Prediction of herb-drug metabolic interactions: a simulation study.
In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb-drug interactions. An attempt was made to simulate the effects of herbal preparation with single or multiple CYP-inhibiting constituents on the area of the plasma concentration-time curve (AUC) of coadministered drug that was either a low clearance drug by intravenous (i.v.) injection or a high clearance drug by oral route. Our simulation studies indicated that the expected increase (Rc) in the AUC of the coadministered drug by inhibiting herbal constituent(s) was dependent on the route of administration. For low clearance drug by i.v. injection, Rc was generally determined by inhibition constant (Ki), unbound inhibitor concentration ([I]), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm), while Rc for a high clearance drug by oral route, Rc was determined by Ki, [I], n and fm. By varying these parameters, Rc changed accordingly. It appeared likely to predict a herb-drug metabolic interaction, if the inhibiting herbal constituents could be quantitatively determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and thus in vivo animal and human studies are always necessary.
Zhou
Shufeng
S
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore. phazsf@nus.edu.sg
Huang
Min
M
Xu
Anlong
A
Yang
Hongyuan
H
Duan
Wei
W
Paxton
James W
JW
D000284:Administration, Oral; D019540:Area Under Curve; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D041743:Herb-Drug Interactions; D006801:Humans; D007275:Injections, Intravenous; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010946:Plants, Medicinal; D011237:Predictive Value of Tests
D010936:Plant Extracts; D003577:Cytochrome P-450 Enzyme System