Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine-warfarin interaction.

Article Details

Citation

Fang ZZ, Zhang YY, Ge GB, Huo H, Liang SC, Yang L

Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine-warfarin interaction.

Br J Clin Pharmacol. 2010 Feb;69(2):193-9. doi: 10.1111/j.1365-2125.2009.03572.x.

PubMed ID
20233183 [ View in PubMed
]
Abstract

AIMS: To investigate the inhibition potential and kinetic information of noscapine to seven CYP isoforms and extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data. METHODS: The activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co- or preincubation with noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data. RESULTS: Among seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC(50) of 10.8 +/- 2.5 microm and 13.3 +/- 1.2 microm. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with K(i) value of 8.8 microm, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with K(i) value of 5.2 microm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (K(I) and k(inact)) were calculated to be 9.3 microm and 0.06 min(-1) for CYP3A4 and 8.9 microm and 0.014 min(-1) for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using C(max) or 0.5% and 0.4% using unbound C(max) with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using C(max) or 41.8% and 32.7% using unbound C(max) with TDI prediction equation. CONCLUSIONS: TDI of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine-warfarin interaction.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
NoscapineCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
NoscapineCytochrome P450 3A4ProteinHumans
Unknown
Inhibitor
Details