.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5306493 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

Characterization of human cytochrome P450 mediated bioactivation of amodiaquine and its major metabolite N-desethylamodiaquine.

Zhang Yongjie Y Vermeulen Nico P E NP Commandeur Jan N M JN

British journal of clinical pharmacology 20161116 3

<h4>Aims</h4>Oxidative bioactivation of amodiaquine (AQ) by cytochrome P450s to a reactive quinoneimine is considered as an important mechanism underlying its idiosyncratic hepatotoxicity. However, because internal exposure to its major metabolite N-desethylamodiaquine (DEAQ) is up to 240-fold higher than AQ, bioactivation of DEAQ might significantly contribute to covalent binding. The aim of the present study was to compare the kinetics of bioactivation of AQ and DEAQ by human liver microsomes ...[more]

PMID: 27718269

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Dataset Information

Characterization of human cytochrome P450 mediated bioactivation of amodiaquine and its major metabolite N-desethylamodiaquine.

Aims

Methods

Results

Conclusions

Publications

Characterization of human cytochrome P450 mediated bioactivation of amodiaquine and its major metabolite N-desethylamodiaquine.

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