RT Journal Article
SR Electronic
T1 Evaluation of P450 Inhibition and Induction by Artemisinin Antimalarials in Human Liver Microsomes and Primary Human Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1757
OP 1764
DO 10.1124/dmd.112.045765
VO 40
IS 9
A1 Xing, Jie
A1 Kirby, Brian J.
A1 Whittington, Dale
A1 Wan, Yakun
A1 Goodlett, David R.
YR 2012
UL http://dmd.aspetjournals.org/content/40/9/1757.abstract
AB Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism. To better understand the autoinduction and metabolic drug-drug interactions (DDIs), we evaluated the P450s (particularly CYP2B6 and CYP3A4) inhibited or induced by two artemisinin drugs, Qing-hao-su (QHS) and dihydroartemisinin (DHA) using human liver microsome, recombinant P450 enzymes, and primary human hepatocytes. The results suggested that QHS was a weak reversible inhibitor of CYP2B6 (Ki 4.6 μM), but not CYP3A4 (IC50 ∼ 50 μM) and did not show measurable time-dependent inhibition of either CYP2B6 or CYP3A4. DHA inhibited neither CYP2B6 nor CYP3A4 (IC50 > 125 μM). In addition, it was found that QHS induced the activity of CYP3A4 (Emax 3.5-fold and EC50 5.9 μM) and CYP2B6 (Emax 1.9-fold and EC50 0.6 μM). Of the other P450s, UDP glucuronosyltransferases, and transporters studied, QHS and DHA had no significant effect except for minor induction of mRNA expression of CYP1A2 (Emax 7.9-fold and EC50 5.2 μM) and CYP2A6 (Emax 11.7-fold and EC50 4.0 μM) by QHS. Quantitative prediction of P450-mediated DDIs indicate autoinduction of QHS clearance with the AUCi/AUC ratio decreasing to 59%, as a result of a 1.9-fold increase in CYP3A4 and a 1.6-fold increase in CYP2B6 activity. These data suggest that QHS drugs are potential inducers of P450 enzymes, and the possible drug interactions (or lack thereof) with artemisinin drugs may be clinically relevant.